[How our view of epileptogenesis and mechanism of epilepsy changes? The system epilepsies' concept]. / Nézetváltozások az epilepszia keletkezésérol és mechanizmusáról. Rendszeralapú megközelítés.

Background and purpose: To examine the ways of epileptogenesis closely linked to the system epilepsies' concept. Methods: We follow the ways of epileptic transformation in the declarative memory-system, in the sleep/arousal twin-systems, in the perisylvian neuronal network and in postinjury epilepsy, which we consider a general model of the epileptic transformation. Results: In the presented systems, epileptogenesis shares a similar mechanism in the form of augmentation and derailment of plasticity and sleep-related synaptic homeo-stasis. This highlights the central role of NREM sleep in those epilepsies. Conclusion: We try to characterize the concept of system epilepsies and suggest a shared mechanism of epileptogenesis.

Structural Remodeling of Active Zones Is Associated with Synaptic Homeostasis.

Perturbations to postsynaptic glutamate receptors (GluRs) trigger retrograde signaling to precisely increase presynaptic neurotransmitter release, maintaining stable levels of synaptic strength, a process referred to as homeostatic regulation. However, the structural change of homeostatic regulation remains poorly defined. At wild-type Drosophila neuromuscular junction synapse, there is one Bruchpilot (Brp) ring detected by superresolution microscopy at active zones (AZs). In the present study, we report multiple Brp rings (i.e., multiple T-bars seen by electron microscopy) at AZs of both male and female larvae when GluRs are reduced. At GluRIIC-deficient neuromuscular junctions, quantal size was reduced but quantal content was increased, indicative of homeostatic presynaptic potentiation. Consistently, multiple Brp rings at AZs were observed in the two classic synaptic homeostasis models (i.e., GluRIIA mutant and pharmacological blockade of GluRIIA activity). Furthermore, postsynaptic overexpression of the cell adhesion protein Neuroligin 1 partially rescued multiple Brp rings phenotype. Our study thus supports that the formation of multiple Brp rings at AZs might be a structural basis for synaptic homeostasis.SIGNIFICANCE STATEMENT Synaptic homeostasis is a conserved fundamental mechanism to maintain efficient neurotransmission of neural networks. Active zones (AZs) are characterized by an electron-dense cytomatrix, which is largely composed of Bruchpilot (Brp) at the Drosophila neuromuscular junction synapses. It is not clear how the structure of AZs changes during homeostatic regulation. To address this question, we examined the structure of AZs by superresolution microscopy and electron microscopy during homeostatic regulation. Our results reveal multiple Brp rings at AZs of glutamate receptor-deficient neuromuscular junction synapses compared with single Brp ring at AZs in wild type (WT). We further show that Neuroligin 1-mediated retrograde signaling regulates multiple Brp ring formation at glutamate receptor-deficient synapses. This study thus reveals a regulatory mechanism for synaptic homeostasis.

Behavioural sleep in two species of buccal pumping sharks (Heterodontus portusjacksoni and Cephaloscyllium isabellum).

Sleep is known to occur in most, if not all, animals studied thus far. Recent studies demonstrate the presence of sleep in flatworms and jellyfish, suggesting that this behaviour evolved early in the evolution of animals. Sharks are the earliest known extant, jawed vertebrates and may play an important role in understanding the evolutionary history of sleep in vertebrates, and yet, it is unknown whether they sleep. The Port Jackson (Heterodontus portusjacksoni) and draughtsboard (Cephaloscyllium isabellum) sharks are both benthic, buccal pumping species and remain motionless for extended periods of time. Whether these periods of prolonged inactivity represent sleep or quiet wakefulness is unknown. A key criterion for separating sleep from other quiescent states is an increased arousal threshold. We show here that inactive sharks of both species require significantly higher levels of electric stimulation before they show a visible response. Sharks deprived of rest, however, show no significant compensatory increase in restfulness during their normal active period following enforced swimming. Nonetheless, increased arousal thresholds in inactive animals suggest that these two species of shark sleep - the first such demonstration for members of this group of vertebrates. Further research, including electrophysiological studies, on these and other sharks, is required for a comprehensive understanding of sleep in cartilaginous fishes.

