With no statutory definition of death, the accepted medical definition relies on brain stem death criteria as a definitive measure of diagnosing death. However, the use of brain stem death criteria in this way is precarious and causes widespread confusion amongst both medical and lay communities. Through critical analysis, this paper considers the insufficiencies of brain stem death. It concludes that brain stem death cannot be successfully equated with either biological death or (...) the loss of integrated bodily function. The overemphasis of the brain-stem and its consequences leaves the criteria open to significant philosophical critique. Further, in some circumstances, the use of brain stem death criteria causes substantial emotional conflict for families and relatives. Accordingly, a more holistic and comprehensive definition of death is required. (shrink)

Adult stem cell populations must coordinate their own maintenance with the generation of differentiated cell types to sustain organ physiology, in a spatially controlled manner and over long periods. Quantitative analyses of clonal dynamics have revealed that, in epithelia, homeostasis is achieved at the population rather than at the single stem cell level, suggesting that feedback mechanisms coordinate stem cell maintenance and progeny generation. In the central nervous system, however, little is known of the possible community processes (...) underlying neural stem cell maintenance. Recent work, in part based on intravital imaging made possible in the adult zebrafish, conclusively highlights that homeostasis in neural stem cell pools may rely on population asymmetry and long‐term spatiotemporal coordination of neural stem cell states and fates. These results suggest that neural stem cell assemblies in the vertebrate brain behave as self‐organized systems, such that the stem cells themselves generate their own intrinsic niche. (shrink)

Recent developments in 3D cultures exploiting the self‐organization ability of pluripotent stem cells have enabled the generation of powerful in vitro systems termed brain organoids. These 3D tissues recapitulate many aspects of human brain development and disorders occurring in vivo. When combined with improved differentiation methods, these in vitro systems allow the generation of more complex “assembloids,” which are able to reveal cell diversities, microcircuits, and cell–cell interactions within their 3D organization. Here, the ways in which human (...) brain organoids have contributed to demystifying the complexities of brain development and modeling of developmental disorders is reviewed and discussed. Furthermore, challenging questions that are yet to be addressed by emerging brain organoid research are discussed. (shrink)

Stem cells isolated from adult mammalian tissues may provide new approaches for the autologous treatment of disease and tissue repair. Although the potential of adult stem cells has received much attention, it has also recently been brought into question. This article reviews the recent work describing the ability of non‐hematopoietic stem cells derived from adult bone marrow to form neural derivatives and their potential for brain repair. Earlier transplantation experiments imply that grafted adult stem cells (...) can differentiate into neural derivatives. Recent reports suggest, however, that such findings may be misleading and grafted cells acquiring different identities may merely be explained by their fusion with host cells and not the result of radical changes to their program of cellular differentiation. Nonetheless, in vitro studies have shown that neural development by bone‐marrow‐derived stem cells also appears possible. Understanding the molecular mechanisms that specify the neural lineage will lead to the development of tools for the targeted production of neural cell types in vitro that may ultimately provide a source of material to treat specific neurological deficits. BioEssays 24:708–713, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

This paper discusses the evidence for the role of CREB in neural stem/progenitor cell (NSPC) function and oncogenesis and how these functions may be important for the development and growth of brain tumours. The cyclic‐AMP response element binding (CREB) protein has many roles in neurons, ranging from neuronal survival to higher order brain functions such as memory and drug addiction behaviours. Recent studies have revealed that CREB also has a role in NSPC survival, differentiation and proliferation. Recent (...) work has shown that over‐expression of CREB in transgenic animals can impart oncogenic properties on cells in various tissues and that aberrant CREB expression is associated with tumours in patients. It is the central position of CREB, downstream of key developmental and growth signalling pathways, which give CREB the ability to influence a spectrum of cell activities, such as cell survival, growth and differentiation in both normal and cancer cells. (shrink)

For nearly two centuries, developmental biologists have known that body organs are derived from distinct germ layers. They have argued that adult stem cells formed in one of these, mesoderm for example, cannot give rise to cells that originate in another. We disagree. An exception to this “rule” has been described in crayfish recently. In this species, hemocytes appear to replenish neurogenic cells. This may happen in humans as well. In women who were given male bone marrow‐derived cells, Y (...) chromosome positive cheek cells and brain neurons were detected. While repopulation of these tissues by bone marrow derived cells may not occur normally, and while it does not appear to be terribly efficient, the phenomenon should be studied in more detail. Perhaps cells in the marrow could be used to regenerate tissues elsewhere. (shrink)

