Recently, the author of this paper and his research team have extended the orthodox quantum theory of atoms in molecules (QTAIM) to a novel paradigm called the two-component QTAIM (TC-QTAIM). This extended framework enables one to incorporate nuclear dynamics into the AIM analysis as well as performing AIM analysis of the exotic species; positronic and muonic species are a few examples. In present paper, this framework has been reviewed, providing some computational examples with particular emphasis on origins and applications, in (...) a non-technical language. The main questions, enigmas and basic ideas that finally yielded the TC-QTAIM are considered in chronological order to help the reader comprehend the intuition behind the math. Finally, it is demonstrated that the TC-QTAIM and its more refined versions are able to tackle problems inaccessible to the orthodox QTAIM. (shrink)

The ability of Glenberg's model to explain the development of complex symbolic abilities is questioned. Specifically, it is proposed that the concepts of clamping and suppression fall short of providing an explanation for higher symbolic processes such as autobiographical memory and language comprehension. A related concept, “holding in mind” (Olson 1993), is proposed as an alternative.

Spin-half fermions are considered to be limited in a spherical potential well with periodic boundary conditions. The whole system is treated like a relativistic Fermi Gas. Solving the corresponding Dirac equation, the density of states, the Fermi energy, the average energy, the density of states of nucleons and the total energy of the ground-state are obtained.

Dr Seuren's study deals with the problem of presenting an adequate model of grammatical description. The model he proposes conforms in its main outlines to the transformational generative grammar established by Chomsky, but differs in important respects. These mainly affect that part of Chomsky's syntactic component known as the 'base', which generates basic or 'deep' structures. In the model of the base proposed here two main constituents are distinguished for every deep structure representation of a sentence, vis-a-vis (...) the operators and the nucleus. The deep structure of a sentence is thus seen to be very similar to the logical structure of a proposition. The arguments given in support of this analysis are based on mainly on considerations of simplicity and semantic adequacy. (shrink)

The estrangement between genetic scientists and theologians originating in the 1960s is reflected in novel combinations of human thought (subject) and genes (investigational object), paralleling each other through the universal process known in chaos theory as self-similarity. The clash and recombination of genes and knowledge captures what Philip Hefner refers to as irony, one of four voices he suggests transmit the knowledge and arguments of the religion-and-science debate. When viewed along a tangent connecting irony to leadership, journal dissemination, and the (...) activities of the "public intellectual" and the public at large, the sequence of voices is shown to resemble the passage of genetic information from DNA to mRNA, tRNA, and protein, and from cell nucleus to surrounding environment. In this light, Hefner's inquiry into the voices of Zygon is bound up with the very subject matter Zygon covers. (shrink)

Aggressive behavior is instinctively driven behavior that helps animals to survive and reproduce and is closely related to multiple behavioral and physiological processes. The dorsal raphe nucleus (DRN) is an evolutionarily conserved midbrain structure that regulates aggressive behavior by integrating diverse brain inputs. The DRN consists predominantly of serotonergic (5‐HT:5‐hydroxytryptamine) neurons and decreased 5‐HT activity was classically thought to increase aggression. However, recent studies challenge this 5‐HT deficiency model, revealing a more complex role for the DRN 5‐HT system (...) in aggression. Furthermore, emerging evidence has shown that non‐5‐HT populations in the DRN and specific neural circuits contribute to the escalation of aggressive behavior. This review argues that the DRN serves as a multifaceted modulator of aggression, acting not only via 5‐HT but also via other neurotransmitters and neural pathways, as well as different subsets of 5‐HT neurons. In addition, we discuss the contribution of DRN neurons in the behavioral and physiological aspects implicated in aggressive behavior, such as arousal, reward, and impulsivity, to further our understanding of DRN‐mediated aggression modulation. (shrink)

The origin of the eukaryotic cell nucleus and the selective forces that drove its evolution remain unknown and are a matter of controversy. Autogenous models state that both the nucleus and endoplasmic reticulum (ER) derived from the invagination of the plasma membrane, but most of them do not advance clear selective forces for this process. Alternative models proposing an endosymbiotic origin of the nucleus fail to provide a pathway fully compatible with our knowledge of cell biology. We (...) propose here an evolutionary scenario that reconciles both an ancestral endosymbiotic origin of the eukaryotic nucleus (endosymbiosis of a methanogenic archaeon within a fermentative myxobacterium) with an autogenous generation of the contemporary nuclear membrane and ER from the bacterial membrane. We specifically state two selective forces that operated sequentially during its evolution: (1) metabolic compartmentation to avoid deleterious co‐existence of anabolic (autotrophic synthesis by the methanogen) and catabolic (fermentation by the myxobacterium) pathways in the cell, and (2) avoidance of aberrant protein synthesis due to intron spreading in the ancient archaeal genome following mitochondrial acquisition and loss of methanogenesis. BioEssays 28: 525–533, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

In agreement with Behrendt & Young (B&Y), we considered the role of perception disturbances in schizophrenia in our first clinical approaches, using the Bender test with schizophrenic patients. Following this, we reproduced nuclear symptoms of schizophrenia in animal models, showing that perceptual disturbances, acquisition disturbances, and decrease in affective levels can be induced by glutamatergic blockade within the nucleus accumbens septi. Our results link the proposed corticostriatal dysfunction with the thalamocortical disturbances underlying perceptual problems reviewed by B&Y.

The nucleolus is a region of the nucleus with high protein density and it acts as a ribosome factory. The nucleolus contains a distinct region of the genome, the ribosomal RNA gene repeats (rDNA) that supply ribosomal RNA (rRNA) molecules. The rDNA is the most‐abundant gene and occupies a large part of the genome, for example, there are thousands of rDNA copies in the genomes of plant cells. Therefore, it is natural to suppose that the condition of the rDNA, (...) such as its stability, might affect cellular functions. Here I would like to propose a new model regarding the roles of the rDNA and nucleolus. The key point of this model is that they act to preserve genome stability and trigger aging. BioEssays 30:267–272, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

High-spin states in the odd-odd N = Z nucleus Co-54 have been investigated by the fusion-evaporation reaction Si-28(S-32,1 alpha 1p1n)Co-54. Gamma-ray information gathered with the Ge detector array Gammasphere was correlated with evaporated particles detected in the charged particle detector system Microball and a 1 pi neutron detector array. A significantly extended excitation scheme of Co-54 is presented, which includes a candidate for the isospin T = 1, 6(+) state of the 1f(7/2)(-2) multiplet. The results are compared to large-scale (...) shell-model calculations in the fp shell. Effective interactions with and without isospin-breaking terms have been used to probe isospin symmetry and isospin mixing. A quest for deformed high-spin rotational cascades proved negative. This feature is discussed by means of cranking calculations. (shrink)

Deep brain stimulation of the subthalamic nucleus is an effective treatment for the motor symptoms of movement disorders including Parkinson's Disease. Despite its therapeutic benefits, STN-DBS has been associated with adverse effects on mood and cognition. Specifically, apathy, which is defined as a loss of motivation, has been reported to emerge or to worsen following STN-DBS. However, it is often challenging to disentangle the effects of STN-DBSper sefrom concurrent reduction of dopamine replacement therapy, from underlying PD pathology or from (...) disease progression. To this end, pre-clinical models allow for the dissociation of each of these factors, and to establish neural substrates underlying the emergence of motivational symptoms following STN-DBS. Here, we performed a systematic analysis of rodent studies assessing the effects of STN-DBS on reward seeking, reward motivation and reward consumption across a variety of behavioral paradigms. We find that STN-DBS decreases reward seeking in the majority of experiments, and we outline how design of the behavioral task and DBS parameters can influence experimental outcomes. While an early hypothesis posited that DBS acts as a “functional lesion,” an analysis of lesions and inhibition of the STN revealed no consistent pattern on reward-related behavior. Thus, we discuss alternative mechanisms that could contribute to the amotivational effects of STN-DBS. We also argue that optogenetic-assisted circuit dissection could yield important insight into the effects of the STN on motivated behavior in health and disease. Understanding the mechanisms underlying the effects of STN-DBS on motivated behavior-will be critical for optimizing the clinical application of STN-DBS. (shrink)