Modeling Neuroimmune Interactions in Human Subjects and Animal Models to Predict Subtype-Specific Multidrug Treatments for Gulf War Illness.

Gulf War Illness (GWI) is a persistent chronic neuroinflammatory illness exacerbated by external stressors and characterized by fatigue, musculoskeletal pain, cognitive, and neurological problems linked to underlying immunological dysfunction for which there is no known treatment. As the immune system and the brain communicate through several signaling pathways, including the hypothalamic-pituitary-adrenal (HPA) axis, it underlies many of the behavioral and physiological responses to stressors via blood-borne mediators, such as cytokines, chemokines, and hormones. Signaling by these molecules is mediated by the semipermeable blood-brain barrier (BBB) made up of a monocellular layer forming an integral part of the neuroimmune axis. BBB permeability can be altered and even diminished by both external factors (e.g., chemical agents) and internal conditions (e.g., acute or chronic stress, or cross-signaling from the hypothalamic-pituitary-gonadal (HPG) axis). Such a complex network of regulatory interactions that possess feed-forward and feedback connections can have multiple response dynamics that may include several stable homeostatic states beyond normal health. Here we compare immune and hormone measures in the blood of human clinical samples and mouse models of Gulf War Illness (GWI) subtyped by exposure to traumatic stress for subtyping this complex illness. We do this via constructing a detailed logic model of HPA-HPG-Immune regulatory behavior that also considers signaling pathways across the BBB to neuronal-glial interactions within the brain. We apply conditional interactions to model the effects of changes in BBB permeability. Several stable states are identified in the system beyond typical health. Following alignment of the human and mouse blood profiles in the context of the model, mouse brain sample measures were used to infer the neuroinflammatory state in human GWI and perform treatment simulations using a genetic algorithm to optimize the Monte Carlo simulations of the putative treatment strategies aimed at returning the ill system back to health. We identify several ideal multi-intervention strategies and potential drug candidates that may be used to treat chronic neuroinflammation in GWI.

Presynaptic inhibition upon CB1 or mGlu2/3 receptor activation requires ERK/MAPK phosphorylation of Munc18-1.

Presynaptic cannabinoid (CB1R) and metabotropic glutamate receptors (mGluR2/3) regulate synaptic strength by inhibiting secretion. Here, we reveal a presynaptic inhibitory pathway activated by extracellular signal-regulated kinase (ERK) that mediates CB1R- and mGluR2/3-induced secretion inhibition. This pathway is triggered by a variety of events, from foot shock-induced stress to intense neuronal activity, and induces phosphorylation of the presynaptic protein Munc18-1. Mimicking constitutive phosphorylation of Munc18-1 results in a drastic decrease in synaptic transmission. ERK-mediated phosphorylation of Munc18-1 ultimately leads to degradation by the ubiquitin-proteasome system. Conversely, preventing ERK-dependent Munc18-1 phosphorylation increases synaptic strength. CB1R- and mGluR2/3-induced synaptic inhibition and depolarization-induced suppression of excitation (DSE) are reduced upon ERK/MEK pathway inhibition and further reduced when ERK-dependent Munc18-1 phosphorylation is blocked. Thus, ERK-dependent Munc18-1 phosphorylation provides a major negative feedback loop to control synaptic strength upon activation of presynaptic receptors and during intense neuronal activity.

Lovastatin Differentially Regulates α7 and α4 Neuronal Nicotinic Acetylcholine Receptor Levels in Rat Hippocampal Neurons.

