Causally Probing the Role of the Hippocampus in Fear Discrimination: A Precision Functional Mapping-Guided, Transcranial Magnetic Stimulation Study in Participants With Posttraumatic Stress Symptoms.

Background: Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety. A dominant model posits that hippocampal pattern separation failures drive overgeneralization. Hippocampal network-targeted transcranial magnetic stimulation (HNT-TMS) has been shown to strengthen hippocampal-dependent learning/memory processes. However, no study has examined whether HNT-TMS can alter fear learning/memory. Methods: Continuous theta burst stimulation was delivered to individualized left posterior parietal stimulation sites derived via seed-based connectivity, precision functional mapping, and electric field modeling methods. A vertex control site was also stimulated in a within-participant, randomized controlled design. Continuous theta burst stimulation was delivered prior to 2 visual discrimination tasks (1 fear based, 1 neutral). Multilevel models were used to model and test data. Participants were undergraduates with posttraumatic stress symptoms (final n = 25). Results: Main analyses did not indicate that HNT-TMS strengthened discrimination. However, multilevel interaction analyses revealed that HNT-TMS strengthened fear discrimination in participants with lower fear sensitization (indexed by responses to a control stimulus with no similarity to the conditioned fear cue) across multiple indices (anxiety ratings: ß = 0.10, 95% CI, 0.04 to 0.17, p = .001; risk ratings: ß = 0.07, 95% CI, 0.00 to 0.13, p = .037). Conclusions: Overgeneralization is an associative process that reflects deficient discrimination of the fear cue from similar cues. In contrast, sensitization reflects nonassociative responding unrelated to fear cue similarity. Our results suggest that HNT-TMS may selectively sharpen fear discrimination when associative response patterns, which putatively implicate the hippocampus, are more strongly engaged.

Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety that is thought to be driven by deficient hippocampal discrimination. Using hippocampal network­targeted transcranial magnetic stimulation (HNT-TMS) in healthy participants with symptoms of posttraumatic stress, Webler et al. report that HNT-TMS did not strengthen discrimination overall, but it did strengthen fear discrimination in participants with lower fear sensitization. Sensitization reflects nonassociative fear responding unrelated to fear cue similarity and therefore is not expected to engage the hippocampal discrimination function. These results suggest that HNT-TMS may selectively sharpen fear discrimination when the hippocampal discrimination function is more strongly engaged.

Crackling Noise during Slow Relaxations in Crumpled Sheets.

The statistics of noise emitted by ultrathin crumpled sheets is measured while they exhibit logarithmic relaxations under load. We find that the logarithmic relaxation advanced via a series of discrete, audible, micromechanical events that are log-Poisson distributed (i.e., the process becomes a Poisson process when time stamps are replaced by their logarithms). The analysis places constraints on the possible mechanisms underlying the glasslike slow relaxation and memory retention in these systems.

Geometric rules for the annihilation dynamics of step lines on fracture fronts.

The roughness of a fracture surface records a crack's complex path through a material and can affect the resultant frictional or fluid transport properties of the broken medium. For brittle fractures, some of the most prominent surface features are long, step-like discontinuities called step lines. In heterogeneous materials, the mean crack surface roughness created by these step lines is well captured by a simple, one-dimensional ballistic annihilation model, which assumes the creation of these steps is a random processes with a single probability that depends on the heterogeneity of the material, and that their destruction occurs via pairwise interactions. Here, through an exhaustive study of experimentally generated crack surfaces in brittle hydrogels, we examine step interactions and show that interaction outcomes depend on the geometry of the incoming steps. The rules that govern step interactions can be categorized into three unique classes and are fully described, providing a complete framework for predicting fracture roughness.

Hitting the mark: probing at the initiation site allows for accurate prediction of a thin shell's buckling load.

Geometric imperfections are understood to play an essential part in the buckling of a thin shell, but how multiple defects interact to control the onset of failure remains unclear. Here, we examine the failure of real cylindrical shells by experimentally poking soda cans with a large imparted dimple. By high-speed imaging of the can's surface, the initiation of buckling from axial loading is directly observed, revealing that larger dimples tend to set the initial buckling location. However, the influence of the shell's background geometric imperfections can still occasionally dominate, causing initiation to occur far from the dimple. In this situation, probing at the dimple leads to an over-prediction of the axial capacity. Using finite-element simulations, we understand our experimental results as a competition between the large dimple and the shell's inherent defect structure. In our simulations, we empirically observe a deformation-based criterion that connects the ideal poking location to the initiation site. This article is part of the theme issue 'Probing and dynamics of shock sensitive shells'.

Measuring the energy landscape: an experimental approach to the study of buckling in thin shells.

Recent research into the buckling load of thin shells has focused on local poking of the shell. In this approach, the shell is poked under load to extract its stability landscape, and a ridge tracking method is performed to estimate the buckling load of the shell. It is the current understanding that the stability landscape measures the local stability of the shell and, as a result, that the accuracy of ridge tracking greatly relies on the location of poking. Currently, there is no method that can predict where poking should be performed on an experimental system. Here, we examine the global response of thin shells to poking through the energy landscape. We present an experimental method for measuring the energy landscape of thin shells and demonstrate its application on a thin plate strip. We show that by analysing the dynamics of the shell in the energy landscape we can experimentally measure the buckling mode of the system, which gives the correct point of poking for accurate ridge tracking, and identify two kinds of buckling points. Finally, we propose how this approach can be applied to more complex systems such as thin cylinders. This article is part of the theme issue 'Probing and dynamics of shock sensitive shells'.