A model is proposed that deals with the observed collinearities (spatial, temporal and quantitative) of Hox gene expression during pattern formation along the primary and secondary axes of vertebrates. In particular, in the proximodistal axis of the developing limb, it is assumed that a morphogen gradient is laid down with its source at the distal tip of the bud. The extracellular signals in every cell of the morphogenetic field are transduced and uniformly amplified so that molecules are produced in (...) the nucleus with appropriate physicochemical properties. These molecules can exert a concentration‐dependent force on the Hox cluster. It is assumed that, before activation, the Hox cluster is packaged as an elongated rigid body inside the chromatin and is covered by a coat that prevents the transcription factors reaching the genes of the cluster. The transcription factors are confined to the interchromatin domain and their density decreases with their distance from the chromatin surface. A gradual increase in the extracellular morphogen concentration causes a corresponding increase in the number of the nuclear molecules and the resulting bigger force pushes the Hox cluster toward the interchromatin domain. The step‐by‐step translocations of the Hox cluster initiate the consecutive exposure of genes to their transcription factors. The model explains how gene activation is triggered and it describes spatial, temporal and quantitative collinearities at the initial stages of gene expression. Some recent experiments of Hox deletions and duplications are accounted for by the model. BioEssays 26:189–195, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Biomedical science has been remarkably successful in explaining illness by categorizing diseases and then by identifying localizable lesions such as a virus and neoplasm in the body that cause those diseases. Not surprisingly, researchers have aspired to apply this powerful paradigm to addiction. So, for example, in a review of the neuroscience of addiction literature, Hyman and Malenka (2001, p. 695) acknowledge a general consensus among addiction researchers that “[a]ddiction can appropriately be considered as a chronic medical illness.” Like other (...) diseases, “Once addiction has taken hold, it tends to follow a chronic course.” (Koob and La Moal 2006, p. ?). Working from this perspective, much effort has gone into characterizing the symptomology of addiction and the brain changes that underlie them. Evidence for involvement of dopamine transmission changes in the ventral tegmental area (VTA) and nucleus accumbens (NAc) have received the greatest attention. Kauer and Malenka (2007, p. 844) put it well: “drugs of abuse can co-opt synaptic plasticity mechanisms in brain circuits involved in reinforcement and reward processing”. Our goal in this chapter to provide an explicit description of the assumptions of medical models, the different forms they may take, and the challenges they face in providing explanations with solid evidence of addiction. <br>. (shrink)

Because little is known about the human trait of affiliation, we provide a novel neurobehavioral model of affiliative bonding. Discussion is organized around processes of reward and memory formation that occur during approach and consummatory phases of affiliation. Appetitive and consummatory reward processes are mediated independently by the activity of the ventral tegmental area (VTA) dopamine (DA)–nucleus accumbens shell (NAS) pathway and the central corticolimbic projections of the u-opiate system of the medial basal arcuate nucleus, respectively, although (...) these two projection systems functionally interact across time. We next explicate the manner in which DA and glutamate interact in both the VTA and NAS to form incentive-encoded contextual memory ensembles that are predictive of reward derived from affiliative objects. Affiliative stimuli, in particular, are incorporated within contextual ensembles predictive of affiliative reward via: (a) the binding of affiliative stimuli in the rostral circuit of the medial extended amygdala and subsequent transmission to the NAS shell; (b) affiliative stimulus-induced opiate potentiation of DA processes in the VTA and NAS; and (c) permissive or facilitatory effects of gonadal steroids, oxytocin (in interaction with DA), and vasopressin on (i) sensory, perceptual, and attentional processing of affiliative stimuli and (ii) formation of social memories. Among these various processes, we propose that the capacity to experience affiliative reward via opiate functioning has a disproportionate weight in determining individual differences in affiliation. We delineate sources of these individual differences, and provide the first human data that support an association between opiate functioning and variation in trait affiliation. Key Words: affiliation corticolimbic-striatal networks; appetitive and consummatory reward; dopamine; oxytocin; personality; social bonds; social memory; u-opiates. (shrink)

This aricle discusses the similarity between the propagation of pathogens (viruses and worms) on computer networks and the proliferation of pathogens in cellular organisms (organisms with genetic material contained within a membrane-encased nucleus). It introduces several biological mechanisms which are used in these organisms to protect against such pathogens and presents security models for networked computers inspired by several biological paradigms, including genomics (RNA interference), proteomics (pathway mapping), and physiology (immune system). In addition, the study of epidemiological models for (...) disease control can inspire methods for controlling the spread of pathogens across multiple nodes of a network. It also presents results based on the authors’ research in immune system modeling. (shrink)

This bibliographical review of the modelling of the mitotic apparatus covers a period of one hundred and twenty years, from the discovery of the bipolar mitotic spindle up to the present day. Without attempting to be fully comprehensive, it will describe the evolution of the main ideas that have left their mark on a century of experimental and theoretical research. Fol and Bütschli's first writings date back to 1873, at a time when Schleiden and Schwann's cell theory was rapidly gaining (...) ground throughout Germany. Both mitosis and chromosomes were to be discovered within the space of thirty years, along with the two key events in the animal and plant reproductive cycle, namely fecondation and meiosis. The mitotic pole, a term still in use to this day, was employed to describe a morphological fact which was noted as early as 1876, namely that the lines and the dots of the karyokinetic figure, with its spindle and asters, looks remarkably like the lines of force around a bar magnet. This was to lead to models designed to explain the movements of chromosomes which take place when the cell nucleus appears to cease to exist as an organelle during mitosis. The nature of those mechanisms and the origin of the forces behind the chromosomes' ordered movements were central to the debate. Auguste Prenant, in a remarkable bibliographical synthesis published in 1910, summed up the opposing viewpoints of the vitalists, on the one hand, who favoured the theory of contractility or extensility in spindle fibres, and of those who believed in models based on physical phenomena, on the other. The latter subdivided into two groups: some, like Bütschli, Rhumbler or Leduc, referred to diffusion, osmosis and superficial tension, whilst the others, led by Gallardo and Hartog, focussed on the laws of electromagnetism. Lillie, Kuwada and Darlington followed up this line of research. The mid-20th century was a major turning point. Most of the modelling mentioned above was criticized and fell into disuse after disappearing from research publications and textbooks.This marked the onset of a new era, as electron microscopes made possible the materialization and detailed study of the macromolecular elements of the fibres, filaments and microtubules of the cytoskeleton. The successive phases of (a) de Harven and Bernhard's 1956 discovery of the centriole's ultrastructure, (b) its identification with the basal body of the cilia and flagella, confirming the theory set out by Henneguy and von Lenhossek (1898–99), (c) the universal presence of microtubules in animal, vegetal and eukaryotic protist cells, (d) the polymerization-depolymerization induced reversible transformations of the tubulin pool in mitosing cells (Inoue, 1960), (e) ultrastructural comparative studies of the mitotic apparatus of eukaryotes illustrating the Pickett-Heaps integrating concept of the MTOC (microtubule-organizing centre), (f) the possibility ofin vitro experiments on mtocs or on microtubules, brings us upon the present day, which has seen the focus placed on the concept of motor-proteins (kinesin, dynein) and on cell cycle models. The latter are based on a close coincidence between the observable modifications of the mitotic apparatus and the periodic variations in intracellular concentrations of calcium or of certain enzymes (cyclins, Cdc2) during the main transitions of the cell cycle. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Philosophy, Psychiatry, & Psychology 9.3 (2002) 219-227 [Access article in PDF] The Practical Kinds Model as a Pragmatist Theory of Classification Peter Zachar Pragmatist theories of scientific classification are intended to be pluralistic models that recognize different ways of cutting up the world as valuable, but do not require us to adopt whatever-goes relativism or metaphysical antirealism. How ironic that my application of pragmatism to psychopathology has been (...) charged with not being sufficiently pluralistic because it tries to fit all psychiatric disorders into the Procrustean bed of practical kinds. The Practical Kinds Model in General As a point of clarification, the practical kinds model is not a description of a type of category combined with an argument that all psychiatric disorders should be seen as belonging to that type. If it were that kind of model, I would fully agree with Haslam that practical kinds, fuzzy kinds, and discrete kinds are all potential types of psychiatric disorders. Like Nick Haslam, I believe that there are many different things in the DSM-IV and the ICD-10, and they cannot neatly be classified as the same type of thing.Rather than identifying a type of category, the practical kinds model is a general theory of scientific classification. It is a nonessentialistic theory. Essentialism is the view that things have real essences. In the Aristotelian version of essentialism, an essence is an internal structure, and it is the internal structure that makes anything be the kind of thing it really is. In this classical category model, category members either have the essence or they do not, and everything that has the appropriate essence is a member of that category. The world is supposed to therefore have a well-defined structure, and the job of the scientist is to discover that structure. Ian Hacking (1999) has termed this view of categorization inherent structurism.The practical kinds model does not deny that things have internal structures; it only denies that internal structure by itself determines category membership. Internal structure is an important consideration in identifying categories, but external criteria can always play a role. External or relational criteria play more important roles in some cases than they do in others, but they cannot be eliminated once and for all. Essentialistic theories, which favor an almost exclusive focus on inherent structures, have the advantage of being more parsimonious, but they do so by ignoring real complexity.The best way to illustrate this point is to examine a category whose identification is heavily weighted in terms of internal criteria, or an inherent structure, such as a chemical element. [End Page 219] For example, hydrogen is defined as the element that has an atomic number of 1. This means that it has one proton in its nucleus and normally one electron orbiting its nucleus. The atomic number reflects an internal property, and anything that has an atomic number of 1 is hydrogen. The same is true for the other elements. Anything that has an atomic number of 79 is gold; anything that has an atomic number of 19 is potassium, and so on. Also part of the essentialistic view is the notion that all the important properties of an element are systematically (or lawfully) related to its internal structure.It would be foolish to deny the practical utility of the atomic theory of chemistry. But even in this strongest of cases, external criteria can potentially play a role in how we decide to carve up the world and what we identify as the relevant categories. The point can be clearly illustrated with a Gedanken experiment based on the ideas of Donnellan (1983). Assume that we were to make contact with extraterrestrial life, and the result of that contact was our initiation into a larger galactic community like those portrayed on Star Trek or Babylon 5. Fortunately for us, it turns out that all planets in the community use a gold-based currency, just like we do on Earth. What we call gold, however, is too common to be the galactic basis of a currency, but a particular isotope... (shrink)