Neuronal α7 and α4ß2 are the predominant nicotinic acetylcholine receptor (nAChR) subtypes found in the brain, particularly in the hippocampus. The effects of lovastatin, an inhibitor of cholesterol biosynthesis, on these two nAChRs endogenously expressed in rat hippocampal neuronal cells were evaluated in the 0.01-1 µM range. Chronic (14 days) lovastatin treatment augmented cell-surface levels of α7 and α4 nAChRs, as measured by fluorescence microscopy and radioactive ligand binding assays. This was accompanied in both cases by an increase in total protein receptor levels as determined by Western blots. At low lovastatin concentrations (10-100 nM), the increase in α4 nAChR in neurites was higher than in neuronal cell somata; the opposite occurred at higher (0.5-1 µM) lovastatin concentrations. In contrast, neurite α7 nAChRs raised more than somatic α7 nAChRs at all lovastatin concentrations tested. These results indicate that cholesterol levels homeostatically regulate α7 and α4 nAChR levels in a differential manner through mechanisms that depend on statin concentration and receptor localization. The neuroprotective pleomorphic effects of statins may act by reestablishing the homeostatic equilibrium.

[Epileptogenesis and consequences for treatment]. / Epileptogenese und Konsequenzen für die Therapie.

Epilepsy is a frequent and disabling neurological disease with a significant burden for patients and their relatives worldwide. Epileptogenesis is understood as the plastic process that after an insult (in acquired epilepsies) finally leads to seizures with a latent period. In some cases, epileptogenesis has been clarified down to the molecular level. In parallel, the discovery of genetic defects has decisively contributed to unravel epileptic disease mechanisms. Both research directions have enabled first personalized treatment options. In addition, genetic variants associated with epilepsy can not only directly cause seizures but likely also induce an epileptogenic process (similar as in acquired epilepsies) and interact with developmental processes of the brain, finally leading to the typical age-dependent manifestation of genetic epilepsy syndromes. This article describes these correlations and the consequences for personalized treatment possibilities.

Activation of brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling in the pedunculopontine tegmental nucleus: a novel mechanism for the homeostatic regulation of rapid eye movement sleep.

Rapid eye movement (REM) sleep dysregulation is a symptom of many neuropsychiatric disorders, yet the mechanisms of REM sleep homeostatic regulation are not fully understood. We have shown that, after REM sleep deprivation, the pedunculopontine tegmental nucleus (PPT) plays a critical role in the generation of recovery REM sleep. In this study, we used multidisciplinary techniques to show a causal relationship between brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling in the PPT and the development of REM sleep homeostatic drive. Rats were randomly assigned to conditions of unrestricted sleep or selective REM sleep deprivation (RSD) with PPT microinjections of vehicle control or a dose of a TrkB receptor inhibitor (2, 3, or 4 nmol K252a or 4 nmol ANA-12). On experimental days, rats received PPT microinjections and their sleep-wake physiological signals were recorded for 3 or 6 h, during which selective RSD was performed in the first 3 h. At the end of all 3 h recordings, rats were killed and the PPT was dissected out for BDNF quantification. Our results show that K252a and ANA-12 dose-dependently reduced the homeostatic responses to selective RSD. Specifically, TrkB receptor inhibition reduced REM sleep homeostatic drive and limited REM sleep rebound. There was also a dose-dependent suppression of PPT BDNF up-regulation, and regression analysis revealed a significant positive relationship between REM sleep homeostatic drive and the level of PPT BDNF expression. These data provide the first direct evidence that activation of BDNF-TrkB signaling in the PPT is a critical step for the development of REM sleep homeostatic drive.

Relevance of the Adjuvant Effect between Cellular Homeostasis and Resistance to Antibiotics in Gram-Negative Bacteria with Pathogenic Capacity: A Study of Klebsiella pneumoniae.

Antibiotic resistance has become a global issue. The most significant risk is the acquisition of these mechanisms by pathogenic bacteria, which can have a severe clinical impact and pose a public health risk. This problem assumes that bacterial fitness is a constant phenomenon and should be approached from an evolutionary perspective to develop the most appropriate and effective strategies to contain the emergence of strains with pathogenic potential. Resistance mechanisms can be understood as adaptive processes to stressful conditions. This review examines the relevance of homeostatic regulatory mechanisms in antimicrobial resistance mechanisms. We focus on the interactions in the cellular physiology of pathogenic bacteria, particularly Gram-negative bacteria, and specifically Klebsiella pneumoniae. From a clinical research perspective, understanding these interactions is crucial for comprehensively understanding the phenomenon of resistance and developing more effective drugs and treatments to limit or attenuate bacterial sepsis, since the most conserved adjuvant phenomena in bacterial physiology has turned out to be more optimized and, therefore, more susceptible to alterations due to pharmacological action.

