Despite that it is commonly accepted that migraine is a disorder of the nervous system with a prominent genetic basis, it is comorbid with a plethora of medical conditions. Several studies have found bidirectional comorbidity between migraine and different disorders including neurological, psychiatric, cardio- and cerebrovascular, gastrointestinal, metaboloendocrine, and immunological conditions. Each of these has its own genetic load and shares some common characteristics with migraine. The bidirectional mechanisms that are likely to underlie this extensive comorbidity between migraine and other (...) diseases are manifold. Comorbid pathologies can induce and promote thalamocortical network dysexcitability, multi-organ transient or persistent pro-inflammatory state, and disproportionate energetic needs in a variable combination, which in turn may be causative mechanisms of the activation of an ample defensive system with includes the trigeminovascular system in conjunction with the neuroendocrine hypothalamic system. This strategy is designed to maintain brain homeostasis by regulating homeostatic needs, such as normal subcortico-cortical excitability, energy balance, osmoregulation, and emotional response. In this light, the treatment of migraine should always involves a multidisciplinary approach, aimed at identifying and, if necessary, eliminating possible risk and comorbidity factors. (shrink)

One of the immediate eukaryotic cellular responses to DNA breakage is the covalent post‐translational modification of nuclear proteins with poly(ADP‐ribose) from NAD+ as precursor, mostly catalysed by poly(ADP‐ribose) polymerase‐1 (PARP‐1). Recently several other polypeptides have been shown to catalyse poly(ADP‐ribose) formation. Poly(ADP‐ribosyl)ation is involved in a variety of physiological and pathophysiological phenomena. Physiological functions include its participation in DNA‐base excision repair, DNA‐damage signalling, regulation of genomic stability, and regulation of transcription and proteasomal function, supporting the previously observed correlation of cellular (...) poly(ADP‐ribosyl)ation capacity with mammalian life. The pathophysiology effects are mediated through PARP‐1 overactivity, which can cause cell suicide by NAD+ depletion. It is apparent that the latter effect underlies the pathogenesis of a wide range of disease states including type‐1 diabetes, ischaemic infarcts in various organs, and septic or haemorrhagic shock. Therefore pharmacological modulation of poly(ADP‐ribosyl)ation may prove to be an exciting option for various highly prevalent, disabling and even lethal diseases. BioEssays 23:795–806, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Ectopeptidases are transmembrane proteins present in a wide variety of tissues and cell types. Dysregulated expression of certain ectopeptidases in human malignancies suggests their value as clinical markers. Ectopeptidase interaction with agonistic antibodies or their inhibitors has revealed that these ectoenzymes are able to modulate bioactive peptide responses and to influence growth, apoptosis and differentiation, as well as adhesion and motility, all functions involved in normal and tumoral processes. There is evidence that ectopeptidase-mediated signal transduction frequently involves tyrosine phosphorylation. Combined (...) analyses of gene organization and regulation of ectopeptidases by various physiological factors have provided insights into their structure–function relationships. Understanding the roles of ectopeptidases in pathophysiology may have implications in considering them as therapeutic targets. BioEssays 23:251–260, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

At the end of the 19th century, medical research in the United States was descriptive and rudimentary. American physician-investigators were primarily defining and categorizing disease entities. However, seeds of more mechanistic research had been laid in Europe, particularly in Germany, including the germ theory of disease etiology resulting from Pasteur and Koch's discoveries and the detailed descriptive pathology of the human body by Virchow and others. Prior to World War I, a graduate of an American medical school with an interest (...) in research commonly spent time in a laboratory of a productive European investigator. This European influence on American medicine and medical research was greatly respected, and a .. (shrink)

Gliomas can display marked changes in the concentrations of energy metabolism molecules such as creatine (Cr), phosphocreatine (PCr) and lactate, as measured using magnetic resonance spectroscopy (MRS). Moreover, the BOLD (blood oxygen level dependent) contrast enhancement in functional magnetic resonance imaging (fMRI) can be reduced or missing within or near gliomas, while neural activity is not significantly reduced (so-called neurovascular decoupling), so that the location of functionally eloquent areas using fMRI can be erroneous. In this paper, we adapt a previously (...) developed model of the coupling between neural activation, energy metabolism and hemodynamics, by including the venous dilatation Balloon model of Buxton and Frank. We show that decreasing the cerebral blood flow (CBF) baseline value, or the CBF increase fraction, results in a decrease of the BOLD signal and an increase of the lactate peak during a sustained activation. Baseline lactate and PCr levels are not significantly affected by CBF baseline reduction, but are altered even by a moderate decrease of mitochondrial respiration. Decreasing the total Cr and PCr concentration reduces the BOLD signal after the initial overshoot. In conclusion, we suggest that the coupled use of BOLD fMRI and MRS could contribute to a better understanding of the neurovascular and metabolic decoupling in gliomas. (shrink)