All animals have evolved solutions to manage their genomes, enabling the efficient organization of meters of DNA strands in the nucleus and allowing for nuanced regulation of gene expression while keeping transposable elements suppressed. Epigenetic modifications are central to accomplishing all these. Recent advances in sequencing technologies and the development of techniques that profile epigenetic marks and chromatin accessibility using reagents that can be used in any species has catapulted epigenomic studies in diverse animal species, shedding light on the (...) multitude of epigenomic mechanisms utilized across the evolutionary tree. Now, comparative epigenomics is a rapidly growing field that is uncovering mechanistic aspects of epigenetic modifications and chromatin organization in non‐model invertebrates, ranging from octopus to sponges. This review puts recent discoveries in the epigenetics of non‐model invertebrates in historical context, and describes new insight into the patterning and functions of DNA methylation and other highly conserved epigenetic modifications. (shrink)

A brief review is given of the continuous spontaneous localization (CSL) model, in which a classical field interacts with quantized particles to cause dynamical wavefunction collapse. One of the model's predictions is that particles “spontaneously” gain energy at a slow rate. When applied to the excitation of a nucleon in a Ge nucleus, it is shown how a limit on the relative collapse rates of neutron and proton can be obtained, and a rough estimate is made from (...) data. When applied to the spontaneous excitation of 1s electrons in Ge, by a more detailed analysis of more accurate data than given previously, an updated limit is obtained on the relative collapse rates of the electron and proton, suggesting that the coupling of the field to electrons and nucleons is mass proportional. (shrink)

Sickle cell haemoglobin polymerization reduces erythrocyte deformability, causing deleterous vaso-occlusions. The double-nucleation model states that polymers grow from HbS aggregates, the nuclei, in solution , onto existing polymers . When linearized at initial HbS concentration, this model predicts early polymerization and its characteristic delay-time :591–610, 611–631, 1985). Addressing its relevance for describing complete polymerization, we constructed the full, non-linearized model . Here, we compare the simulated outputs to experimental progress curves . Within 10% from start, average root (...) mean square deviation between simulated and experimental curves is 0.04 ± 0.01 . Conversely, for complete progress curves, averaged rms is 0.48 ± 0.04. This figure is improved to 0.13 ± 0.01 by adjusting heterogeneous pathway parameters : the nucleus stability , and the fraction of polymer surface available for nucleation , from 5e−7, to 13 . Similar results are obtained at 37°C. We conclude that the physico-chemical description of heterogeneous nucleation warrants refinements in order to capture the whole HbS polymerization process. (shrink)

This article introduces practical and theoretical investigations in fields of art and technology related to biotelematics, hybridization and transcultural experimentation based on research carried out over the last four years at the Nucleus of Art and New Organisms (NANO). We will approach this subject by considering three main points of view: field theory (Ascott 1980; Nóbrega 2009); the concept of coherence (Ho 1993; Ho & Popp 1989; Simondon 1980); and the state of connectedness (Ascott 2006). These will act as (...) integrative models for the understanding of an emerging hybrid organic structure presented as an aesthetic organism (Nóbrega 2009). The concept of field theory is applied as a working model for the systemic role of information within the immaterial, invisible, dynamical flow that intercommunicates natural (i.e. humans and other living systems) and artificial (i.e. machine) organisms in the process of invention, as well as in the fruition of artwork. In terms of the concept of coherence, we propose the idea of artworks as transducers of energy; more specifically, as resonators of coherent fields that interconnect the artist and audience in an integrated, dynamical whole. Furthermore, we approach the state of connectedness as a fundamental notion for the dynamics involved in the invention, exhibition and absorption of contemporary artworks. NANO Lab’s involvement with artistic research is not only understood as a physical space for experimentation, but also as an environment in which our practice reflects concepts applied in artistic work. In this sense, we can highlight two theoretical references (other than Roy Ascott’s work) which guide this methodology: Humberto Maturana (2001; Varela & Maturana 1992) and the idea of a conserved ‘autopoiesis’, a systematic medium (space) in which all recursive dynamics of reciprocal interactions occur to sustain the survival of life, processes and systems, and where technology can be conceived as a powerful instrument/medium to expand our knowledge about structural and sensitive coherences within living and non-living systems; and, Jorge de Albuquerque Vieira’s (2006; 2009) approach to art as a type of knowledge related to any process that guarantees the permanence or survival of a system based on three major characteristics for the survival of an open system – sensitivity (to operate information flows), memory (to transfer and retain information), and capability (to elaborate or prepare information according to its needs). (shrink)

This article addresses the historical problem of how it was possible for Lise Meitner and her nephew Otto Robert Frisch to arrive at their novel interpretation of nuclear fission at the end of 1938. To understand this requires an analysis of the origin and subsequent development of the liquid-drop model of the nucleus. We begin by discussing George Gamow’s conception of the liquid-drop model in 1928 and then explore its extension, particularly by Werner Heisenberg and Carl Friedrich (...) von Weizsäcker, between 1933 and 1936. We then examine the role played by the liquid-drop model in Niels Bohr’s theory of the compound nucleus between 1936 and 1938. We argue that these two stages in the development of the liquid-drop model focused on two distinctly different features of the model, its static and dynamic characteristics, which were employed to understand two distinctly different phenomena, nuclear mass defects and nuclear reactions and excitations. The liquid-drop model thus became embedded in two distinctly different scientific traditions. We conclude by showing how these two traditions merged in the minds of Meitner and Frisch, leading them to their interpretation of nuclear fission. (shrink)

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

How environmental mechanical forces affect cellular functions is a central problem in cell biology. Theoretical models of cellular biomechanics provide relevant tools for understanding how the contributions of deformable intracellular components and specific adhesion conditions at the cell interface are integrated for determining the overall balance of mechanical forces within the cell. We investigate here the spatial distributions of intracellular stresses when adherent cells are probed by magnetic twisting cytometry. The influence of the cell nucleus stiffness on the simulated (...) nonlinear torque-bead rotation response is analyzed by considering a finite element multi-component cell model in which the cell and its nucleus are considered as different hyperelastic materials. We additionally take into account the mechanical properties of the basal cell cortex, which can be affected by the interaction of the basal cell membrane with the extracellular substrate. In agreement with data obtained on epithelial cells, the simulated behaviour of the cell model relates the hyperelastic response observed at the entire cell scale to the distribution of stresses and strains within the nucleus and the cytoskeleton, up to cell adhesion areas. These results, which indicate how mechanical forces are transmitted at distant points through the cytoskeleton, are compared to recent data imaging the highly localized distribution of intracellular stresses. (shrink)

A brief review is given of the continuous spontaneous localization (CSL) model, in which a classical field interacts with quantized particles to cause dynamical wavefunction collapse. One of the model's predictions is that particles “spontaneously” gain energy at a slow rate. When applied to the excitation of a nucleon in a Ge nucleus, it is shown how a limit on the relative collapse rates of neutron and proton can be obtained, and a rough estimate is made from (...) data. When applied to the spontaneous excitation of 1s electrons in Ge, by a more detailed analysis of more accurate data than given previously, an updated limit is obtained on the relative collapse rates of the electron and proton, suggesting that the coupling of the field to electrons and nucleons is mass proportional. (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)