Critical Role for 24-Hydroxylation in Homeostatic Regulation of Vitamin D Metabolism.

Context: The body has evolved homeostatic mechanisms to maintain free levels of Ca+2 and 1,25-dihydroxyvitamin D [1,25(OH)2D] within narrow physiological ranges. Clinical guidelines emphasize important contributions of PTH in maintaining this homeostasis. Objective: To investigate mechanisms of homeostatic regulation of vitamin D (VitD) metabolism and to apply mechanistic insights to improve clinical assessment of VitD status. Design: Crossover clinical trial studying participants before and after VitD3-supplementation. Setting: Community. Participants: 11 otherwise healthy individuals with VitD-deficiency (25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL). Interventions: VitD3-supplements (50,000 IU once or twice a week depending on BMI, for 4-6 weeks) were administered to achieve 25(OH)D≥30 ng/mL. Results: VitD3-supplementation significantly increased mean 25(OH)D by 2.7-fold and 24,25-dihydroxyvitamin D [24,25(OH)2D] by 4.3-fold. In contrast, mean levels of PTH, FGF23, and 1,25(OH)2D did not change. Mathematical modeling suggested that 24-hydroxylase activity was maximal for 25(OH)D≥50 ng/mL and achieved a minimum (~90% suppression) with 25(OH)D<10-20 ng/mL. The 1,25(OH)2D/24,25(OH)2D ratio better predicted modeled 24-hydroxylase activity (h) (ρ=-0.85; p=0.001) compared to total plasma 25(OH)D (ρ=0.51; p=0.01) and the 24,25(OH)2D/25(OH)D ratio (ρ=0.37; p=0.3). Conclusions: Suppression of 24-hydroxylase provides a first line of defense against symptomatic VitD-deficiency by decreasing metabolic clearance of 1,25(OH)2D. The 1,25(OH)2D/24,25(OH)2D ratio provides a useful index of VitD status since it incorporates 24,25(OH)2D levels and therefore, provides insight into 24-hydroxylase activity. When VitD availability is limited, this suppresses 24-hydroxylase activity - thereby decreasing the level of 24,25(OH)2D and increasing the 1,25(OH)2D/24,25(OH)2D ratio. Thus, an increased 1,25(OH)2D/24,25(OH)2D ratio signifies triggering of homeostatic regulation, which occurs at early stages of VitD-deficiency.

Critical Role for 24-Hydroxylation in Homeostatic Regulation of Vitamin D Metabolism.

CONTEXT: The body has evolved homeostatic mechanisms to maintain free levels of Ca+2 and 1,25-dihydroxyvitamin D [1,25(OH)2D] within narrow physiological ranges. Clinical guidelines emphasize important contributions of PTH in maintaining this homeostasis. OBJECTIVE: To investigate mechanisms of homeostatic regulation of vitamin D (VitD) metabolism and to apply mechanistic insights to improve clinical assessment of VitD status. DESIGN: Crossover clinical trial studying participants before and after VitD3-supplementation. SETTING: Community. PARTICIPANTS: 11 otherwise healthy individuals with VitD-deficiency (25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL). INTERVENTIONS: VitD3-supplements (50,000 IU once or twice a week depending on BMI, for 4-6 weeks) were administered to achieve 25(OH)D≥30 ng/mL. RESULTS: VitD3-supplementation significantly increased mean 25(OH)D by 2.7-fold and 24,25-dihydroxyvitamin D [24,25(OH)2D] by 4.3-fold. In contrast, mean levels of PTH, FGF23, and 1,25(OH)2D did not change. Mathematical modeling suggested that 24-hydroxylase activity was maximal for 25(OH)D≥50 ng/mL and achieved a minimum (∼90% suppression) with 25(OH)D<10-20 ng/mL. The 1,25(OH)2D/24,25(OH)2D ratio better predicted modeled 24-hydroxylase activity (h) (ρ=-0.85; p=0.001) compared to total plasma 25(OH)D (ρ=0.51; p=0.01) and the 24,25(OH)2D/25(OH)D ratio (ρ=0.37; p=0.3). CONCLUSIONS: Suppression of 24-hydroxylase provides a first line of defense against symptomatic VitD-deficiency by decreasing metabolic clearance of 1,25(OH)2D. The 1,25(OH)2D/24,25(OH)2D ratio provides a useful index of VitD status since it incorporates 24,25(OH)2D levels and therefore, provides insight into 24-hydroxylase activity. When VitD availability is limited, this suppresses 24-hydroxylase activity - thereby decreasing the level of 24,25(OH)2D and increasing the 1,25(OH)2D/24,25(OH)2D ratio. Thus, an increased 1,25(OH)2D/24,25(OH)2D ratio signifies triggering of homeostatic regulation, which occurs at early stages of VitD-deficiency.