In 1968, the Harvard criteria equated irreversible coma and apnea with human death and later, the Uniform Determination of Death Act was enacted permitting organ procurement from heart-beating donors. Since then, clinical studies have defined a spectrum of states of impaired consciousness in human beings: coma, akinetic mutism, minimally conscious state, vegetative state and brain death. In this article, we argue against the validity of the Harvard criteria for equating brain death with human death. Brain death does (...) not disrupt somatic integrative unity and coordinated biological functioning of a living organism. Neurological criteria of human death fail to determine the precise moment of an organism’s death when death is established by circulatory criterion in other states of impaired consciousness for organ procurement with non-heart-beating donation protocols. The criterion of circulatory arrest 75 s to 5 min is too short for irreversible cessation of whole brain functions and respiration controlled by the brain stem. Brain -based criteria for determining death with a beating heart exclude relevant anthropologic, psychosocial, cultural, and religious aspects of death and dying in society. Clinical guidelines for determining brain death are not consistently validated by the presence of irreversible brain stem ischemic injury or necrosis on autopsy; therefore, they do not completely exclude reversible loss of integrated neurological functions in donors. The questionable reliability and varying compliance with these guidelines among institutions amplify the risk of determining reversible states of impaired consciousness as irreversible brain death. The scientific uncertainty of defining and determining states of impaired consciousness including brain death have been neither disclosed to the general public nor broadly debated by the medical community or by legal and religious scholars. Heart-beating or non-heart-beating organ procurement from patients with impaired consciousness is de facto a concealed practice of physician-assisted death, and therefore, violates both criminal law and the central tenet of medicine not to do harm to patients. Society must decide if physician-assisted death is permissible and desirable to resolve the conflict about procuring organs from patients with impaired consciousness within the context of the perceived need to enhance the supply of transplantable organs. (shrink)

Since the 1980s, Islamic scholars and medical experts have used the tools of Islamic law to formulate ethico-legal opinions on brain death. These assessments have varied in their determinations and remain controversial. Some juridical councils such as the Organization of Islamic Conferences' Islamic Fiqh Academy (OIC-IFA) equate brain death with cardiopulmonary death, while others such as the Islamic Organization of Medical Sciences (IOMS) analogize brain death to an intermediate state between life and death. Still other councils have (...) repudiated the notion entirely. Similarly, the ethico-legal assessments are not uniform in their acceptance of brain-stem or whole-brain criteria for death, and consequently their conceptualizations of, brain death. Within the medical literature, and in the statements of Muslim medical professional societies, brain death has been viewed as sanctioned by Islamic law with experts citing the aforementioned rulings. Furthermore, health policies around organ transplantation and end-of-life care within the Muslim world have been crafted with consideration of these representative religious determinations made by transnational, legally-inclusive, and multidisciplinary councils. The determinations of these councils also have bearing upon Muslim clinicians and patients who encounter the challenges of brain death at the bedside. For those searching for ‘Islamically-sanctioned’ responses that can inform their practice, both the OIC-IFA and IOMS verdicts have palpable gaps in their assessments and remain clinically ambiguous. In this paper we analyze these verdicts from the perspective of applied Islamic bioethics and raise several questions that, if answered by future juridical councils, will better meet the needs of clinicians and bioethicists. (shrink)

The concept of brain death was recently described as being “at once well settled and persistently unresolved.” Every day, in the United States and around the world, physicians diagnose patients as brain dead, and then proceed to transplant organs from these patients into others in need. Yet as well settled as this practice has become, brain death continues to be the focus of controversy, with two journals in bioethics dedicating major sections to the topic within the last (...) two years.By way of background, the Uniform Determination of Death Act states that “[a]n individual who has sustained either: irreversible cessation of circulatory and respiratory functions, or irreversible cessation of all functions of the entire brain, including the brain stem, is dead. A determination of death must be made in accordance with accepted medical standards.” In other words, death can be defined by either cardiorespiratory or neurological criteria, with “brain death” representing the loss of all brain function. This standard, or closely related variants, has become the accepted approach throughout the United States and in many parts of the world. (shrink)

Balancing self‐renewal and differentiation of stem cells is an important issue in stem cell and cancer biology. Recently, the Drosophila neuroblast (NB), neural stem cell has emerged as an excellent model for stem cell self‐renewal and tumorigenesis. It is of great interest to understand how defects in the asymmetric division of neural stem cells lead to tumor formation. Here, we review recent advances in asymmetric division and the self‐renewal control of Drosophila NBs. We summarize molecular (...) mechanisms of asymmetric cell division and discuss how the defects in asymmetric division lead to tumor formation. Gain‐of‐function or loss‐of‐function of various proteins in the asymmetric machinery can drive NB overgrowth and tumor formation. These proteins control either the asymmetric protein localization or mitotic spindle orientation of NBs. We also discuss other mechanisms of brain tumor suppression that are beyond the control of asymmetric division. (shrink)