I explicate how various relational interactions between (M,R)-systems may have realizations in pathophysiology, and how the possible reversals of the effects of these interactions then become therapeutic models. Functional entailment receives a rigorous category-theoretic treatment, and plays a crucial role in this continuing saga of relational biology.

This mini-review provides a detailed outline of studies that have used multimodal approaches in non-invasive brain stimulation to investigate the pathophysiology of the three common movement disorders, namely, essential tremor, Parkinson’s disease, and dystonia. Using specific search terms and filters in the PubMed®database, we finally shortlisted 27 studies in total that were relevant to this review. While two-thirds (Brittain et al., 2013) of these studies were performed on Parkinson’s disease patients, we could find only three studies that were conducted (...) in patients with essential tremor. We clearly show that although multimodal non-invasive brain stimulation holds immense potential in unraveling the physiological mechanisms that are disrupted in movement disorders, the technical challenges and pitfalls of combining these methods may hinder their widespread application by movement disorder specialists. A multidisciplinary team with clinical and technical expertise may be crucial in reaping the fullest benefits from such novel multimodal approaches. (shrink)

Evidence for a dysfunction in cognitive coordination in schizophrenia is emerging, but it is not specific enough to prove (or disprove) this long-standing hypothesis. Many aspects of the external world are spatially mapped in the brain. A comprehensive internal representation relies on integration of information across space. Focus on spatial integration in the perceptual and cognitive processes will generate empirical data that shed light on the pathophysiology of schizophrenia.

Protein disulfide isomerase (PDI) is one of the most abundant and critical protein folding catalysts in the endoplasmic reticulum of eukaryotic cells. PDI consists of four thioredoxin domains and interacts with a wide range of substrate and partner proteins due to its intrinsic conformational flexibility. PDI plays multifunctional roles in a variety of pathophysiological events, both as an oxidoreductase and a molecular chaperone. Recent studies have revealed that the conformation and activity of PDI can be regulated in multiple ways, including (...) posttranslational modification and substrate/ligand binding. Here, we summarize recent advances in understanding the function and regulation of PDI in different pathological and physiological events. We propose that the multifunctional roles of PDI are regulated by multiple mechanisms. Furthermore, we discuss future directions for the study of PDI, emphasizing how different regulatory modes are linked to the conformational changes and biological functions of PDI in the context of diverse pathophysiologies. (shrink)

Glycogen is synthesized and stored to maintain postprandial blood glucose homeostasis and to ensure an uninterrupted energy supply between meals. Although the regulation of glycogen turnover has been well studied, the effects of glycogen on aging and disease development have been largely unexplored. In Caenorhabditis elegans fed a high sugar diet, glycogen potentiates resistance to oxidants, but paradoxically, shortens lifespan. Depletion of glycogen by oxidants or inhibition of glycogen synthesis extends the lifespan of worms by an AMPK‐dependent mechanism. Thus, glycogen (...) is not merely an inert storage molecule, but also an active regulator of energy balance and aging. Its depletion by oxidants may be beneficial in the treatment of hyperglycemia and glycogen‐related diseases. (shrink)

Recent studies indicate a role of the sympathetic nervous system in acute and chronic pain. However, the terminology of the clinical sympathetically maintained pain (SMP) syndromes continues to be confusing and the criteria for diagnosis of SMP are being refined. (blumberg et al.) Despite significant progress in recent years, the mechanisms of the interaction between the sympathetic and sensory systems in SMP remain puzzling.