The ascription of intentional states to the self involves knowledge, or at least claims to knowledge. Armed with the working definition of knowledge as 'the ability to do things, or refrain from doing things, or believe, or want, or doubt things, for reasons that are facts' [Hyman, J. Philos. Quart. 49:432—451], I sketch a simple competence model of acting and believing from knowledge and when knowledge is defeated by un-experienced changes of state. The model takes the form of (...) three concentric circles. The 'periphery' is analogous to Fodor's [(1983), The modularity of mind. MIT Press, Cambridge, MA] input systems. The 'core' contains copies of peripheral representations, and between these representations there is executive competition. At the 'nucleus', operations are performed on the core representations of, at least, negation and recursion. I argue that this provides a fruitful way in which to conceptualise why theory-of-mind tasks challenge pre-school children, how some degree of first-person authority is mental state attribution is possible, and how executive inhibition is achieved. (shrink)

Previous research on the neural basis of cognitive control processes has mainly focused on cortical areas, while the role of subcortical structures in cognitive control is less clear. Models of basal ganglia function as well as clinical studies in neurodegenerative diseases suggest that the striatum (putamen and caudate nucleus) modulates the inhibition of interfering responses and thereby contributes to an important aspect of cognitive control, namely response interference control. To further investigate the putative role of the striatum in the (...) control of response interference, 23 patients with stroke-induced lesions of the striatum and 32 age-matched neurologically healthy controls performed a unimanual version of the Simon task. In the Simon task, the correspondence between stimulus location and response location is manipulated so that control over response interference can be inferred from the reaction time costs in incongruent trials. Results showed that stroke patients responded overall slower and more erroneous than controls. The difference in response times (RTs) between incongruent and congruent trials (known as the Simon effect) was smaller in the ipsilesional/-lateral hemifield, but did not differ significantly between groups. However, in contrast to controls, stroke patients exhibited an abnormally stable Simon effect across the reaction time distribution indicating a reduced efficiency of the inhibition process. Thus, in stroke patients unilateral lesions of the striatum did not significantly impair the general ability to control response interference, but led to less efficient selective inhibition of interfering responses. (shrink)

In the wake of recent advancements in the field of AI, this paper investigates the impact of recommender systems and generative models on human decisional and creative autonomy. For this purpose, we adopt Dennett’s conception of autonomy as self-control. We show that recommender systems can play a double role in relation to decisional autonomy: as information filter, they can augment self-control in decision-making, but also act as mechanisms of remote control that clamp degrees of freedom. As for generative models in (...) AI, we show that they can be seen as a powerful system of selection and suggestion (similar to standard recommender systems) but also as an instrument for information production. We suggest that the latter perspective opens new possibilities in terms of creative autonomy. Additionally, for both systems we propose a distinction between “extrinsic” and “intrinsic” mechanisms and effects. Through Dennett’s theory of self-control, this paper offers new insights into the relation between AI and human autonomy by framing it in terms of remote or self-control and by addressing the impact of generative models on creative autonomy. (shrink)

In the present study, we have demonstrated hysteresis phenomena in the excitability of single, enzymatically dissociated guinea pig ventricular myocytes. Membrane potentials were recorded with patch pipettes in the whole-cell current clamp configuration. Repetitive stimulation with depolarizing current pulses of constant cycle length and duration but varying strength led to predictable excitation (1:l) and non-excitation (1:0) patterns depending on current strength. In addition, transition between patterns depended on the direction of current intensity change and stable hysteresis loops were obtained in (...) stimulus:response pattern vs. current intensity plots in 14 cells. Increase of pulse duration and decrease of stimulation rate contributed to a reduction in hysteresis loop areas. Changes in amplitude and shape of the subthreshold responses during the transitions from one stable pattern to the other, suggested that activity led to an increase in membrane resistance, particularly in the voltage domain between resting potential, and threshold. Therefore, we modelled the dynamic behaviour of the single cells as a function of diastolic membrane resistance, using previously published analytical solutions. Numerical iteration of the analytical model equations closely reproduced the experimental hysteresis loops in both qualitative and quantitative ways. In particular, the effect of stimulation frequency on the model was similar to the experimental findings. The overall study suggests that the excitability pattern of guinea pig ventricular myocytes accounts for hysteresis and bistabilities when current intensity is allowed to fluctuate around threshold levels. (shrink)

The complete sequencing of the genome of the fruit fly Drosophila melanogaster offers the prospect of detailed functional analysis of the extensive gene families in this genetic model organism. Comprehensive functional analysis of family members is facilitated by access to a robust, stable and inducible expression system in a fly cell line. Here we show how the Schneider S2 cell line, derived from the Drosophila embryo, provides such an expression system, with the bonus that radioligand binding studies, second messenger (...) assays, ion imaging, patch‐clamp electrophysiology and gene silencing can readily be applied. Drosophila is also ideal for the study of new control strategies for insect pests since the receptors and ion channels that many new animal health drugs and crop protection chemicals target can be expressed in this cell line. In addition, many useful orthologues of human disease genes are emerging from the Drosophila genome and the study of their functions and interactions is another area for postgenome applications of S2 cell lines. BioEssays 24:1066–1073, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

We present a population density and moment-based description of the stochastic dynamics of domain $${\text{Ca}}^{2+}$$ -mediated inactivation of L-type $${\text{Ca}}^{2+}$$ channels. Our approach accounts for the effect of heterogeneity of local $${\text{Ca}}^{2+}$$ signals on whole cell $${\text{Ca}}^{2+}$$ currents; however, in contrast with prior work, e.g., Sherman et al. :985–995, 1990), we do not assume that $${\text{Ca}}^{2+}$$ domain formation and collapse are fast compared to channel gating. We demonstrate the population density and moment-based modeling approaches using a 12-state Markov chain (...) class='Hi'>model of an L-type $${\text{Ca}}^{2+}$$ channel introduced by Greenstein and Winslow :2918–2945, 2002). Simulated whole cell voltage clamp responses yield an inactivation function for the whole cell $${\text{Ca}}^{2+}$$ current that agrees with the traditional approach when domain dynamics are fast. We analyze the voltage-dependence of $${\text{Ca}}^{2+}$$ inactivation that may occur via slow heterogeneous domain [ $${\text{Ca}}^{2+}$$ ]. Next, we find that when channel permeability is held constant, $${\text{Ca}}^{2+}$$ -mediated inactivation of L-type channels increases as the domain time constant increases, because a slow domain collapse rate leads to increased mean domain [ $${\text{Ca}}^{2+}$$ ] near open channels; conversely, when the maximum domain [ $${\text{Ca}}^{2+}$$ ] is held constant, inactivation decreases as the domain time constant increases. Comparison of simulation results using population densities and moment equations confirms the computational efficiency of the moment-based approach, and enables the validation of two distinct methods of truncating and closing the open system of moment equations. In general, a slow domain time constant requires higher order moment truncation for agreement between moment-based and population density simulations. (shrink)

Childhood adversity is associated with altered or dysregulated stress reactivity; these altered patterns of physiological functioning persist into adulthood. Evidence from both preclinical animal models and human neuroimaging studies indicates that early life experience differentially influences stressor-evoked activity within central visceral neural circuits proximally involved in the control of stress responses, including the subgenual anterior cingulate cortex (sgACC), paraventricular nucleus of the hypothalamus (PVN), bed nucleus of the stria terminalis (BNST) and amygdala. However, the relationship between childhood adversity (...) and the resting-state connectivity of this central visceral network remains unclear. To this end, we examined relationships between childhood threat and childhood socioeconomic deprivation, the resting-state connectivity between our regions of interest (ROIs), and affective symptom severity and diagnoses. We recruited a transdiagnostic sample of young adult males and females (n= 100; mean age = 27.28,SD= 3.99; 59 females) with a full distribution of maltreatment history and symptom severity across multiple affective disorders. Resting-state data were acquired using a 7.2-min functional magnetic resonance imaging (fMRI) sequence; noted ROIs were applied as masks to determine ROI-to-ROI connectivity. Threat was determined by measures of childhood traumatic events and abuse. Socioeconomic deprivation (SED) was determined by a measure of childhood socioeconomic status (parental education level). Covarying for age, race and sex, greater childhood threat was significantly associated with lower BNST-PVN, amygdala-sgACC and PVN-sgACC connectivity. No significant relationships were found between SED and resting-state connectivity. BNST-PVN connectivity was associated with the number of lifetime affective diagnoses. Exposure to threat during early development may entrain altered patterns of resting-state connectivity between these stress-related ROIs in ways that contribute to dysregulated neural and physiological responses to stress and subsequent affective psychopathology. (shrink)