Are there persuasive approaches to embryonic stem cell (ESC) research that appeal, not just to those fellow-citizens in one’s own ideological camp, nor just to those undecided citizens in the middle, but to those citizens on the other side of the issue? I believe that there are such arguments and in this short paper I try to develop one of them. In particular, I argue that certain beliefs shared by some proponents and some opponents of ESC research—beliefs about the (...) personal identity and moral status of those who are victims of terrible brain diseases—are beliefs that should lead us to adopt a qualified endorsement of ESC research. (shrink)

Progress in the neurosciences is profoundly changing our conception of ourselves. Contrary to time-honored intuition, the mind turns out to be a complex of brain functions. And contrary to the wishful thinking of some philosophers, there is no stemming the revolutionary impact that brain research will have on our understanding of how the mind works. Brain-Wise is the sequel to Patricia Smith Churchland's Neurophilosophy, the book that launched a subfield. In a clear, conversational manner, this book examines (...) old questions about the nature of the mind within the new framework of the brain sciences. What, it asks, is the neurobiological basis of consciousness, the self, and free choice? How does the brain learn about the external world and about its own introspective world? What can neurophilosophy tell us about the basis and significance of religious and moral experiences? Drawing on results from research at the neuronal, neurochemical, system, and whole-brain levels, the book gives an up-to-date perspective on the state of neurophilosophy—what we know, what we do not know, and where things may go from here. (shrink)

Brain organoid research raises ethical challenges not seen in other forms of stem cell research. Given that brain organoids partially recapitulate the development of the human brain, it is plausible that brain organoids could one day attain consciousness and perhaps even higher cognitive abilities. Brain organoid research therefore raises difficult questions about these organoids' moral status – questions that currently fall outside the scope of existing regulations and guidelines. This paper shows how these gaps (...) can be addressed. We outline a moral framework for brain organoid research that can address the relevant ethical concerns without unduly impeding this important area of research. (shrink)

While philosophers have, for centuries, pondered upon the relation between mind and brain, neuroscientists have only recently been able to explore the connection analytically — to peer inside the black box. This ability stems from recent advances in technology and emerging neuroimaging modalities. It is now possible not only to produce remarkably detailed images of the brain’s structure (i.e. anatomical imaging) but also to capture images of the physiology associated with mental processes (i.e. functional imaging). We are able (...) to see how specific regions of the brain ‘light up’ when activities such as reading this book are performed, and how our neurons and their elaborate cast of supporting cells organize and coordinate their tasks. As demonstrated in the other chapters of this book, the mapping of the human mind (mostly by measuring regional changes in blood flow, initially by positron emission tomography (PET) and recently by functional magnetic resonance imaging or (fMRI)) has provided insight into the functional neuroanatomy of neuropsychiatric diseases. Amazingly, the idea that regional cerebral blood flow (rCBF) is related intimately to brain function goes back more than a century. As is often the case in science, this idea was initially the result of unexpected observations. The Italian physiologist Angelo Mosso first expressed the idea while studying pulsations of the living human brain that keep pace with the heartbeat (Mosso, 1881). These brain pulsations can be observed on the surface of the fontanelles in newborn children. Mosso believed that they reflected blood flow to the brain. He observed similar pulsations in an adult with a post-traumatic skull defect over the frontal lobes. While studying this subject, a peasant named Bertino, Mosso observed a sudden increase in the magnitude of the ‘brain’s heart-beats’ when the church bells signalled 12 o’clock, the time for a required prayer. The changes in brain pulsations occurred independently of any change in pulsations in the forearm.. (shrink)

A hypothesis on the physiological conditions of consciousness is presented. It is assumed that the occurrence of states of consciousness causally depends on the formation of complex representational structures. Cortical neural networks that exhibit a high representational activity develop higher-order, self-referential representations as a result of self-organizing processes. The occurrence of such states is identical with the appearance of states of consciousness. The underlying physiological processes can be identified. It is assumed that neural assemblies instantiate mental representations; hence consciousness depends (...) on the rate at which large active assemblies are generated. The formation of assemblies involves the activation of the N-methyl-D-aspartate receptor channel complex which controls different forms of synaptic plasticity including rapid changes of the connection strengths. The various causes of unconsciousness (e.g., anaesthetics or brain stem lesions) have a common denominator: they directly or indirectly inhibit the formation of assemblies. (shrink)