An examination of the early history of Nobel Committee deliberations, coupled with a survey of discoveries for which prizes have been awarded to date – and, equally revealing, discoveries for which prizes have not been awarded – reveals a pattern. This pattern suggests that Committee members may have internalized the received, biomedical model and conferred awards in accord with the physicalistic premises that ground this model. I consider the prospect of a paradigm change in medical science and the possible repercussions (...) of such a change on the distribution of Nobel prizes within the domain of physiology or medicine. For expository purposes, I contrast a model based on a science of pathophysiology with one based on a science of pathopsychophysiology. I propose a means whereby members might minimize the potentially blinding effects of model-dependence and come to evaluate medical discoveries from an inter-model rather than an exclusively intra-model perspective. By bringing to light questions rarely asked and proposing answers, I seek to open a dialogue and furnish a vehicle by which the putative delimiting effects of model-dependence might be overcome. (shrink)

Abundant pathophysiological and clinical evidence suggests that the algogenic code responsible for cardiac pain is not based on mechanisms (mcmahon). Recent evidence, however, has led various authors to postulate that some degree of specificity might be involved in visceral pain arising from other sources, but a intensity pattern is still the most plausible hypothesis for the genesis of visceral pain.

Evidence-based medicine (EBM) has thus far failed to adequately account for the appropriate incorporation of other potential warrants for medical decision making into clinical practice. In particular, EBM has struggled with the value and integration of other kinds of medical knowledge, such as those derived from clinical experience or based on pathophysiologic rationale. The general priority given to empirical evidence derived from clinical research in all EBM approaches is not epistemically tenable. A casuistic alternative to EBM approaches recognizes that five (...) distinct topics, 1) empirical evidence, 2) experiential evidence, 3) pathophysiologic rationale, 4) patient goals and values, and 5) system features are potentially relevant to any clinical decision. No single topic has a general priority over any other and the relative importance of a topic will depend upon the circumstances of the particular case. The skilled clinician must weigh these potentially conflicting evidentiary and non-evidentiary warrants for action, employing both practical and theoretical reasoning, in order to arrive at the best choice for an individual patient. (shrink)

Evolutionary medicine (EM) is an emerging field of medical studies that uses evolutionary theory to explain the ultimate causes of health and disease. The field’s main objective is to reconceptualize bodily vulnerabilities and pathophysiologies as evolutionary tradeoffs—many the result of an evolutionary mismatch between our ancient genome and modern lifestyle. This conceptual shift allows EM to describe health and disease in terms of adaptive functions and to prescribe treatments that best complement our evolved bodies. The goal is to “transform the (...) way patients and doctors see disease” (Nesse and Williams 1994, p. 245) in order to harness a renewed “feeling for the organism as a product of natural selection” .. (shrink)

Trafficking and persistence of fetal microchimeric cells (fMCs) and circulating extracellular vesicles (EVs) have been observed in animals and humans, but their consequences in the maternal body and their mechanistic contributions to maternal physiology and pathophysiology are not yet fully defined. Fetal cells and EVs may help remodel maternal organs after pregnancy‐associated changes, but the cell types and EV cargos reaching the mother in preterm pregnancies after exposure to various risk factors can be distinct from term pregnancies. As preterm (...) delivery‐associated maternal complications are rising, revisiting this topic and formulating scientific questions for future research to reduce the risk of maternal morbidities are timely. Epidemiological studies report maternal cardiovascular risk as one of the major complications after preterm delivery. This paper suggests a potential link between fMCs and circulating EVs and adverse maternal cardiovascular outcomes post‐pregnancies, the underlying mechanisms, consequences, and methods for and how this link might be assessed. (shrink)

The concept that alterated communications between the gut microbiome and the brain may play an important role in human brain disorders has recently received considerable attention. This is the result of provocative preclinical and some clinical evidence supporting early hypotheses about such communication in health and disease. Gastrointestinal symptoms are a common comorbidity in patients with autism spectrum disorders (ASD), even though the underlying mechanisms are largely unknown. In addition, alteration in the composition and metabolic products of the gut microbiome (...) has long been implicated as a possible causative mechanism contributing to ASD pathophysiology, and this hypothesis has been supported by several recently published evidence from rodent models of autism induced by prenatal insults to the mother. Recent evidence in one such model involving maternal infection, that is characterized by alterations in behavior, gut physiology, microbial composition, and related metabolite profile, suggests a possible benefit of probiotic treatment on several of the observed abnormal behaviors. (shrink)

