Surgical, ethical, and psychosocial considerations in human head transplantation.

Transplanting a head and brain is perhaps the final frontier of organ transplantation. The goal of body-to-head transplantation (BHT) is to sustain the life of individuals who suffer from terminal disease, but whose head and brain are healthy. Ideally BHT could provide a lifesaving treatment for several conditions where none currently exists. BHT is no ordinary experiment, to transfer a head to another body involves extraordinarily complex medical challenges as well as ethical and existential dilemmas that were previously confined to the imagination of writers of fiction. The possibility of replacing an incurably ill body with a healthy one tests not only our surgical limits, but also the social and psychological boundaries of physical life and alters what we recognize life to be. The purpose of this target article, the complementary manuscript focused on immunological issues in BHT, and the accompanying Commentaries by scholars and practitioners in medicine, immunology, and bioethics is to review major surgical and psychosocial-ethical and immunological considerations surrounding body-to-head transplantation. We hope that together these ideas will provide readers with a comprehensive overview of the possibilities and challenges associated with BHT and initiate professional discussion and debate through which this new frontier in medicine is considered and approached.

CNS stem cell transplantation: clinical and ethical perspectives.

Central nervous system disorders evoke special fear though their varied and unrelenting threats to memory, cognition, mobility, and every aspect of personal integrity and independence. Understandably, neurologic patients and their families become desperate for help, making fully free, informed consent problematic but not impossible. This desperation mandates our anticipatory attention to ethical questions related to any aggressive new therapy, including central nervous system grafting. In the United States, the right-to-life issue dominates ethical discussions on neural grafting. A variety of alternative tissue sources may permit technically suitable preparations, at least for some uses. If plentiful supplies of grafting cells can be made commercially, this should reduce problems related to allocating scarce resources, although financial and other scarcity barriers may still raise ethical problems. Many contemporary conceptions of selfhood depend on the identity and intactness of the mind and, by implication, the brain as substrate of mind. How much can we reweave the cerebral tapestry without creating a new self, a new identity? These philosophical questions will probably be approached pragmatically and incrementally, in the context of many other developments in human genetics and biomedicine. Our vision of the self will evolve amidst conflicting religious, ethical and pragmatic perspectives.

Health-related quality of life following bilateral intrastriatal transplantation in Parkinson's disease.

Intrastriatal transplantation of embryonic dopaminergic tissue is a new, experimental approach for the treatment of Parkinson's disease (PD). Clinical trials have shown longterm graft survival and therapeutically valuable improvements with decreased L-dopa dose and time spent in the "off"-phase, and reduced rigidity and hypokinesia. We have measured health-related quality of life (HRQoL) using the Nottingham Health Profile (NHP) in five patients subjected to bilateral transplantation in the caudate and putamen to explore the influence of intrastriatal grafts on HRQoL and the value of such measures in trials of restorative therapies. The results demonstrate improved HRQoL following transplantation, with individual patients showing striking improvements within different dimensions of the NHP as well as the NHP distress index (NHPD). The most pronounced improvements after grafting were observed for physical mobility along with emotional reactions and energy. These results indicate that intrastriatal transplantation of embryonic dopaminergic tissue can give rise to improvements within most areas of HRQoL, and that HRQoL measurements provide important information additional to that obtained by traditional, symptom-oriented assessment protocols. However, the optimal approach to HRQoL measurement in PD remains to be determined.

Do brain tissue transplants alter personal identity? Inadequacies of some "standard" arguments.

Currently, brain tissue transplantations are being developed as a clinical-therapeutic tool in neurodegenerative diseases such as Parkinson's or Alzheimer's disease. From an ethical point of view, distinguishing between the preservation and an alteration of personal identity seems to be central to determining the scope for further application of brain tissue transplantation therapy. The purpose of this article is to review "standard" arguments which are used on the one hand by proponents to prove preservation of personal identity and by opponents on the other hand to prove that brain tissue transplantation results in an altered personal identity. Proponents and opponents are shown to use the same arguments, albeit with different presuppositions. These presuppositions concern the meaning of the term "identity", either numerical or qualitative, the definition of brain identity, either structurally or functionally, and the relationship between mental states, psychological functions and neurophysiological properties as criteria for personal identity. Furthermore the respective neurophysiological, clinical and philosophical evidence for the different presuppositions are discussed. It is concluded that evaluation of personal identity in brain tissue transplantation should not only rely on the "standard" arguments but, additionally, neurophysiological, clinical and philosophical implications should be discussed.

Psychiatric status after human fetal mesencephalic tissue transplantation in Parkinson's disease.

This report describes the prospective and systematic psychiatric assessment of nine patients who received transplantation of human fetal mesencephalic tissue into the caudate nucleus for treatment of Parkinson's disease. Unlike adrenal medullary transplantation, which often causes psychosis or delirium, this procedure appeared to have few perioperative sequelae. On longer-term follow-up, there was some statistical evidence of deterioration in psychiatric status, as manifested primarily in depressive and nonspecific emotional and behavioral symptoms. This group effect was partly attributable to the occurrence of discrete episodes of illness (major depression and panic disorder with agoraphobia) in some patients, but it was unclear whether such episodes occurred more often than would ordinarily be expected in Parkinson's disease. Differences in the neurobiological effects of fetal mesencephalic and adrenal medullary grafts may account for differences in the psychiatric sequelae of patients receiving these procedures.