This article proposes a methodological schema for engaging in a productive discussion of ethical issues regarding human brain organoids, which are three-dimensional cortical neural tissues created using human pluripotent stem cells. Although moral consideration of HBOs significantly involves the possibility that they have consciousness, there is no widely accepted procedure to determine whether HBOs are conscious. Given that this is the case, it has been argued that we should adopt a precautionary principle about consciousness according to which, if (...) we are not certain whether HBOs have consciousness—and where treating HBOs as not having consciousness may cause harm to them—we should proceed as if they do have consciousness. This article emphasizes a methodological advantage of adopting the precautionary principle: it enables us to sidestep the question of whether HBOs have consciousness and, instead, directly address the question of what kinds of conscious experiences HBOs can have, where the what-kind-question is more tractable than the whether-question. By addressing the what-kind-question, we will be able to examine how much moral consideration HBOs deserve. With this in mind, this article confronts the what-kind-question with the assistance of experimental studies of consciousness and suggests an ethical framework which supports restricting the creation and use of HBOs in bioscience. (shrink)

Is there anything special about the ethical problems of intracerebral stem-cell transplantation and other forms of cell or tissue transplantation in the brain that provides neuroethics with a distinctive normative profile, setting it apart from other branches of medical ethics? This is examined with reference to some of the ethical problems associated with interventions in the brain such as potential changes in personal identity and potential changes in personality. It is argued that these problems are not sufficiently (...) specific to justify the autonomy of neuroethics as a separate discipline and can be handled by the established principles of medical ethics. The paper concludes with a constructive proposal how to deal with interventions in the brain for which the patient is unable to give valid ex-ante consent. (shrink)

It is a commonplace of contemporary thought that the mind is located in the brain. Although there have been some challenges to this view, it has remained mainstream outside of a few specialized discussions, and plays a prominent role in a wide variety of philosophical arguments. It is further assumed that the source of this view is empirical. I argue it is not. Empirical discoveries show conclusively that the brain is the central organ of mental life, but do (...) not show that it is the mind's location . The data are just as compatible with a view where mentality is a human capacity on the model of circulation or respiration, with the brain playing the same kind of role as the heart or lungs. The standard conception of the brain as the locus of mind stems, I claim, from the imposition of a Cartesian conception of the self on a materialist ontology. Recognizing that the empirical data do not justify such a move casts doubt on the foundations of a number of philosophical discussions and raises new questions about the nature of the psychological subject. (shrink)

The complexity of the human brain creates a spectrum of sophisticated behavioral repertoires, such as language, tool use, self-awareness, symbolic thought, cultural learning, and consciousness. Understanding how the human brain achieves that has been a longstanding challenge for neuroscientists and may bring insights into the evolution of human cognition and disease states. Human pluripotent stem cells could differentiate into specialized cell types and tissues in vitro. From this pluripotent state, it is possible to generate models of the (...) human brain, such as brain organoids. The recent observation that brain organoids can spontaneously develop complex neural network activity in a dish can help one understand how neural network oscillations evolve and vary between normal and disease states. Moreover, this finding can be leveraged to other applications outside medicine, including engineering and artificial intelligence. However, as the brain model technology becomes more complex, it raises a series of ethical and moral dilemmas. This article discusses the status of this technology, some of its current limitations, and a vision of the future. (shrink)

The goal of this article is to review some aspects of brain anatomy and neurophysiology that are important for consciousness, and which hopefully may be of benefit to philosophers investigating the conscious mind. Taking as an initial point of reference the distinction between “the hard problem” and “the weak problems” of consciousness, we shall concentrate on questions pertaining to the second of these. A putative “consciousness system” in the brain will be presented, paying special attention to diffuse projection (...) systems. The “center of gravity” will be brain connectivity, since consciousness must, critically, be dependent on coherent activity and timing. “Detectors” of synchronicity and coincidence, like NMDA receptors, also necessarily play a role here. To be conscious, we do not need an entire brain. While even large hemispherectomies need not unequivocally affect consciousness, far smaller brain-stem lesions may be devastating in this regard. Even so, the recent discovery by Matthew F. Glasser et al. of 180 separate areas in the human brain cortex is intriguing from a teleological perspective, as it is quite unthinkable that any of them could be “redundant. (shrink)