It is one of the central aims of the philosophy of science to elucidate the meanings of scientific terms and also to think critically about their application. The focus of this essay is the scientific term predict and whether there is credible evidence that animal models, especially in toxicology and pathophysiology, can be used to predict human outcomes. Whether animals can be used to predict human response to drugs and other chemicals is apparently a contentious issue. However, when one (...) empirically analyzes animal models using scientific tools they fall far short of being able to predict human responses. This is not surprising considering what we have learned from fields such evolutionary and developmental biology, gene regulation and expression, epigenetics, complexity theory, and comparative genomics. (shrink)

Although researchers in psychiatry have been trying for decades to elucidate the pathophysiology underlying mental disorders, relatively little progress has been made. One explanation for this failure is that diagnostic categories in psychiatry are unlikely to track underlying neurological mechanisms. Because of this, the US National Institutes of Mental Health has recently developed a novel ontology to guide research in biological psychiatry: the Research Domain Criteria. In this paper, I argue that while RDoC may lead to better neuroscientific explanations (...) for mental disorders, it is unlikely that this new knowledge will then lead to an improved diagnostic system. I therefore suggest that researchers in psychiatry should work toward the development of two new ontologies: one for research and one for clinical practice. (shrink)

The subjective experience of time is a fundamental constituent of human consciousness and can be disturbed under conditions of mental disorders such as schizophrenia or affective disorders. Besides the scientific domain of psychiatry, time consciousness is a topic that has been extensively studied both by theoretical philosophy and cognitive neuroscience. It can be shown that both approaches exemplified by the philosophical analysis of time consciousness and the neuroscientific theory of cross-temporal contingencies as the neurophysiological basis of human consciousness implemented in (...) the prefrontal cortex converge in 2 respects. Firstly, a tripartite conception of consciousness divides human cognition in 3 different temporal domains comprising retention, presentation, and protention and the past, the present, and the future corresponding to working memory, interference control, and preparatory set. Secondly, both concepts refer to the present as an extended duration that integrates information from the recent past and the future. We propose that the integration of phenomenological and neuroscientific approaches can stimulate the development of enriched pathophysiological concepts of mental disorders. This approach appears to be particularly fruitful with respect to schizophrenia that is interpreted as a structural disturbance of time consciousness. (shrink)

Evidence-based medicine (EBM) has long deemphasized mechanistic reasoning and pathophysiological rationale in assessing the effectiveness of interventions. The EBM+ movement has challenged this stance, arguing that evidence of mechanisms and comparative studies should both be seen as necessary and complementary. Advocates of EBM+ provide a combination of theoretical arguments and examples of mechanistic reasoning in medical research. However, EBM+ proponents have not provided recent examples of how downplaying mechanistic reasoning resulted in worse medical results than would have occurred otherwise. Such (...) examples are necessary to make the case that EBM+ responds to a problem in clinical practice that urgently demands a solution. In light of this, we examine the failed rollout of efavirenz as a first-line HIV treatment in Zimbabwe as evidence of the importance of mechanistic reasoning in improving clinical practice and public health policy decisions. We suggest that this case is analogous to examples commonly given to support EBM. (shrink)

The Unified Medical Language System and the Gene Ontology are among the most widely used terminology resources in the biomedical domain. However, when we evaluate them in the light of simple principles for wellconstructed ontologies we find a number of characteristic inadequacies. Employing the theory of granular partitions, a new approach to the understanding of ontologies and of the relationships ontologies bear to instances in reality, we provide an application of this theory in relation to an example drawn from the (...) context of the pathophysiology of hypertension. This exercise is designed to demonstrate how, by taking ontological principles into account we can create more realistic biomedical ontologies which will also bring advantages in terms of efficiency and robustness of associated software applications. (shrink)

What makes a high-quality biomarker experiment? The success of personalized medicine hinges on the answer to this question. In this paper, I argue that judgment about the quality of biomarker experiments is mediated by the problem of theoretical underdetermination. That is, the network of biological and pathophysiological theories motivating a biomarker experiment is sufficiently complicated that it often frustrates valid interpretation of the experimental results. Drawing on a case-study in biomarker diagnostic development from neurooncology, I argue that this problem of (...) underdetermination can be overcome with greater coordination across the biomarker research trajectory. I then sketch an account for how coordination across a research trajectory can be evaluated. I ultimate conclude that what makes a high-quality biomarker experiment must be judged by the epistemic contribution it makes to this coordinated research effort. (shrink)