Subthalamic nucleus deep brain stimulation is an established therapy for Parkinson’s disease motor symptoms. The ideal site for implantation within STN, however, remains controversial. While many argue that placement of a DBS lead within the sensorimotor territory of the STN yields better motor outcomes, others report similar effects with leads placed in the associative or motor territory of the STN, while still others assert that placing a DBS lead “anywhere within a 6-mm-diameter cylinder centered at the presumed middle of (...) the STN produces similar clinical efficacy.” These discrepancies likely result from methodological differences including targeting preferences, imaging acquisition and the use of brain atlases that do not account for patient-specific anatomic variability. We present a first-in-kind within-patient demonstration of severe mood side effects and minimal motor improvement in a Parkinson’s disease patient following placement of a DBS lead in the limbic/associative territory of the STN who experienced marked improvement in motor benefit and resolution of mood side effects following repositioning the lead within the STN sensorimotor territory. 7 Tesla magnetic resonance imaging data were used to generate a patient-specific anatomical model of the STN with parcellation into distinct functional territories and computational modeling to assess the relative degree of activation of motor, associative and limbic territories. (shrink)

Humans’ interactions with each other or with socially competent machines exhibit lawful coordination patterns at multiple levels of description. According to Coordination Dynamics, such laws specify the flow of coordination states produced by functional synergies of elements (e.g., cells, body parts, brain areas, people…) that are temporarily organized as single, coherent units. These coordinative structures or synergies may be mathematically characterized as informationally coupled self-organizing dynamical systems (Coordination Dynamics). In this paper, we start from a simple foundation, an elemental (...) class='Hi'>model system for social interactions, whose behavior has been captured in the Haken-Kelso-Bunz (HKB) model. We follow a tried and tested scientific method that tightly interweaves experimental neurobehavioral studies and mathematical models. We use this method to further develop a body of empirical research that advances the theory toward more generalized forms. In concordance with this interdisciplinary spirit, the present paper is written both as an overview of relevant advances and as an introduction to its mathematical underpinnings. We demonstrate HKB’s evolution in the context of social coordination along several directions, with its applicability growing to increasingly complex scenarios. In particular, we show that accommodating for symmetry breaking in intrinsic dynamics and coupling, multiscale generalization and adaptation are principal evolutions. We conclude that a general framework for social coordination dynamics is on the horizon, in which models support experiments with hypothesis generation and mechanistic insights. (shrink)

Recent research on algebraic models of _quasi-Nelson logic_ has brought new attention to a number of classes of algebras which result from enriching (subreducts of) Heyting algebras with a special modal operator, known in the literature as a _nucleus_. Among these various algebraic structures, for which we employ the umbrella term _intuitionistic modal algebras_, some have been studied since at least the 1970s, usually within the framework of topology and sheaf theory. Others may seem more exotic, for their primitive operations (...) arise from algebraic terms of the intuitionistic modal language which have not been previously considered. We shall for instance investigate the variety of _weak implicative semilattices_, whose members are (non-necessarily distributive) meet semilattices endowed with a nucleus and an implication operation which is not a relative pseudo-complement but satisfies the postulates of Celani and Jansana’s strict implication. For each of these new classes of algebras we establish a representation and a topological duality which generalize the known ones for Heyting algebras enriched with a nucleus. (shrink)

Ojectives Low energy hip fractures are one of the greatest causes of morbidity and mortality in orthopaedics. This study aims to evaluate written consent forms with respect to basic standards as set out in the Good Practice in Consent Initiative. In particular the stated risks and benefits of each procedure were assessed. Methods 100 consecutive consent forms were reviewed prospectively. The stated procedure, side and complications were recorded. Appropriate signature and legibility was assessed. 13 consultant orthopaedic surgeons were surveyed to (...) identify what risks and benefits they thought should be stated. Results Of 100 consent forms, 31 were for patients who are unable to consent. All 100 consent forms were correctly filled in with patient details and signed. 98% were legible. All stated the side of the operation. The number of complications listed per form ranged from 4 to 11. Infection, bleeding and thromboembolic complications were stated in the majority of consent forms. In total, 30 different complications were recorded; some were only stated once. Discussion and Conclusions This work suggests consent forms are completed well with respect to patient identifiers, legibility and procedure. The variability of complications stated is vast. We suggest standard pre-printed consent forms containing risks and benefits should be used as this may improve standards of informed consent. This has also been recently supported by the British Orthopaedic Association. (shrink)

The lambda model predicts that the command received by each motor nucleus during locomotion is specific for the joint at which its muscle acts and is independent of external conditions. However, investigation of the commands received by motor nuclei during fictive locomotion and of the sensitivity of these commands to feedback from the limb during locomotion indicates that neither condition is satisfied.

According to the model presented in this paper, the beginning of life was marked by the coupling of two complementary nucleotide bases: adenine and thymine. The adenine-thymine system received photons from the sun and stored their energy in the form of a chemical high-energy bond between two phosphoric acid molecules, which were before-hand fixed by adenine from the aqueous environment. The energy of the high-energy bond was then delivered in the form of two waves of electronic excitation. These were (...) utilized to synthesize new molecules, starting from the carbonic acid and ammonia molecules, fixed from the aqueous environment by the polar groups of the nucleotide bases. In this way, a nucleotides-histone protosystem was self-synthesized, evolving step by step towards complexity, by means of some internal cybernetic and informational mechanisms. During its evolution, the NHPS synthesized a limiting membrane, produced the organizing elements of the cellular organelles and constructed microtubules and microfilaments. Subsequently, the NHPS evolved to the building of DNA-histone system and formed the cellular nucleus. (shrink)

The suggested model is discussed with reference to two clinical populations with memory disorders – patients with misidentification syndromes and those with source memory impairment, both of whom may present with (broadly conceived) déjà vu phenomenon, without insight into false feeling of familiarity. The role of the anterior thalamic nucleus and retrosplenial cortex for autobiographical memory and familiarity is highlighted.

Considerable evidence from preclinical and clinical investigations implicates disturbances of brain dopamine (DA) function in the pathophysiology of several psychiatric and neurologic disorders. We describe a neural model that may help organize theseindependent experimental observations. Cortical regions classically associated with the limbic system interact with infracortical structures, including the nucleus accumbens, ventral pallidum, and dorsomedial nucleus of the thalamus. In our model, overactivity in forebrain DA systems results in the loss of lateral inhibitory interactions in the (...) nucleus accumbens, causing disinhibition of pallidothalamic efferents; this in turn causes rapid changes and a loss of focused corticothalamic activity in cortical regions controlling cognitive and emotional processes. These effects might be manifested clinically by some symptoms of psychoses. Underactivity of forebrain DA results in excess lateral inhibition in the nucleus accumbens, causing tonic inhibition of pallidothalamic efferents; this perpetuates tonic corticothalamic activity and prevents the initiation of new activity in other critical cortical regions. These effects might be manifested clinically by some symptoms of depression. This model parallels existing explanations for the etiology of several movement disorders, and may lead to testable inferences regarding the neural substrates of specific psychopathologies. (shrink)