The current debate regarding the suitability of anencephalics as organ donors is due primarily to misunderstandings. The anatomical and neurophysiological literature shows that the anencephalic lacks a cerebrum because of the failure of neuralplate fusion. However, even the incomplete function of an atrophic brain stem is currently accepted at law in most if not all countries as sufficient for brain life: which is to say, cessation of breathing is currently required in order to make the diagnosis of (...) brain death. Because of the extensive incompleteness of the anencephalic's brain, it is not possible to postpone death significantly by mechanical ventilation and intravenous feeding. It is acceptable to maintain life for a short period of time in order to allow organ transplantation subsequent to the declaration of death at the point of cessation of the capacity for spontaneous respiration. The most important issue is not transplantation, but the issue of brain life raised by the case of anencephalics. Since brain life in any significant sense begins only after the closure of the neural tube on the 30th day after conception, it is reasonable to take this as the point at which brain life begins. Laws should be amended in all countries to allow the abortion of anencephalics at any time, in that they do not at any time possess brain life. (shrink)

The Uniform Determination of Death Act (UDDA) provides that “an individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions or (2) irreversible cessation of all functions of the entire brain, including the brain stem, is dead.” We show that the UDDA contains two conflicting interpretations of the phrase “cessation of functions.” By one interpretation, what matters for the determination of death is the cessation of spontaneous functions only, regardless of their generation by artificial (...) means. By the other, what matters is the cessation of both spontaneous and artificially supported functions. Because each UDDA criterion uses a different interpretation, the law is conceptually inconsistent. A single consistent interpretation would lead to the conclusion that conscious individuals whose respiratory and circulatory functions are artificially supported are actually dead, or that individuals whose brain is entirely and irreversibly destroyed may be alive. We explore solutions to mitigate the inconsistency. (shrink)

There is a persisting tension that exists between the block universe conception of time in modern physics and philosophy and the conception of time that stems naturally from experience, and entropic asymmetries have been proposed to explain this tension. This article argues that as biochemical processes in the brain depend upon spontaneous entropy increases in the forward-time direction, this should provide an entropic basis for the unidirectionality of psychological processes. As this view does not depend on considerations of abstract (...) information processing or a past hypothesis, it provides advantages over previous entropy-based proposals attempting to explain asymmetries in temporal experience. (shrink)

The current model of adult neurogenesis in mammals suggests that adult‐born neurons are generated by stem cells that undergo long‐term self‐renewal, and that a lifetime supply of stem cells resides in the brain. In contrast, it has recently been demonstrated that adult‐born neurons in crayfish are generated by precursors originating in the immune system. This is particularly interesting because studies done many years ago suggest that a similar mechanism might exist in rodents and humans, with bone marrow (...) providing stem cells that can generate neurons. However, the relevance of these findings for natural mechanisms underlying adult neurogenesis in mammals is not clear, because of uncertainties at many levels. We argue here that the recent findings in crayfish send a strong signal to re‐examine existing data from rodents and humans, and to design new experiments that will directly test the contributions of the immune system to adult neurogenesis in mammals. (shrink)

The convergence of human and artificial intelligence is currently receiving considerable scholarly attention. Much debate about the resulting _Hybrid Minds_ focuses on the integration of artificial intelligence into the human brain through intelligent brain-computer interfaces as they enter clinical use. In this contribution we discuss a complementary development: the integration of a functional in vitro network of human neurons into an _in silico_ computing environment. To do so, we draw on a recent experiment reporting the creation of silico-biological (...) intelligence as a case study (Kagan et al., 2022b ). In this experiment, multielectrode arrays were plated with stem cell-derived human neurons, creating a system which the authors call _DishBrain_. By embedding the system into a virtual game-world, neural clusters were able to receive electrical input signals from the game-world and to respond appropriately with output signals from pre-assigned motor regions. Using this design, the authors demonstrate how the _DishBrain_ self-organises and successfully learns to play the computer game ‘Pong’, exhibiting ‘sentient’ and intelligent behaviour in its virtual environment. The creation of such hybrid, silico-biological intelligence raises numerous ethical challenges. Following the neuroscientific framework embraced by the authors themselves, we discuss the arising ethical challenges in the context of Karl Friston’s Free Energy Principle, focusing on the risk of creating synthetic phenomenology. Following the _DishBrain’s_ creator’s neuroscientific assumptions, we highlight how DishBrain’s design may risk bringing about artificial suffering and argue for a congruently cautious approach to such synthetic biological intelligence. (shrink)

If education is to make a difference it is widely acknowledged that we must aim to educate for understanding, but this means being clear about what we mean by understanding. This paper argues for a concept of personal understanding, recognising both the commonality and individuality of each pupil's understandings, and the relationship between understanding and interpretation, analysis and synopsis, and the quest for meaning. In supporting this view, the paper advocates an emergentist notion of person‐hood, and considers the neurophysiological reasons (...) for asserting the individuality of human minds, brains, and the creation of personal meanings. The notion of personal meanings would, however, seem to run counter to the post‐modern denial of the autonomous self, and the tradition in philosophy, most recently stemming from Wittgenstein, that insists that meanings and understandings are essentially social, and not personal—a view also advocated by John White in regard to education. In contrast, this paper argues that meanings and understandings are both social and personal. Once we reinstate the notion of personal minds and personal understandings, alongside the social, we may see more clearly what it means to educate for understanding, and why this might begin to make a difference. (shrink)