In this paper we examine the functional anatomy of volition, as revealed by modern brain imaging techniques, in conjunction with neuropsychological data derived from human and non-human primates using other methodologies. A number of brain regions contribute to the performance of consciously chosen, or ‘willed', actions. Of particular importance is dorsolateral prefrontal cortex , together with those brain regions with which it is connected, via cortico-subcortical and cortico-cortical circuits. That aspect of free will which is concerned with the voluntary selection (...) of one action rather than another critically depends upon the normal functioning of DLPFC and associated brain regions. Disease, or dysfunction, of these circuits may be associated with a variety of disorders of volition: Parkinson's disease, ‘utilization’ behaviour, ‘alien’ and ‘phantom’ limbs, and delusions of ‘alien control’ . Brain imaging has allowed us to gain some access to the pathophysiology of these conditions in living patients. At a philosophical level, the distinction between ‘intentions to act', and ‘intentions in action’ may prove particularly helpful when addressing these complex disturbances of human cognition and conscious experience. The exercise and experience of free will depends upon neural mechanisms located in prefrontal cortex and associated brain systems. (shrink)

Unresponsive wakefulness syndrome (UWS, previously known as vegetative state) occurs after patients survive a severe brain injury. Patients suffering from UWS have lost awareness of themselves and of the external environment and do not retain any trace of their subjective experience. Current data demonstrate that neuronal functions subtending consciousness are not completely reset in UWS; however, they are reduced below the threshold required to experience consciousness. The critical factor that determines whether patients will recover consciousness is the distance of their (...) neuronal functions from this threshold level. Recovery of consciousness occurs through functional and/or structural changes in the brain, i.e., through neuronal plasticity. Although some of these changes may occur spontaneously, a growing body of evidence indicates that rehabilitative interventions can improve functional outcome by promoting adaptive functional and structural plasticity in the brain, especially if a comprehensive neurophysiological theory of consciousness is followed. In this review we will focus on the pathophysiological mechanisms involved in UWS and on the plastic changes operating on the recovery of consciousness. (shrink)

Are the small and indolent cancers found in abundance in cancer screening normal variations, risk factors, or disease? Naturalists in philosophy of medicine turn to pathophysiological findings to decide such questions objectively. To understand the role of pathophysiological findings in disease definition, we must understand how they mislead in diagnostic reasoning. Participants on all sides of the definition of disease debate attempt to secure objectivity via reductionism. These reductivist routes to objectivity are inconsistent with the Bayesian nature of clinical reasoning; (...) when they appeal to the sciences, they are inconsistent with what philosophy of biology tells us about its natural kinds. Proposals that we narrow the scope of our claims in the disease definition debates are useful, but paradigms can still distort our reasoning in particular cases, even when we are self-conscious about their status. (shrink)