Homeostatic regulation of neuronal function: importance of degeneracy and pleiotropy.

Neurons maintain their average firing rate and other properties within narrow bounds despite changing conditions. This homeostatic regulation is achieved using negative feedback to adjust ion channel expression levels. To understand how homeostatic regulation of excitability normally works and how it goes awry, one must consider the various ion channels involved as well as the other regulated properties impacted by adjusting those channels when regulating excitability. This raises issues of degeneracy and pleiotropy. Degeneracy refers to disparate solutions conveying equivalent function (e.g., different channel combinations yielding equivalent excitability). This many-to-one mapping contrasts the one-to-many mapping described by pleiotropy (e.g., one channel affecting multiple properties). Degeneracy facilitates homeostatic regulation by enabling a disturbance to be offset by compensatory changes in any one of several different channels or combinations thereof. Pleiotropy complicates homeostatic regulation because compensatory changes intended to regulate one property may inadvertently disrupt other properties. Co-regulating multiple properties by adjusting pleiotropic channels requires greater degeneracy than regulating one property in isolation and, by extension, can fail for additional reasons such as solutions for each property being incompatible with one another. Problems also arise if a perturbation is too strong and/or negative feedback is too weak, or because the set point is disturbed. Delineating feedback loops and their interactions provides valuable insight into how homeostatic regulation might fail. Insofar as different failure modes require distinct interventions to restore homeostasis, deeper understanding of homeostatic regulation and its pathological disruption may reveal more effective treatments for chronic neurological disorders like neuropathic pain and epilepsy.

A comparative study of natural variation in hemolymph glucose levels under different dietary sugar conditions in Drosophila melanogaster and D. simulans.

Physiological responses to environmental changes play important roles in adaptive evolution. In particular, homeostatic regulatory systems that maintain constant circulating glucose levels are crucial in animals. However, variation in circulating glucose levels and the genetic effects on phenotypic variation in natural populations remain to be clarified. Here, we investigated the hemolymph glucose levels in natural populations of Drosophila melanogaster and its sibling species, D. simulans, in Japan. We quantified hemolymph glucose concentrations in third instar larvae of 27 lines for each species, which were reared on either glucose-free or glucose-rich food. In both species, genetic variation was not a major component of phenotypic variation on either glucose-free or glucose-rich food. The hemolymph glucose concentrations were much higher in D. simulans than in D. melanogaster. Genetic variance was larger in D. simulans than in D. melanogaster. The observed differences between the two species may be associated with the much more recent colonization history of D. simulans populations in Japan and/or the tolerance to environmental stresses. Our findings suggest that natural selection acting on hemolymph glucose levels in D. melanogaster is different from that in D. simulans.

PD-1 and CTLA-4 exert additive control of effector regulatory T cells at homeostasis.

At homeostasis, a substantial proportion of Foxp3+ T regulatory cells (Tregs) have an activated phenotype associated with enhanced TCR signals and these effector Treg cells (eTregs) co-express elevated levels of PD-1 and CTLA-4. Short term in vivo blockade of the PD-1 or CTLA-4 pathways results in increased eTreg populations, while combination blockade of both pathways had an additive effect. Mechanistically, combination blockade resulted in a reduction of suppressive phospho-SHP2 Y580 in eTreg cells which was associated with increased proliferation, enhanced production of IL-10, and reduced dendritic cell and macrophage expression of CD80 and MHC-II. Thus, at homeostasis, PD-1 and CTLA-4 function additively to regulate eTreg function and the ability to target these pathways in Treg cells may be useful to modulate inflammation.