Brain death or determination of death based on the neurological criterion has been an enduring source of controversy in academic and clinical circles. The controversy chiefly concerns how death is defined, and it also bears on the justification of the proposed criteria for death determination and their interpretation. Part of the controversy on brain death and death determination stems from disputed crucial medical facts, but in this paper I formulate another hypothesis about the nature of ongoing controversies. At (...) stake is a misunderstood relationship between, on the one hand, the nature of our lay views about death and, on the other hand, the nature of scientific insights into death and its determination. The misunderstanding of this relationship has partly anchored the controversy and continues to fuel it. Based on a perspective inspired by pragmatism, which stresses the positive contribution of science to ethical and policy debates but also challenges different forms of scientism in science and philosophy found in foundationalist interpretations, I scrutinize three different stances regarding the relationship between lay and scientific perspectives about the definition of death: foundational lay views, foundational expert views, and co-evolving views. I argue that only the latter is sustainable given recent challenges to foundationalist interpretations. (shrink)

The reality of current clinical practice in the UK is that where a patient’s family refuses to agree to testing for brain stem death (BD), such cases will ultimately end up in court. This situation is true of both adults and children and reinforced by recent legal cases. While recourse to the courts might be regrettable in such tragic cases, if public trust in the medical diagnosis of BD is to be maintained all aspects of the process must (...) be conducted in a way that is transparent and open to scrutiny. This is not an ‘ineffective expenditure’ of resources, but an essential element of a human rights-compliant legal system. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Death Perception:How Temporary Ventilator Disconnection Helped my Family Accept Brain Death and Donate OrgansThomas B. FreemanThe night of my nephew’s closed head injury in Boston, I was on call as a neurosurgeon at Tampa General Hospital. I was therefore not shocked at first when my telephone rang at four o’clock in the morning, but I soon understood the severity of the tragic news. The next half hour was (...) a blur of frantic phone calls and devastating decisions leading to surgery to remove a subdural hematoma from my nephew’s head, even though he was only two brain stem reflexes away from brain death.I thought that my experience as a neurosurgeon would somehow help me. However, when my sister–in–law asked me if this was just like the other tragic closed head injuries that I had seen in 26 years of practice, my answer was very simple: this was the only severe closed head injury I had ever seen—in my family. At this point, I was no longer a neurosurgeon. I was an uncle. My nephew’s closed head injury overwhelmed both his brain’s capacity to survive and my entire family’s ability to think rationally or objectively while grieving so intensely.It is in this context that we were asked to consider organ donation. The appeal for organ donation is one of altruism. My nephew’s parents agreed that organ donation would be an important way to honor their son’s life, allow him to make one final contribution to save the lives of several patients, and help to bring peace to the family.I will never forget, however, my niece’s distraught response. She is altruistic by nature, but was tremendously conflicted by the choice to donate her own brother’s organs. At this point, all discussions about organ donation stopped until we could understand the source of her conflict. Since she did not have legal authority regarding the final decision, some family members wondered if organ donation should be allowed if she could not come to terms with the choice. She felt isolated, because she was the only person in the room who was experiencing conflict. As a neurosurgeon, I have always advised other families in this situation that they may have more peace if they can make such decisions unanimously, regardless of who has the ultimate legal authority for decision–making. This helps bring healing to the family, eliminates disruption of family values and unity, and reduces possible feelings of guilt.I asked my niece what she was feeling. She stated something that I had never heard before as a neurosurgeon. She had listened to the words that her brother was brain dead, but she felt that he was somehow still alive, since he was breathing on a ventilator and his heart was beating. She felt powerless due to her inability to do anything more for [End Page 9] him. She also wanted to be there when her brother “died,” which she would recognize by the cessation of his heartbeat. She would not abandon her brother.I searched for a way to respect my niece’s wishes and her legitimate request, while preserving the ability to proceed with organ donation. Solving this conundrum proved to be a pivotal part of the beginning of both her mourning process and acceptance of his death.As an uncle, I experienced the clear dissociation that modern medicine creates between medical care and the natural human process of recognizing and accepting death. My family observed the subtle difference between a deep coma and brain death. They noticed that my nephew’s color had changed when his temperature dropped to 94o F before the heating blanket was placed. They perceived the decrease in muscle tone when he stopped breathing faster than the ventilator rate. Outside of that, there was no significant difference in his appearance when he was “alive” or “dead.”In spite of heroic measures and superlative surgical and medical care, his closed head injury progressed unremittingly until he became brain dead 36 hours later. The diagnosis of “brain death” was pronounced to the family. Accepting the death of someone who is... (shrink)