Carbon monoxide intoxication leads to acute and chronic neurological deficits, but little is known about the specific noxious mechanisms. 1 H magnetic resonance spectroscopy may allow insight into the pathophysiology of CO poisoning by monitoring neurochemical disturbances, yet only limited information is available to date on the use of this protocol in determining the neurological effects of CO poisoning. To further examine the short-term and long-term effects of CO on the central nervous system, we have studied seven patients with (...) CO poisoning assessed by gray and white matter MRS, magnetic resonance imaging and neuropsychological testing. Five patients suffered from acute high-dose CO intoxication and were in coma for 1–6 days. In these patients, MRI revealed hyperintensities of the white matter and globus pallidus and also showed increased choline and decreased N -acetyl aspartate ratios to creatine, predominantly in the white matter. Lactate peaks were detected in two patients during the early phase of high-dose CO poisoning. Two patients with chronic low-dose CO exposure and without loss of consciousness had normal MRI and MRS scans. On follow-up. five of our seven patients had long-lasting intellectual impairment, including one individual with low-dose CO exposure. The MRS results showed persisting biochemical alterations despite the MRI scan showing normalization of morphological changes. In conclusion, the MRS was normal in patients suffering from chronic low-dose CO exposure; in contrast, patients with high-dose exposure showed abnormal gray and white matter levels of NAA/Cr, Cho/Cr and lactate, as detected by 1 H MRS, suggesting disturbances of neuronal function, membrane metabolism and anaerobic energy metabolism, respectively. Early increases in Cho/Cr and decreases of NAA/Cr may be related to a poor long-term outcome, but confirmation by future studies is needed. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Philosophy, Psychiatry, & Psychology 10.1 (2003) 53-55 [Access article in PDF] A Pragmatic Consideration of the Relation between Depression and Melancholia David H. Brendel THE MELANCHOLIA OF THE PAST and the major depression of the present are extraordinarily complex notions that represent different things to different people. With her compelling article "Is This Dame Melancholy? Equating Today's Depression and Past Melancholia," Jennifer Radden makes an important contribution to the (...) debate on whether these concepts are identical, overlapping, or distinct. Exploring both conditions from descriptive and causal points of view, Radden appropriately concludes that fully equating the two of them would constitute a "troubling oversimplification." Her line of reasoning runs as follows. Because past descriptions of melancholia and current descriptions of major depression are marked by dissimilarities (such as the genius and creativity associated with the former and the self-loathing and emphasis on loss associated with the latter), only an underlying causal base common to both conditions would justify our equating them. But the cause (or causes) of melancholia and depression remain mysterious. Thus, although Radden acknowledges that a causal explanation might yield substantial benefits ("research possibilities, further hypotheses, and even hope of prevention, or cure"), she suggests that we remain in a descriptive mode when comparing the two conditions and conclude that they are not one and the same.Radden's argument that past melancholia and contemporary depression are descriptively distinct is convincing and, I think, indisputable. But I would like to challenge and expand upon some of her ideas about considerations of causality and about the role of pragmatic reasoning in working out the relation between melancholia and depression. First of all, although Radden is correct that the cause of many (or perhaps most) depressive states is unknown, she underrates the extent of the empirical knowledge that we have acquired about the causation of depression and, in so doing, undervalues the relevance of causal reasoning to making the melancholia/depression distinction. Recent empirical research has revealed that major depressive episodes can result from brain lesions such as left-sided strokes or metabolic disorders such as hypothyroidism (Yudofsky and Hales 2002). Psychosocial research, moreover, has suggested that stressful life events also can be understood as causes of depression (Kendler, [End Page 53] Karkowski, and Prescott 1999). These findings provide some hope that the identification of causes of various clinical states is a real possibility. Identification of such causes, I believe, could empower us to make some plausible claims about the similarities or differences between past melancholia and current depression. A melancholic individual like van Gogh, for example, had a different illness than a contemporary stroke patient with major depression in a present-day hospital, not only on the basis of descriptive distinctions between their conditions, but also on the basis of the causes of their respective states. Although of course we cannot know the cause of van Gogh's melancholia, we can reasonably assume that it was not the result of a left-sided stroke due to the absence in his case of other clinical deficits that usually result from such a stroke (such as language and motor deficits). Plausible assertions about the causes of melancholic and depressive states would add to the robustness of any claims regarding the distinctness of the conditions.Conversely, careful consideration of the etiology of various clinical presentations might prompt us to hypothesize a shared pathophysiology and thereby lead us to believe that they are essentially identical conditions. It is difficult or impossible to discover a cause of melancholia in individuals who lived in past eras. But we might achieve our goal by comparing well-defined major depression to various forms of what Radden calls "masked depression," such as those seen in cross-cultural settings, where the subjective symptoms of sad mood are absent but numerous somatic signs of depression are observed. If it turned out that major depression and masked depression had the same cause, then differences in their clinical phenomenology would become merely surface differences that belie a shared etiological process. How might one discover the existence of such a process... (shrink)

Centuries of scientific progress have been devoted to reducing uncertainty. Newtonian physics, introduced over 300 years ago, allowed for precise prediction of planetary and tidal motion, falling bodies and infinitely more, in addition to allowing the construction of the material world. The 20th century witnessed a revolution in our understanding of organ and cellular function and dysfunction, elucidation of pathways, mediators, receptors, and molecular interactions, and breakthroughs in the characterization of replication, transcription, and translation, all of which has been integral (...) to our understanding of human physiology and pathophysiology. Clinical epidemiology has had a revolutionary impact on our .. (shrink)