[Psychological aspects of neurotransplantation]. / Psychologiche Aspekte der Neurotransplantation.

The psychological situation of Parkinson patients and the functions and roles of others involved--doctors, donors, caregivers--are discussed with reference to ethically based decisions about neurotransplantation. Psychological stressors and changes of psychological functions in Parkinson's disease are described. Possible psychological risks due to short and long term changes, especially changes in emotionality, are discussed. Proposals are made for pre- and post-transplantation care involving broad neuropsychological follow up testing and psychological counseling, particularly to deal with unfulfilled expectations.

[Open questions in neurotransplantation. Attempted at an unbiased ethical analysis]. / Offene Fragen an die Neurotransplantation. Versuch einer unvoreingenommenen ethischen Analyse.

Neurotransplantation utilizing fetal (embryonic) tissue for treating Morbus Parkinson is a matter of ethical debate, among professionals as well as the public at large. Here, we take a systematic approach to the questions raised to facilitate an unbiased ethical analysis and to attempt adequate answers. Possible functions of ethics in medicine, principles of ethical reflexion in medicine and perspectives of ethical reflexion are differentiated resp. combined. Relevant areas of ethical conflict may thus be identified separating at the same time the context of explantation from that of implantation. Taking as our starting point a systematic discussion of the various open questions, we put forward 5 conclusions. These should help clarify under which conditions the therapy model of neurotransplantation will be admissible.

[Identity of the personality and personal identity: philosophical questions in relation to transplantation of brain tissue]. / Identität der Persönlichkeit und Identität der Person: Philosophische Fragen im Zusammenhang mit der Transplantation von Hirngewebe.

Advanced medical technology, though primarily a problem-solver, is also a problem-generator. Its progress confronts us with ever new problems of decision and with the problem of giving these decisions a sound ethical backing. The challenge for philosophy is, in this situation, to act as a kind of go-between: It should make a serious attempt to mediate between innovative medical technology and popular scepticism, and it should provide intellectual guidance for a structured and rational debate. Brain tissue transplantation is confronted mainly with two ethical problems: 1. Under which conditions are we justified to take transplantable brain tissue from aborted human embryos or fetuses? 2. Is it acceptable that the implantation of brain tissue taken from a human embryo or fetus might disturb, in one way or other, the identity of the recipient? To answer these questions, difficult anthropological issues must be discussed: 1. What are the criteria of death applying to embryos and fetuses? 2. What are the conditions for saying that the identity of a person is changed? The present contribution makes an effort to clarify the latter question. It examines the concept of identity in the context of brain tissue transplantation, makes a distinction between identity of personality and personal identity, and argues that even major changes of personality resulting from brain tissue transplantation would not by themselves amount to a change in personal identity. This result has to be reconsidered, however, in the light of the fact that brain tissue transplantation alters the make-up of the recipient's brain.(ABSTRACT TRUNCATED AT 250 WORDS)

[Transplantation of human fetal brain cells: theological-ethical aspects]. / Transplantation humaner fetaler Gehirnzellen: Theologisch-ethische Aspekte.

Using fetal brain cells for therapeutic purposes after a spontaneous abortion can be justified under similar pre-conditions like the removal of an organ post mortem. With an artificially induced abortion, however, there is the danger of justifying the act of abortion by combining it with that positive purpose. In this case any therapeutic utilization of fetal brain cells would only be justifiable, if every step of such a procedure could completely be isolated from the ethically unjustifiable abortion.

Behavioural consequences of neural transplantation.

Neural grafts can reverse many functional deficits associated with brain damage, whether of traumatic, toxic, neurodegenerative or genetic origin. In some model systems recovery can be partial or complete; whereas in others the grafts have limited effects or may actually cause further dysfunction. In order to devise rational and effective transplantation strategies it is necessary to understand the mechanisms by which grafts exert their functional effects. Several alternatives have been proposed, and these include non-specific consequences of surgery, acute diffuse neurotrophic and growth mechanisms, chronic diffuse release of deficient neurochemicals, bridging tissues for host regeneration, diffuse reinnervation of the host brain, and reciprocal graft-host reconnection. These alternative mechanisms are not necessarily exclusive in any particular situation, and all have been seen to apply in different model systems.

Behavioral effects of cholinergic grafts.