Researchers are enthusiastically concerned about neural stem cell (NSC) therapy in a wide array of diseases, including stroke, neurodegenerative disease, spinal cord injury (SCI) and depression. Although enormous evidences have demonstrated that neurobehavioral improvement may benefit from NSC-supporting regeneration in animal models, approaches to endogenous and transplanted NSCs are blocked by hurdles of migration, proliferation, maturation and integration of NSCs. Electrical stimulation (ES) may be a selective nondrug approach for mobilizing NSCs in the central nervous system (CNS). This technique (...) is suitable for clinic application, because it is well established and its potential complications are manageable. Here, we provide a comprehensive review of the emerging positive role of different electrical cues in regulating NSC biology in vitro and in vivo, as well as biomaterial-based and chemical stimulation of NSCs. In the future, ES combined with stem cell therapy or other cues probably becomes an approach for promoting brain repair. (shrink)

Cerebral organoid models in-of-themselves are considered as an alternative to research animal models. But their developmental and biological limitations currently inhibit the probability that organoids can fully replace animal models. Furthermore, these organoid limitations have, somewhat ironically, brought researchers back to the animal model via xenotransplantation, thus creating hybrids and chimeras. In addition to attempting to study and overcome cerebral organoid limitations, transplanting cerebral organoids into animal models brings an opportunity to observe behavioral changes in the animal itself. Traditional animal (...) ethics frameworks, such as the well-known three Rs (reduce, refine, and replace), have previously addressed chimeras and xenotransplantation of tissue. But these frameworks have yet to completely assess the neural-chimeric possibilities. And while the three Rs framework was a historical landmark in animal ethics, there are identifiable gaps in the framework that require attention. The authors propose to utilize an expanded three Rs framework initially developed by David DeGrazia and Tom L. Beauchamp, known as the Six Principles (6Ps). This framework aims to expand upon the three Rs, fill in the gaps, and be a practical means for assessing animal ethical issues like that of neural-chimeras and cerebral organoid xenotransplantation. The scope of this 6Ps application will focus on two separate but recent studies, which were published in 2019 and 2020. First, they consider a study wherein cerebral organoids were grown from donors with Down syndrome and from neurotypical donors. After these organoids were grown and studied, they were then surgically implanted into mouse models to observe the physiological effects and any behavioral change in the chimera. Second, they consider a separate study wherein neurotypical human embryonic stem cell-derived cerebral organoids were grown and transplanted into mouse and macaque models. The aim was to observe if such a transplantation method would contribute to therapies for brain injury or stroke. The authors place both studies under the lens of the 6Ps framework, assess the relevant contexts of each case, and provide relevant normative conclusions. In this way, they demonstrate how the 6Ps could be applied in future cases of neural-chimeras and cerebral organoid xenotransplantation. (shrink)

While there is increasing pressure on scarce health care resources, advances in medical science have blurred the boundary between life and death. Individuals can survive for decades without consciousness and individuals whose whole brains are dead can be supported for extended periods. One suggested response is to redefine death, justifying a higher brain criterion for death. This argument fails because it conflates two distinct notions about the demise of human beings--the one, biological and the other, ontological. Death is a (...) biological phenomenon. This view entails the rejection of a higher brain criterion of death. Moreover, I claim that the justification of the whole brain (or brain stem) criterion of death is also cast into doubt by these advances in medical science. I proceed to argue that there is no need to redefine death in order to identify which treatments ought to be provided for the permanently and irreversibly unconscious. There are already clear treatment guidelines. (shrink)

If stem cells ever show promise in treating diseases of the human brain, any potential therapy would need to be tested in animals. But putting human brain stem cells into monkeys or apes could raise awkward ethical dilemmas, like the possibility of generating a humanlike mind in a chimpanzee's body.