The human self model comprises essential features such as the experiences of ownership, of body-centered spatial perspectivity, and of a long-term unity of beliefs and attitudes. In the pathophysiology of schizophrenia, it is suggested that clinical subsyndromes like cognitive disorganization and derealization syndromes reflect disorders of this self model. These features are neurobiologically instantiated as an episodically active complex neural activation pattern and can be mapped to the brain, given adequate operationalizations of self model features. In its unique capability (...) of integrating external and internal data, the prefrontal cortex (PFC) appears to be an essential component of the neuronal implementation of the self model. With close connections to other unimodal association cortices and to the limbic system, the PFC provides an internally represented world model and internal milieu data of the organism, both serving world orientation. In the pathophysiology of schizophrenia, it is the dysfunction of the PFC that is suggested to be the neural correlate for the different clinical schizophrenic subsyndromes. The pathophysiological study of psychiatric disorders may contribute to the theoretical debate on the neuronal basis of the self model. (shrink)

The reigning paradigm of rational drug discovery in translational medicine attempts to exploit biological theories and pathophysiological explanations to identify novel drug targets and therapeutic strategies. Given that there are limited human and material resources available for testing experimental therapeutics, this theory- and explanation-driven strategy of drug development seems to make good sense: it narrows the number of plausible drug candidates to be put through rigorous and expensive testing; it potentially improves the success rate of clinical translation; and it provides (...) some epistemological basis to extrapolate evidence from one domain to another and potentially minimize risks to patient-subjects.Yet... (shrink)

Institutional Review Board decisions hinge on the availability and interpretation of information. This is demonstrated by the following well-known historical example. In 2001, 24-year-old Ellen Roche died from respiratory distress and organ failure as a result of her participation in a study at Johns Hopkins Asthma and Allergy Center. The non-therapeutic physiological study, “Mechanisms of Deep Inspiration-Induced Airway Relaxation,” was designed to examine airway hyperresponsiveness in healthy individuals in order to better understand the pathophysiology of asthma. Participants inhaled hexamethonium, (...) a chemical ganglionic blocker that was not FDA-approved for use as specified in the experimental protocol. Risks of inhaling hexamethonium, including lung damage, had been reported in the 1950s and ‘60s. An investigation conducted after Roche's death determined that the study's principal investigator had failed to adequately search the medical literature; the protocol submitted for IRB review cited articles indexed in online literature databases that went back only as far as the 1970s. (shrink)

Based on recent insight into the thalamocortical system and its role in perception and conscious experience, a unified pathophysiological framework for hallucinations in neurological and psychiatric conditions is proposed, which integrates previously unrelated neurobiological and psychological findings. Gamma-frequency rhythms of discharge activity from thalamic and cortical neurons are facilitated by cholinergic arousal and resonate in networks of thalamocortical circuits, thereby transiently forming assemblies of coherent gamma oscillations under constraints of afferent sensory input and prefrontal attentional mechanisms. If perception is based (...) on synchronisation of intrinsic gamma activity in the thalamocortical system, then sensory input to specific thalamic nuclei may merely play a constraining role. Hallucinations can be regarded as underconstrained perceptions that arise when the impact of sensory input on activation of thalamocortical circuits and synchronisation of thalamocortical gamma activity is reduced. In conditions that are accompanied by hallucinations, factors such as cortical hyperexcitability, cortical attentional mechanisms, hyperarousal, increased noise in specific thalamic nuclei, and random sensory input to specific thalamic nuclei may, to a varying degree, contribute to underconstrained activation of thalamocortical circuits. The reticular thalamic nucleus plays an important role in suppressing random activity of relay cells in specific thalamic nuclei, and its dysfunction may be implicated in the biological vulnerability to hallucinations in schizophrenia. Combined with general activation during cholinergic arousal, this leads to excessive disinhibition in specific thalamic nuclei, which may allow cortical attentional mechanisms to recruit thalamic relay cells into resonant assemblies of gamma oscillations, regardless of their actual sensory input, thereby producing an underconstrained perceptual experience. Key Words: Charles Bonnet syndrome; gamma oscillations; hallucinations; late paraphrenia; Lewy body dementia; perception; schizophrenia; thalamocortical system. (shrink)