ABSTRACT I argue that this examination and appreciation for the shift to abductive reasoning should be extended to the intersection of neuroscience and novel brain-computer interfaces too. This paper highlights the implications of applying abductive reasoning to personalized implantable neurotechnologies. Then, it explores whether abductive reasoning is sufficient to justify insurance coverage for devices absent widespread clinical trials, which are better applied to one-size-fits-all treatments. INTRODUCTION In contrast to the classic model of randomized-control trials, often with a large number (...) of subjects enrolled, precision medicine attempts to optimize therapeutic outcomes by focusing on the individual.[i] A recent publication highlights the strengths and weakness of both traditional evidence-based medicine and precision medicine.[ii] Plus, it outlines a tension in the shift from evidence-based medicine’s inductive reasoning style (the collection of data to postulate general theories) to precision medicine’s abductive reasoning style (the generation of an idea from the limited data available).[iii] The paper’s main example is the application of precision medicine for the treatment of cancer.[iv] I argue that this examination and appreciation for the shift to abductive reasoning should be extended to the intersection of neuroscience and novel brain-computer interfaces too. As the name suggests, brain-computer interfaces are a significant advancement in neurotechnology that directly connects someone’s brain to external or implanted devices.[v] Among the various kinds of brain-computer interfaces, adaptive deep brain stimulation devices require numerous personalized adjustments to their settings during the implantation and computation stages in order to provide adequate relief to patients with treatment-resistant disorders. What makes these devices unique is how adaptive deep brain stimulation integrates a sensory component to initiate the stimulation. While not commonly at the level of sophistication as self-supervising or generative large language models,[vi] they currently allow for a semi-autonomous form of neuromodulation. This paper highlights the implications of applying abductive reasoning to personalized implantable neurotechnologies. Then, it explores whether abductive reasoning is sufficient to justify insurance coverage for devices absent widespread clinical trials, which are better applied to one-size-fits-all treatments.[vii] ANALYSIS I. The State of Precision Medicine in Oncology and the Epistemological Shift While a thorough overview of precision medicine for the treatment of cancer is beyond the scope of this article, its practice can be roughly summarized as identifying clinically significant characteristics a patient possesses (e.g., genetic traits) to land on a specialized treatment option that, theoretically, should benefit the patient the most.[viii] However, in such a practice of stratification patients fall into smaller and smaller populations and the quality of evidence that can be applied to anyone outside these decreases in turn.[ix] As inductive logic helps to articulate, the greater the number of patients that respond to a particular therapy the higher the probability of its efficacy. By straying from this logical framework, precision medicine opens the treatment of cancer to more uncertainty about the validity of these approaches to the resulting disease subcategories.[x] Thus, while contemporary medical practices explicitly describe some treatments as “personalized”, they ought not be viewed as inherently better founded than other therapies.[xi] A relevant contemporary case of precision medicine out of Norway focuses on the care of a patient with cancer between the ventricles of the heart and esophagus, which had failed to respond to the standard regimen of therapies over four years.[xii] In a last-ditch effort, the patient elected to pay out-of-pocket for an experimental immunotherapy (nivolumab) at a private hospital. He experienced marked improvements and a reduction in the size of the tumor. Understandably, the patient tried to pursue further rounds of nivolumab at a public hospital. However, the hospital initially declined to pay for it given the “lack of evidence from randomised clinical trials for this drug relating to this [patient’s] condition.”[xiii] In rebuttal to this claim, the patient countered that he was actually similar to a subpopulation of patients who responded in “open‐label, single arm, phase 2 studies on another immune therapy drug” (pembrolizumab).[xiv] Given this interpretation of the prior studies and the patient’s response, further rounds of nivolumab were approved. Had the patient not had improvements in the tumor’s size following a round of nivolumab, then pembrolizumab’s prior empirical evidence in isolation would have been insufficient, inductively speaking, to justify his continued use of nivolumab.[xv] The case demonstrates a shift in reasoning from the traditional induction to abduction. The phenomenon of ‘cancer improvement’ is considered causally linked to nivolumab and its underlying physiological mechanisms.[xvi] However, “the weakness of abductions is that there may always be some other better, unknown explanation for an effect. The patient may for example belong to a special subgroup that spontaneously improves, or the change may be a placebo effect. This does not mean, however, that abductive inferences cannot be strong or reasonable, in the sense that they can make a conclusion probable.”[xvii] To demonstrate the limitations of relying on the abductive standard in isolation, commentators have pointed out that side effects in precision medicine are hard to rule out as being related to the initial intervention itself unless trends from a group of patients are taken into consideration.[xviii] As artificial intelligence (AI) assists the development of precision medicine for oncology, this uncertainty ought to be taken into consideration. The implementation of AI has been crucial to the development of precision medicine by providing a way to combine large patient datasets or a single patient with a large number of unique variables with machine learning to recommend matches based on statistics and probability of success upon which practitioners can base medical recommendations.[xix] The AI is usually not establishing a causal relationship[xx] – it is predicting. So, as AI bleeds into medical devices, like brain-computer interfaces, the same cautions about using abductive reasoning alone should be carried over. II. Responsive Neurostimulation, AI, and Personalized Medicine Like precision medicine in cancer treatment, computer-brain interface technology similarly focuses on the individual patient through personalized settings. In order to properly expose the intersection of AI, precision medicine, abductive reasoning, and implantable neurotechnologies, the descriptions of adaptive deep brain stimulation systems need to deepen.[xxi] As a broad summary of adaptive deep brain stimulation, to provide a patient with the therapeutic stimulation, a neural signal, typically referred to as a local field potential,[xxii] must first be detected and then interpreted by the device. The main adaptive deep brain stimulation device with premarket approval, the NeuroPace Responsive Neurostimulation system, is used to treat epilepsy by detecting and storing “programmer-defined phenomena.”[xxiii] Providers can optimize the detection settings of the device to align with the patient’s unique electrographic seizures as well as personalize the reacting stimulation’s parameters.[xxiv] The provider adjusts the technology based on trial and error. One day machine learning algorithms will be able to regularly aid this process in myriad ways, such as by identifying the specific stimulation settings a patient may respond to ahead of time based on their electrophysiological signatures.[xxv] Either way, with AI or programmers, adaptive neurostimulation technologies are individualized and therefore operate in line with precision medicine rather than standard treatments based on large clinical trials. Contemporary neurostimulation devices are not usually sophisticated enough to be prominent in AI discussions where the topics of neural networks, deep learning, generative models, and self-attention dominate the conversation. However, implantable high-density electrocorticography arrays (a much more sensitive version than adaptive deep brain stimulation systems use) have been used in combination with neural networks to help patients with neurologic deficits from a prior stroke “speak” through a virtual avatar.[xxvi] In some experimental situations, algorithms are optimizing stimulation parameters with increasing levels of independence.[xxvii] An example of neurostimulation that is analogous to the use of nivolumab in Norway surrounds a patient in the United States who was experiencing both treatment-resistant OCD and temporal lobe epilepsy.[xxviii]Given the refractory nature of her epilepsy, implantation of an adaptive deep brain stimulation system was indicated. As a form of experimental therapy, her treatment-resistant OCD was also indicated for the off-label use of an adaptive deep brain stimulation set-up. Another deep brain stimulation lead, other than the one implanted for epilepsy, was placed in the patient’s right nucleus accumbens and ventral pallidum region given the correlation these nuclei had with OCD symptoms in prior research. Following this, the patient underwent “1) ambulatory, patient-initiated magnet-swipe storage of data during moments of obsessive thoughts; (2) lab-based, naturalistic provocation of OCD-related distress (naturalistic provocation task); and (3) lab-based, VR [virtual reality] provocation of OCD-related distress (VR provocation task).”[xxix] Such signals were used to identify when to deliver the therapeutic stimulation in order to counter the OCD symptoms. Thankfully, following the procedure and calibration the patient exhibited marked improvements in their OCD symptoms and recently shared her results publicly.[xxx] In both cases, there is a similar level of abductive justification for the efficacy of the delivered therapy. In the case study in which the patient was treated with adaptive deep brain stimulation, they at least had their neural activity tested in various settings to determine the optimum parameters for treatment to avoid them being based on guesswork. Additionally, the adaptive deep brain stimulation lead was already placed before the calibration trials were conducted, meaning that the patient had already taken on the bulk of the procedural risk before the efficacy could be determined. Such an efficacy test could have been replicated in the first patient’s cancer treatment, had it been biopsied and tested against the remaining immunotherapies in vitro. Yet, in the case of cancer with few options, one previous dose of a drug that appeared to work on the patient may justify further doses. However, as the Norwegian case presents, corroboration with known responses to a similar drug (from a clinical trial) could be helpful to validate the treatment strategy. (It should be noted that both patients were resigned to these last resort options regardless of the efficacy of treatment.) There are some elements of inductive logic seen with adaptive deep brain stimulation research in general. For example, abductively the focus could be that patient X’s stimulation parameters are different from patient Y’s and patient Z’s. In contrast, when grouped as subjects who obtained personalized stimulation, patients X, Y, and Z demonstrate an inductive aspect to this approach’s safety and/or efficacy. The OCD case holds plenty of abductive characteristics in line with precision medicine’s approach to treating cancer and as more individuals try the method, there will be additional data. With the gradual integration of AI into brain-computer interfaces in the name of efficacy, this reliance on abduction will continue, if not grow, over time. Moving forward, if a responsive deep brain stimulation treatment is novel and individualized (like the dose of nivolumab) and there is some other suggestion of efficacy (like clinical similarities to other patients in the literature), then it may justify insurance coverage for the investigative intervention, absent other unrelated reasons to deny it. III. Ethical Implications and Next Steps While AI’s use in oncology and neurology is not yet as prominent as its use in other fields (e.g., radiology), it appears to be on the horizon for both.[xxxi] AI can be found in both the functioning of the neurotechnologies as well as the implementation of precision medicine. The increasing use of AI may serve to further individualize both oncologic and neurological therapies. Given these implications and the handful of publications cited in this article, it is important to have a nuanced evaluation of how these treatments, which heavily rely on abductive justification, ought to be managed. The just use an abductive approach may be difficult as AI infused precision medicine is further pursued. At baseline, such technology relies on a level of advanced technology literacy among the general public and could exclude populations who lack access to basic technological infrastructure or know-how from participation.[xxxii] Even among nations with adequate infrastructure, as more patients seek out implantable neurotechnologies, which require robust healthcare resources, the market will favor patient populations that can afford this complex care.[xxxiii] If patients already have the means to pay for an initial dose/use of a precision medicine product out of pocket, should insurance providers be required to cover subsequent treatments?[xxxiv] That is, if a first dose of a cancer drug or a deep brain stimulator over its initial battery life is successful, patients may feel justified in having the costs of further treatments covered. The Norwegian patient’s experience implies there is a precedent for the idea that some public insurance companies ought to cover successful cancer therapies, however, insurance companies may not all see themselves as obligated to cover neurotechnologies that rely on personalized settings or that are based on precision/abductive research more than on clinical trials. CONCLUSION The fact that the cases outlined above rely on abductive style of reasoning implies that there may not be as strong a justification for coverage by insurance, as they are both experimental and individualized, when compared to the more traditional large clinical trials in which groups have the same or a standardized protocol (settings/doses). If a study is examining the efficacy of a treatment with a large cohort of patients or with different experimental groups/phases, insurance companies may conclude that the resulting symptom improvements are more likely to be coming from the devices themselves. A preference for inductive justification may take priority when ruling in favor of funding someone’s continued use of an implantable neurostimulator. There are further nuances to this discussion surrounding the classifications of these interventions as research versus clinical care that warrant future exploration, since such a distinction is more of a scale[xxxv] than binary and could have significant impacts on the “right-to-try” approach to experimental therapies in the United States.[xxxvi] Namely, given the inherent limitations of conducting large cohort trials for deep brain stimulation interventions on patients with neuropsychiatric disorders, surgically innovative frameworks that blend abductive and inductive methodologies, like with sham stimulation phases, have traditionally been used.[xxxvii] Similarly, for adaptive brain-computer interface systems, if there are no large clinical trials and instead only publications that demonstrate that something similar worked for someone else, then, in addition to the evidence that the first treatment/dose worked for the patient in question, the balance of reasoning would be valid and arguably justify insurance coverage. As precision approaches to neurotechnology become more common, frameworks for evaluating efficacy will be crucial both for insurance coverage and for clinical decision making. ACKNOWLEDGEMENT This article was originally written as an assignment for Dr. Francis Shen’s “Bioethics & AI” course at Harvard’s Center for Bioethics. I would like to thank Dr. Shen for his comments as well as my colleagues in the Lázaro-Muñoz Lab for their feedback. - [i] Jonathan Kimmelman and Ian Tannock, “The Paradox of Precision Medicine,” Nature Reviews. Clinical Oncology 15, no. 6 (June 2018): 341–42, https://doi.org/10.1038/s41571-018-0016-0. [ii] Henrik Vogt and Bjørn Hofmann, “How Precision Medicine Changes Medical Epistemology: A Formative Case from Norway,” Journal of Evaluation in Clinical Practice 28, no. 6 (December 2022): 1205–12, https://doi.org/10.1111/jep.13649. [iii] David Barrett and Ahtisham Younas, “Induction, Deduction and Abduction,” Evidence-Based Nursing 27, no. 1 (January 1, 2024): 6–7, https://doi.org/10.1136/ebnurs-2023-103873. [iv] Vogt and Hofmann, “How Precision Medicine Changes Medical Epistemology,” 1208. [v] Wireko Andrew Awuah et al., “Bridging Minds and Machines: The Recent Advances of Brain-Computer Interfaces in Neurological and Neurosurgical Applications,” World Neurosurgery, May 22, 2024, S1878-8750(24)00867-2, https://doi.org/10.1016/j.wneu.2024.05.104. [vi] Mark Riedl, “A Very Gentle Introduction to Large Language Models without the Hype,” Medium (blog), May 25, 2023, https://mark-riedl.medium.com/a-very-gentle-introduction-to-large-language-models-without-the-hype-5 f67941fa59e. [vii] David E. Burdette and Barbara E. Swartz, “Chapter 4 - Responsive Neurostimulation,” in Neurostimulation for Epilepsy, ed. Vikram R. Rao (Academic Press, 2023), 97–132, https://doi.org/10.1016/B978-0-323-91702-5.00002-5. [viii] Kimmelman and Tannock, 2018. [ix] Kimmelman and Tannock, 2018. [x] Simon Lohse, “Mapping Uncertainty in Precision Medicine: A Systematic Scoping Review,” Journal of Evaluation in Clinical Practice 29, no. 3 (April 2023): 554–64, https://doi.org/10.1111/jep.13789. [xi] Kimmelman and Tannock, “The Paradox of Precision Medicine.” [xii] Vogt and Hofmann, 1206. [xiii] Vogt and Hofmann, 1206. [xiv] Vogt and Hofmann, 1206. [xv] Vogt and Hofmann, 1207. [xvi] Vogt and Hofmann, 1207. [xvii] Vogt and Hofmann, 1207. [xviii] Vogt and Hofmann, 1210. [xix] Mehar Sahu et al., “Chapter Three - Artificial Intelligence and Machine Learning in Precision Medicine: A Paradigm Shift in Big Data Analysis,” in Progress in Molecular Biology and Translational Science, ed. David B. Teplow, vol. 190, 1 vols., Precision Medicine (Academic Press, 2022), 57–100, https://doi.org/10.1016/bs.pmbts.2022.03.002. [xx] Stefan Feuerriegel et al., “Causal Machine Learning for Predicting Treatment Outcomes,” Nature Medicine 30, no. 4 (April 2024): 958–68, https://doi.org/10.1038/s41591-024-02902-1. [xxi] Sunderland Baker et al., “Ethical Considerations in Closed Loop Deep Brain Stimulation,” Deep Brain Stimulation 3 (October 1, 2023): 8–15, https://doi.org/10.1016/j.jdbs.2023.11.001. [xxii] David Haslacher et al., “AI for Brain-Computer Interfaces,” 2024, 7, https://doi.org/10.1016/bs.dnb.2024.02.003. [xxiii] Burdette and Swartz, “Chapter 4 - Responsive Neurostimulation,” 103–4; “Premarket Approval (PMA),” https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P100026. [xxiv] Burdette and Swartz, “Chapter 4 - Responsive Neurostimulation,” 104. [xxv] Burdette and Swartz, 126. [xxvi] Sean L. Metzger et al., “A High-Performance Neuroprosthesis for Speech Decoding and Avatar Control,” Nature 620, no. 7976 (August 2023): 1037–46, https://doi.org/10.1038/s41586-023-06443-4. [xxvii] Hao Fang and Yuxiao Yang, “Predictive Neuromodulation of Cingulo-Frontal Neural Dynamics in Major Depressive Disorder Using a Brain-Computer Interface System: A Simulation Study,” Frontiers in Computational Neuroscience 17 (March 6, 2023), https://doi.org/10.3389/fncom.2023.1119685; Mahsa Malekmohammadi et al., “Kinematic Adaptive Deep Brain Stimulation for Resting Tremor in Parkinson’s Disease,” Movement Disorders 31, no. 3 (2016): 426–28, https://doi.org/10.1002/mds.26482. [xxviii] Young-Hoon Nho et al., “Responsive Deep Brain Stimulation Guided by Ventral Striatal Electrophysiology of Obsession Durably Ameliorates Compulsion,” Neuron 0, no. 0 (October 20, 2023), https://doi.org/10.1016/j.neuron.2023.09.034. [xxix] Nho et al. [xxx] Nho et al.; Erik Robinson, “Brain Implant at OHSU Successfully Controls Both Seizures and OCD,” OHSU News, accessed March 3, 2024, https://news.ohsu.edu/2023/10/25/brain-implant-at-ohsu-successfully-controls-both-seizures-and-ocd. [xxxi] Awuah et al., “Bridging Minds and Machines”; Haslacher et al., “AI for Brain-Computer Interfaces.” [xxxii] Awuah et al., “Bridging Minds and Machines.” [xxxiii] Sara Green, Barbara Prainsack, and Maya Sabatello, “The Roots of (in)Equity in Precision Medicine: Gaps in the Discourse,” Personalized Medicine 21, no. 1 (January 2024): 5–9, https://doi.org/10.2217/pme-2023-0097. [xxxiv] Green, Prainsack, and Sabatello, 7. [xxxv] Robyn Bluhm and Kirstin Borgerson, “An Epistemic Argument for Research-Practice Integration in Medicine,” The Journal of Medicine and Philosophy: A Forum for Bioethics and Philosophy of Medicine 43, no. 4 (July 9, 2018): 469–84, https://doi.org/10.1093/jmp/jhy009. [xxxvi] Vijay Mahant, “‘Right-to-Try’ Experimental Drugs: An Overview,” Journal of Translational Medicine 18 (June 23, 2020): 253, https://doi.org/10.1186/s12967-020-02427-4. [xxxvii] Michael S. Okun et al., “Deep Brain Stimulation in the Internal Capsule and Nucleus Accumbens Region: Responses Observed during Active and Sham Programming,” Journal of Neurology, Neurosurgery & Psychiatry 78, no. 3 (March 1, 2007): 310–14, https://doi.org/10.1136/jnnp.2006.095315. (shrink)