The paradigmatic assumption that REM sleep is the physiological equivalent of dreaming is in need of fundamental revision. A mounting body of evidence suggests that dreaming and REM sleep are dissociable states, and that dreaming is controlled by forebrain mechanisms. Recent neuropsychological, radiological, and pharmacological findings suggest that the cholinergic brain stem mechanisms that control the REM state can only generate the psychological phenomena of dreaming through the mediation of a second, probably dopaminergic, forebrain mechanism. The latter mechanism (...) (and thus dreaming itself) can also be activated by a variety of nonREM triggers. Dreaming can be manipulated by dopamine agonists and antagonists with no concomitant change in REM frequency, duration, and density. Dreaming can also be induced by focal forebrain stimulation and by complex partial (forebrain) seizures during nonREM sleep, when the involvement of brainstem REM mechanisms is precluded. Likewise, dreaming is obliterated by focal lesions along a specific (probably dopaminergic) forebrain pathway, and these lesions do not have any appreciable effects on REM frequency, duration, and density. These findings suggest that the forebrain mechanism in question is the final common path to dreaming and that the brainstem oscillator that controls the REM state is just one of the many arousal triggers that can activate this forebrain mechanism. The “REM-on” mechanism (like its various NREM equivalents) therefore stands outside the dream process itself, which is mediated by an independent, forebrain “dream-on” mechanism. Key Words: acetylcholine; brainstem; dopamine; dreaming; forebrain; NREM; REM; sleep. (shrink)

This superbly written and finery argued philosophical essay has potentially revolutionary importance for understanding "human consciousness, " and its author has accordingly been celebrated by the likes of Oliver Sachs and Karl Pribram. Showing the relevance of neuropathology for understanding the unifying processes behind perception, memory, and language, Jason Brown offers an exciting new approach to the mind/brain problem, freely crossing the boundaries of neurophysiology, psychology, and philosophy of mind. Hard science and the study of the nature of mind (...) (including Buddhist perspectives) come together in new ways, and without advocating the reductionist "computational model" for the mind/brain relation which dominates cognitive science today. Brown finds that every event in conscious life passes through highly determinate stages in a fraction of a second. These repeat both the stages of individual growth and of the evolution of the species: Not only does ontogeny recapitulate phylogeny, but the emergence of every moment of awareness recapitulates them both. This process begins deep in the brain stem with the mere awareness of duration, proceeds through concept-formation and image selection, and terminates with the apprehension of an object in the external world. The external object acts as a realistic constraint on consciousness. But in conditions such as brain damage, dream, meditation, as well as creativity, the preconscious stages enter into direct awareness, giving us explicit glimpses of developmental and evolutionary process and presenting a startling reversal of common ideas about the development of mind. Concept and image do not derive from perception and sensation, theycome first. And the principle of consciousness, rather than being a latecomer on the evolutionary and developmental scene, is a potentiality throughout. This lucidly written book will not disappoint the many readers concerned with the great frontier of scientific exploration -- the nature of consciousness. (shrink)

The cerebral cortex controls our most distinguishing higher cognitive functions. Human‐specific gene expression differences are abundant in the cerebral cortex, yet we have only begun to understand how these variations impact brain function. This review discusses the current evidence linking non‐coding regulatory DNA changes, including enhancers, with neocortical evolution. Functional interrogation using animal models reveals converging roles for our genome in key aspects of cortical development including progenitor cell cycle and neuronal signaling. New technologies, including iPS cells and organoids, (...) offer potential alternatives to modeling evolutionary modifications in a relevant species context. Several diseases rooted in the cerebral cortex uniquely manifest in humans compared to other primates, thus highlighting the importance of understanding human brain differences. Future studies of regulatory loci, including those implicated in disease, will collectively help elucidate key cellular and genetic mechanisms underlying our distinguishing cognitive traits. (shrink)

In the adult mammalian brain, neurogenesis is restricted to few regions, while gliogenesis continues in a wide‐spread manner. Here we discuss our knowledge of extrinsic and intrinsic factors regulating neuro‐ and gliogenesis in the adult brain and propose a model of fate specification identifying the states of easiest transition between glio‐ and neurogenesis, highlighting the unique mechanisms stabilising the neural stem cell state. The model also encompasses the fate alterations achieved by direct reprogramming, and hence addresses a (...) novel avenue for repair, namely eliciting neurogenesis from glial cells outside the neurogenic niches. (shrink)

The author of The Reality of Time and the Existence of God turns his critical conceptual acumen to finding an intellectually viable path between the current polarities of dualism and materialism. By considering human beings as language-using animals he can critically appraise “representational” views of concept formation, as well as show how current “research programs” which presuppose a “materialist” basis stem from an unwitting adoption of a dualist picture of mind and body. His alternative is rooted in classical thinkerslike (...) Aquinas and responsive to the critiques of Wittgenstein, yet constructive in ways in which those critiques failed to be. This essay aims to help readers undertake a taxing inquiry by guiding them through its main theses. (shrink)