Stem cells derived from pluripotent cells offer the hope of new treatments for diseases for which current therapy is inadequate. Clinical trials are essential in developing effective and safe stem cell therapies and fulfilling this promise. However, such clinical trials raise ethical issues that are more complex than those raised in clinical trials using drugs, cord blood stem cells, or adult stem cells. Several clinical trials are now being carried out with stem cells derived from pluripotent cells, and many more (...) can be expected in light of the rapid scientific progress in the field.Degenerative neurological diseases are desirable targets for stem cell clinical trials. The FDA has approved Phase 1 clinical trials of neural stem cell transplantation for Batten Disease, Pelizaeus-Merzbacher Disease, and spinal cord injury. In Parkinson Disease, stem cell transplantation could correct the primary pathophysiological defect — inadequate levels of the neurotransmitter dopamine. Current treatment is unsatisfactory in late-stage PD. (shrink)

Haeusermann et al. (Citation2023) draw three overall conclusions from their study on closed loop neuromodulation and self-perception in clinical treatment of refractory epilepsy. The first is that closed-loop neuromodulation devices did not substantially change epileptic patient’s personalities or self-perception postoperatively. The second is that some patients and caregivers attributed observed changes in personality and self-perception to the epilepsy itself and not to the DBS treatments. The third is that the devices provided participants with novel ways to make sense of their (...) illness. These findings further demonstrate a misalignment between some neuroethicists’ concerns about putative postoperative changes to personality, and the empirical evidence for such changes. Haeusermann et al. nonetheless concede that “neurotechnology directed at persisting rather than episodic clinical phenomena could have greater implications for personality or self-perception, either because they operate more continuously or are directed at clinical phenomena that are more stably integrated into patients’ self-concepts” (41). We acknowledge that the hypothesis that participants did not report changes because they were only episodically and not continually stimulated offers an interesting line for future investigation. Nonetheless, we would like to propose that potential postoperative personality changes might be correlated with the pathophysiology itself, rather than the stimulation effects of the technology. Generally, we advance the view that unintended effects solely induced by the technology cannot be excluded per se. Regardless, this comment aims to highlight that ethicists’ starting premise should be that patients suffering from diverse pathophysiology, or patients who are treated with stimulation in different brain regions and with differing parameters, would likely not react in the same way to treatment. (shrink)

Science starts by using terms such as ‘temperature’ or ‘fish’ or ‘gene’ to preliminarily delimitate the extension of a phenomenon, and concludes by giving most of them a technical meaning based on an explanatory model. This transforma- tion of the meaning of the term is an essential part of its naturalization. Debating on the definition of ‘disease’, what most philosophers of medicine have examined is the pre-naturalized meaning of the term: for that reason they have focused on the task of (...) delimiting disease and non-disease (health), mainly used conceptual analysis as a method of choice, and considered the nosological level of ‘disease judgments’ rather than the pathophysiological or psychopathological level of disease mechanisms, thus making them impervious to most scientific discoveries. By focusing instead on the naturalized concept of disease and following some suggestions by philosophers of biology and scientists in cutting-edge fields of biomedical research, they could gar- ner results from a comparison of the mechanisms of diseases. This would ultimately result in a general theory of disease linked with our most general theories on living beings, among them, systems biology and network medicine. Before undertaking such a task, preliminary questions arise: is it likely that there are biological features common to different types of disease? Is it a philosopher’s job to determine what they consist in? What use would such a general theoretical definition of disease be? (shrink)

This article considers the foundation of nursing as a moral practice. Its basic claim is that all nursing knowledge and action reside on a moral foundation. The clinical gaze meets vulnerability in the patient’s human condition. To see a patient’s wound is to see his or her hurt and discomfort; it is a concerned observation. To see the factual and pathophysiological is at the same time to see the ethical: the moral realities of suffering, pain and discomfort. A nurse’s emotional (...) sensitivities are central to understanding a patient’s experiences of illness. Emotions reveal value and ascribe moral importance to certain situations; they are addressed centrally by vulnerability and the moral realities of illness. Hence, the essence of nursing knowledge and nursing performance cannot be understood merely as ontology (i.e. as being-with-the-other). Nursing is basically being-for-the-other; it is responsibility; it is ethics. (shrink)