Experimental work in animals and, to a more limited extent, in humans, has demonstrated that the cholinergic system is involved in mechanisms which control learning and memory. Since there is cholinergic loss in a variety of dementing illnesses, any treatment designed to alleviate the mental symptoms of these diseases must address the issue of cholinergic dysfunction even if other treatments are also required to overcome other neurotransmitter imbalances. Work in rodents has demonstrated that cholinergic-rich fetal neural tissue transplants can, under certain circumstances, alleviate the behavioral effects of cholinergic lesions or of cholinergic decline associated with aging. More complex cognitive testing can be achieved using primates and, in this case, the common marmoset is a suitable species to use because its rapid and reliable reproductive rate aids the provision of appropriate transplant tissue. Marmosets with transection of the fornix are deprived of a cholinergic input into the dentate gyrus, posterior hippocampus and entorhinal cortex and are specifically impaired on learning tasks which require remembering a rule of responding (non-evaluative memory). Transplantation of cholinergic-rich fetal septal tissue into the hippocampus of such animals completely restores their ability to learn this type of task, whereas transplantation of cholinergic-poor fetal hippocampal tissue into the same area produces no such improvements. These results demonstrate that where a learning impairment is produced by a relatively simple procedure which has a major effect on one neurotransmitter, that function can be restored by transplantation of tissue containing that neurotransmitter even where the impairment consists of a very "high level" cognitive dysfunction.

Behavioral effects of fetal neural transplants: relevance to Huntington's disease.

Animal models of Huntington's disease (HD) and other neurological disorders have proven useful for examining the anatomical, neurochemical, and behavioral alterations in these diseases. Investigators have taken advantage of new excitotoxic models that appear to successfully simulate the neurobiological and behavioral characteristics of HD with remarkable homology. Selective excitotoxic compounds allow for a more precise and controlled lesion with which to examine the relationship between striatal damage and behavioral abnormalities. In addition, these models provide new approaches for developing and testing various treatments for HD. Fetal neural tissue transplanted into the excitotoxin-lesioned animal can integrate with the host brain and promote neurochemical and functional recovery. Neural grafting paradigms may be viewed as potential therapies for treating neurodegenerative diseases and as aids in deciphering the regenerative mechanisms of the central nervous system. Further research is necessary, however, to determine the negative and positive effects of neural transplantation. In addition, existing behavioral models need to be refined to allow for better evaluation of the subtle topographic changes in behavior resulting from fetal tissue transplantation.

Anatomical and behavioral sequelae of fetal brain transplants in rats with trimethyltin-induced neurodegeneration.

The effect of transplants of either fetal hippocampal or dorsal ventricular ridge (DVR) tissue into the brains of adult male rats exposed to TMT was determined for two behavioral tasks. Administration of TMT produced deficits in acquisition and performance of an operant differential reinforcement of low response rates (DRL) schedule and learning in the Morris water maze. The fetal transplants developed well within the TMT-damaged brains of the adult rats and numerous axons could be shown to cross the host-transplant interface. The transplants significantly reduced the DRL deficit produced by exposure to TMT. However, the TMT-induced deficit in water maze acquisition was made significantly worse by the hippocampal transplants. The improvement in DRL performance is attributed to the effect on the host brain of an unidentified trophic substance produced by the transplants. However, this positive effect may not protect the brain sufficiently to produce recovery in tasks demanding more complex neural computations than are required to withhold lever-press responses. The transplant-induced deficit observed in some aspects of water maze acquisition and performance may be attributable to either a tumor-like deleterious effect of the mass of the transplant or to abnormal neuronal activity transmitted from the transplant to the host brain. The results of the present study, and those from other similar studies, suggest that transplants of fetal tissue may be useful in producing changes in the brain of an animal exposed to an environmental neurotoxin, but that research should be focused upon development of transplant methodology that will minimize adverse effects of the grafts.

Behavioral effects of neural transplants into the intact striatum.

The behavioral effects of fetal brain tissue and adrenal medulla transplants into the intact striatum of rats were investigated. Following a bilateral injection of 1.5, 3 or 6 microliters of fetal striatal tissue, a volume-related weight loss was found in all transplanted groups, including the SHAM group, during the first 7 days after the surgery. Rearing behavior was changed in a transplant volume-related manner. Histological analysis suggested that the locomotor effects of transplants into the intact striatum are related to the volume of the transplants. Following bilateral transplantation of fetal cortex (CTX), substantia nigra (SN), striatum (STR), or adrenal medulla (AM) into the striatum, the different behavioral deficits were observed among these transplant groups. The SN group showed a decrease in spontaneous locomotion, significantly increased rearing activity in response to administration of amphetamine, reduction of food intake and water intake and a reduction in body weight. The CTX and AM groups showed a marked increase in spontaneous rearing activities. Hyporesponsiveness to the administration of apomorphine (1 mg/kg) and amphetamine (1 mg/kg) was evident in the CTX, STR, AM groups and SHAM groups. In contrast, the haloperidol-induced catalepsy scores of the CTX, STR, SN and AM were significantly higher than those of a normal control group. In addition, the CTX group showed a deficit in the delayed reward alternation test. These results indicated that the behavioral deficits produced by transplants into normal striatum may be related to both mechanical destruction due to transplant expansion and specific neurochemical interactions of each tissue type between the host and the transplant. Therefore, potential negative consequences of neural transplantation therapy should be considered as well as the beneficial effects.