The contrast between the strategies of research employed in reductionism and holism masks a radical contradiction between two different scientific philosophies. We concentrate in particular on an analysis of the key philosophical issues which give structure to holistic thought. A first (non-exhaustive) analysis of the philosophical tradition will dwell upon: a) the theory of emergence: each level of organisation is characterised by properties whose laws cannot be deduced from the laws of the inferior levels of organisation (Engels, Morgan); b) clarification (...) of the relations between the “whole” and the “parts” (Woodger, Needham); c) the ontological or epistemological nature of the emergent properties; are they a phenomenological reality or solely an artefact of the state of our knowledge? (Pepper, Henle, Hempel and Oppenheim); d) the proposition of the holistic theoretical and methodological model ( Novikoff, Feibleman). I then go on to examine the differences that exist between the reductionist and the holistic approaches at various levels of analysis: that is to say, the differences which affect their ontologies, methodologies and epistemologies respectively. I attempt to understand the spirit of a holistic approach to ecology by analyzing the major work of E.P. Odum Fundamentals of ecology (1953, 1959, 1971). I set forward what might be meant by the “holistic approach”, which is implicated in all the different levels of organisation at which the problem of “complexity” is debated. Ecology presents itself as an “holistic science” and Odum’s book offers a vision of the world which dates far back in the history of philosophy. By looking at the three different editions of this fundamental text on ecology, we may become aware of the evolution of Odum’s thought. In fact, only in the third and last edition is there a conscious appropriation of the holistic approach (by using the theoretical models of Feibleman who, for his part, refers to Novikoff). However, even when formally referring to the theory of emergence (that is to say the ontological nucleus of every holistic approach), Odum’s systemic analysis presents the same logical errors, which push him back into the reductionist domain. Above all, in his examination of the main concepts of “population”, “community” and “ecosystem”, there is a misunderstanding of the profound difference between “collective properties” and “emergent properties”. Moreover, the cybernetic models of Odum’s systemic analysis (introduced into ecology by Margalef), allowed him to vastly oversimplify his methodological task: in fact, neither how many levels nor which levels of organization are fundamental for the study of each individual level is clearly marked. Finally, Odum analyses the ecosystem as composed of energetic flux and cycles of matter, referring to the trophic-dynamic vision of Lindeman. That is to say, in my opinion, he juxtaposes a reductionistic methodology and epistemology to an holistic ontology. (shrink)