Neuronal Population Transitions Across a Quiescent-to-Active Frontier and Bifurcation.

The mechanistic understanding of why neuronal population activity hovers on criticality remains unresolved despite the availability of experimental results. Without a coherent mathematical framework, the presence of power-law scaling is not straightforward to reconcile with findings implying epileptiform activity. Although multiple pictures have been proposed to relate the power-law scaling of avalanche statistics to phase transitions, the existence of a phase boundary in parameter space is until now an assumption. Herein, a framework based on differential inclusions, which departs from approaches constructed from differential equations, is shown to offer an adequate consolidation of evidences apparently connected to criticality and those linked to hyperexcitability. Through this framework, the phase boundary is elucidated in a parameter space spanned by variables representing levels of excitation and inhibition in a neuronal network. The interpretation of neuronal populations based on this approach offers insights on the role of pharmacological and endocrinal signaling in the homeostatic regulation of neuronal population activity.

Effect of cellular aging on memory T-cell homeostasis.

The fact that T-cell numbers remain relatively stable throughout life, and that T-cell proliferation rates increase during lymphopenia, has led to the consensus that T-cell numbers are regulated in a density-dependent manner. Competition for resources among memory T cells has been proposed to underlie this 'homeostatic' regulation. We first review how two classic models of resource competition affect the T-cell receptor (TCR) diversity of the memory T-cell pool. First, 'global' competition for cytokines leads to a skewed repertoire that tends to be dominated by the very first immune response. Second, additional 'cognate' competition for specific antigens results in a very diverse and stable memory T-cell pool, allowing every antigen to be remembered, which we therefore define as the 'gold-standard'. Because there is limited evidence that memory T cells of the same specificity compete more strongly with each other than with memory T cells of different specificities, i.e., for 'cognate' competition, we investigate whether cellular aging could account for a similar level of TCR diversity. We define cellular aging as a declining cellular fitness due to reduced proliferation. We find that the gradual erosion of previous T-cell memories due to cellular aging allows for better establishment of novel memories and for a much higher level of TCR diversity compared to global competition. A small continual source (either from stem-cell-like memory T-cells or from naive T-cells due to repeated antigen exposure) improves the diversity of the memory T-cell pool, but remarkably, only in the cellular aging model. We further show that the presence of a source keeps the inflation of chronic memory responses in check by maintaining the immune memories to non-chronic antigens. We conclude that cellular aging along with a small source provides a novel and immunologically realistic mechanism to achieve and maintain the 'gold-standard' level of TCR diversity in the memory T-cell pool.

Are homeostatic mechanisms aiding the reconstitution of the T-cell pool during lymphopenia in humans?

A timely recovery of T-cell numbers following haematopoietic stem-cell transplantation (HSCT) is essential for preventing complications, such as increased risk of infection and disease relapse. In analogy to the occurrence of lymphopenia-induced proliferation in mice, T-cell dynamics in humans are thought to be homeostatically regulated in a cell density-dependent manner. The idea is that T cells divide faster and/or live longer when T-cell numbers are low, thereby helping the reconstitution of the T-cell pool. T-cell reconstitution after HSCT is, however, known to occur notoriously slowly. In fact, the evidence for the existence of homeostatic mechanisms in humans is quite ambiguous, since lymphopenia is often associated with infectious complications and immune activation, which confound the study of homeostatic regulation. This calls into question whether homeostatic mechanisms aid the reconstitution of the T-cell pool during lymphopenia in humans. Here we review the changes in T-cell dynamics in different situations of T-cell deficiency in humans, including the early development of the immune system after birth, healthy ageing, HIV infection, thymectomy and hematopoietic stem cell transplantation (HSCT). We discuss to what extent these changes in T-cell dynamics are a side-effect of increased immune activation during lymphopenia, and to what extent they truly reflect homeostatic mechanisms.