The authors present a neurological theory of how cognitive information and emotional information are integrated in the nucleus accumbens during effective decision making. They describe how the nucleus accumbens acts as a gateway to integrate cognitive information from the ventromedial prefrontal cortex and the hippocampus with emotional information from the amygdala. The authors have modeled this integration by a network of spiking artificial neurons organized into separate areas and used this computational model to simulate 2 kinds of (...) cognitive–affective integration. The model simulates successful performance by people with normal cognitive–affective integration. The model also simulates the historical case of Phineas Gage as well as subsequent patients whose ability to make decisions became.. (shrink)

The pursuit of mechanistic explanations in biology has produced a great deal of knowledge about the parts, operations, and organization of mechanisms taken to be responsible for biological phenomena. Holist critics have often raised important criticisms of proposed mechanistic explanations, but until recently holists have not had alternative research strategies through which to advance explanations. This paper argues both that the results of mechanistic strategies has forced mechanists to confront ways in which whole systems affect their components and that new (...) representational and modeling strategies are providing tools for understanding these effects of whole systems upon components. Drawing from research on the mechanism responsible for circadian rhythms in mammals, I develop two examples in which mechanistic analysis is being integrated into a more holist perspective: research revealing intercellular integration of circadian mechanisms with those involved in cell metabolism and research revealing that stable␣rhythms are dependent on how individual cells in the suprachiasmatic nucleus synchronize with each other to generate regular rhythms. Tools such as network diagramming and computational modeling are providing means to integrate mechanistic models into accounts of whole systems. (shrink)

For two decades, the integrated causal model of evolutionary psychology (EP) has constituted an interdisciplinary nucleus around which a single unified theoretical and empirical behavioral science has been crystallizing – while progressively resolving problems (such as defective logical and statistical reasoning) that bedevil Gintis's beliefs, preferences, and constraints (BPC) framework. Although both frameworks are similar, EP is empirically better supported, theoretically richer, and offers deeper unification. (Published Online April 27 2007).

Between 1975 and 1985 a series of experiments demonstrated that cancer, whatever its causative agent, is due to the activation, by modification or overexpression, of a family of genes highly conserved during evolution, called the cellular oncogenes. These genes participate in the control of cell division in every living cell. Their products belong to the regulatory network relaying external signals from the membranes towards the nucleus and allowing cells to adapt their division rate to the demand of the organism. (...) These discoveries constitute what may be called the 'oncogene paradigm'. Although the existence of cellular oncogenes, assumed in early models of oncogenesis, was demonstrated as early as 1976, we will show in this article that this discovery was not sufficient for the development of the new paradigm. We will describe its slow and complex formation between 1980 and 1985 followed by its rapid acceptance by the scientific community. (shrink)

Plastids and mitochondria arose through endosymbiotic acquisition of formerly free-living bacteria. During more than a billion years of subsequent concerted evolution, the three genomes of plant cells have undergone dramatic structural changes to optimize the expression of the compartmentalized genetic material and to fine-tune the communication between the nucleus and the organelles. The chimeric composition of many multiprotein complexes in plastids and mitochondria (one part of the subunits being nuclear encoded and another one being encoded in the organellar genome) (...) provides a paradigm for co-evolution at the cellular level. In this paper, we discuss the co-evolution of nuclear and organellar genomes in the context of environmental adaptation in species and populations. We highlight emerging genetic model systems and new experimental approaches that are particularly suitable to elucidate the molecular basis of co-adaptation processes and describe how nuclear-cytoplasmic co-evolution can cause genetic incompatibilities that contribute to the establishment of hybridization barriers, ultimately leading to the formation of new species. (shrink)

Gender roles are anti-dichotomous and malleable social constructs that should theoretically be constructed independently from biological sex. However, it is unclear whether and how the factor of sex is related to neural mechanisms involved in social constructions of gender roles. Thus, the present study aimed to investigate sex specificity in gender role constructions and the corresponding underlying neural mechanisms. We measured gender role orientation using the Bem Sex-Role Inventory, used a voxel-based global brain connectivity method based on resting-state functional magnetic (...) resonance imaging to characterize the within-network connectivity in the brain reward network, and analyzed how the integration of the reward network is related to gender role scores between sex groups. An omnibus analysis of voxel-wise global brain connectivity values within a two-level linear mixed model revealed that in female participants, femininity scores were positively associated with integration in the posterior orbitofrontal cortex and subcallosal cortex, whereas masculinity scores were positively associated with integration in the frontal pole. By contrast, in male participants, masculinity was negatively correlated with integration in the nucleus accumbens and subcallosal cortex. For the first time, the present study revealed the sex-specific neural mechanisms underlying distinct gender roles, which elucidates the process of gender construction from the perspective of the interaction between reward sensitivity and social reinforcement. (shrink)

The multifunctional zinc‐finger protein CCCTC‐binding factor (CTCF) is a very strong candidate for the role of coordinating the expression level of coding sequences with their three‐dimensional position in the nucleus, apparently responding to a “code” in the DNA itself. Dynamic interactions between chromatin fibers in the context of nuclear architecture have been implicated in various aspects of genome functions. However, the molecular basis of these interactions still remains elusive and is a subject of intense debate. Here we discuss the (...) nature of CTCF‐DNA interactions, the CTCF‐binding specificity to its binding sites and the relationship between CTCF and chromatin, and we examine data linking CTCF with gene regulation in the three‐dimensional nuclear space. We discuss why these features render CTCF a very strong candidate for the role and propose a unifying model, the “CTCF code,” explaining the mechanistic basis of how the information encrypted in DNA may be interpreted by CTCF into diverse nuclear functions. (shrink)