Neural Correlates of Music Listening: Does the Music Matter?

The last decades have seen a proliferation of music and brain studies, with a major focus on plastic changes as the outcome of continuous and prolonged engagement with music. Thanks to the advent of neuroaesthetics, research on music cognition has broadened its scope by considering the multifarious phenomenon of listening in all its forms, including incidental listening up to the skillful attentive listening of experts, and all its possible effects. These latter range from objective and sensorial effects directly linked to the acoustic features of the music to the subjectively affective and even transformational effects for the listener. Of special importance is the finding that neural activity in the reward circuit of the brain is a key component of a conscious listening experience. We propose that the connection between music and the reward system makes music listening a gate towards not only hedonia but also eudaimonia, namely a life well lived, full of meaning that aims at realizing one's own "daimon" or true nature. It is argued, further, that music listening, even when conceptualized in this aesthetic and eudaimonic framework, remains a learnable skill that changes the way brain structures respond to sounds and how they interact with each other.

Cultural life: Theory and empirical testing.

"What is life?" and Erwin Schrödinger's answer, "negative entropy", inspired researchers in the 20th century to unite physics, chemistry, and physiology into a new synthesis that many believe to be an important foundation for life science today. Decades after Schrödinger, life scientists are still fascinated by the riddle that entropy can only accumulate in physical systems, which often leads to biological deterioration and death, but life finds ways to persist and prevail. So to say, life "negates" entropy. Can this fascination and research concept be broadened even further to human culture? Short after Schrödinger's publication, Claude Shannon coined the term "information entropy." Information entropy accumulates when noise interferes during communication. Eventually, all useful information is lost. Yet, from this observation, something surprising can be inferred. Not only biological life but also cultural life has the ability to persist and prevail in spite of the accumulation of entropy. Does this insight mean that cultural life also negates entropy, in Schrödinger's sense? These questions guided me over several years of research during which I developed and tested a new theory of culture based on variation-selection processes and homeostatic regulation. My contribution is to discover that these two processes not only make statements about biological life. They also explain some of the most important phenomena of culture: returning fashions, polarization, diversification, cycles of growth and reform, and the formation of common ethos across entire bodies of knowledge. With access to big data and supercomputing, I tested my theory against hundreds of thousands of news, magazine articles, books, and TV transcripts as well as textual content collected from the social media. Historical, institutional, and geographical information was extracted from these data using a new method; and new interactive tools were created to interpret the results. What should not be missed when reading this article is that the theory proposed here reveals a striking equivalence between nature and culture. The article states this equivalence in mathematical terms, and contextualizes it in the history of science. The mathematical breakthrough is relevant because it aligns the humanities to science while also allowing for live evaluation of what I call "cultural diversification cycles."

The effect of amyloid deposition on longitudinal resting-state functional connectivity in cognitively normal older adults.

BACKGROUND: Pathological processes contributing to Alzheimer's disease begin decades prior to the onset of clinical symptoms. There is significant variation in cognitive changes in the presence of pathology, functional connectivity may be a marker of compensation to amyloid; however, this is not well understood. METHODS: We recruited 64 cognitively normal older adults who underwent neuropsychological testing and biannual magnetic resonance imaging (MRI), amyloid imaging with Pittsburgh compound B (PiB)-PET, and glucose metabolism (FDG)-PET imaging for up to 6 years. Resting-state MRI was used to estimate connectivity of seven canonical neural networks using template-based rotation. Using voxel-wise paired t-tests, we identified neural networks that displayed significant changes in connectivity across time. We investigated associations among amyloid and longitudinal changes in connectivity and cognitive function by domains. RESULTS: Left middle frontal gyrus connectivity within the memory encoding network increased over time, but the rate of change was lower with greater amyloid. This was no longer significant in an analysis where we limited the sample to only those with two time points. We found limited decline in cognitive domains overall. Greater functional connectivity was associated with better attention/processing speed and executive function (independent of time) in those with lower amyloid but was associated with worse function with greater amyloid. CONCLUSIONS: Increased functional connectivity serves to preserve cognitive function in normal aging and may fail in the presence of pathology consistent with compensatory models.