Causally mapping human threat extinction relevant circuits with depolarizing brain stimulation methods.

Laboratory threat extinction paradigms and exposure-based therapy both involve repeated, safe confrontation with stimuli previously experienced as threatening. This fundamental procedural overlap supports laboratory threat extinction as a compelling analogue of exposure-based therapy. Threat extinction impairments have been detected in clinical anxiety and may contribute to exposure-based therapy non-response and relapse. However, efforts to improve exposure outcomes using techniques that boost extinction - primarily rodent extinction - have largely failed to date, potentially due to fundamental differences between rodent and human neurobiology. In this review, we articulate a comprehensive pre-clinical human research agenda designed to overcome these failures. We describe how connectivity guided depolarizing brain stimulation methods (i.e., TMS and DBS) can be applied concurrently with threat extinction and dual threat reconsolidation-extinction paradigms to causally map human extinction relevant circuits and inform the optimal integration of these methods with exposure-based therapy. We highlight candidate targets including the amygdala, hippocampus, ventromedial prefrontal cortex, dorsal anterior cingulate cortex, and mesolimbic structures, and propose hypotheses about how stimulation delivered at specific learning phases could strengthen threat extinction.

Beyond quality and quantity: Spatial distribution of contact encodes frictional strength.

Classically, the quantity of contact area A_{R} between two bodies is considered a proxy for the force of friction. However, bond density across the interface-quality of contact-is also relevant, and contemporary debate often centers around the relative importance of these two factors. In this work, we demonstrate that a third factor, often overlooked, plays a significant role in static frictional strength: The spatial distribution of contact. We perform static friction measurements, µ, on three pairs of solid blocks while imaging the contact plane. By using linear regression on hundreds of image-µ pairs, we are able to predict future friction measurements with three to seven times better accuracy than existing benchmarks, including total quantity of contact area. Our model has no access to quality of contact, and we therefore conclude that a large portion of the interfacial state is encoded in the spatial distribution of contact, rather than its quality or quantity.

How Material Heterogeneity Creates Rough Fractures.

Fractures are a critical process in how materials wear, weaken, and fail, whose unpredictable behavior can have dire consequences. While the behavior of smooth cracks in ideal materials is well understood, it is assumed that for real, heterogeneous systems, fracture propagation is complex, generating rough fracture surfaces that are highly sensitive to specific details of the medium. Here we show how fracture roughness and material heterogeneity are inextricably connected via a simple framework. Studying hydraulic fractures in brittle hydrogels that have been supplemented with microbeads or glycerol to create controlled material heterogeneity, we show that the morphology of the crack surface depends solely on one parameter: the probability to perturb the front above a critical size to produce a steplike instability. This probability scales linearly with the number density, and with heterogeneity size to the 5/2 power. The ensuing behavior is universal and is captured by the 1D ballistic propagation and annihilation of steps along the singular fracture front.

Observation of Remote Electroconvection and Inert-Cation Concentration Valley within Supporting Electrolytes in a Microfluidic-Based Electrochemical Device.

The electrochemical system is playing an increasingly important role in the advanced technology development for drinkable water and energy storage. While the binary electrolyte has been widely studied, such as the associated intriguing interfacial instabilities, multi-component electrolyte is by far less known. Here, based on the classic Cu|CuSO4 |Cu electrochemical system, the effect of supporting electrolyte is systematically investigated by highlighting the inert cations. In an annulus microfluidic device, the suppression of a previously known electro-osmotic instability and the emergence of an array of the remote electroconvection along the azimuthal direction is found. A distinctive inert-cation concentration valley propagates radially outward at a speed limited by the electromigration velocity. Remarkably, the simultaneous visualization of spatiotemporal evolution demonstrates the correlation of the concentration valley and electroconvection at a microscopic level. The underlying physical mechanism of their correlation is discussed, and the scaling analysis agrees with experiments. This work might inspire more future work on the multi-component electrolyte, such as for the suppression of interfacial hydrodynamic instability and mitigation of dendrite growth, with the technological implications for water treatment and energy storage in batteries.

Vitamin D deficiency is associated with higher risks for SARS-CoV-2 infection and COVID-19 severity: a retrospective case-control study.

Robust evidence of whether vitamin D deficiency is associated with COVID-19 infection and its severity is still lacking. The aim of the study was to evaluate the association between vitamin D levels and the risks of SARS-CoV-2 infection and severe disease in those infected. A retrospective study was carried out among members of Clalit Health Services (CHS), the largest healthcare organization in Israel, between March 1 and October 31, 2020. We created two matched case-control groups of individuals for which vitamin D levels and body mass index (BMI) were available before the pandemic: group (A), in which 41,757 individuals with positive SARS-CoV-2 PCR tests were matched with 417,570 control individuals without evidence of infection, and group (B), in which 2533 patients hospitalized in severe condition for COVID-19 were matched with 2533 patients who were tested positive for SARS-CoV-2, but were not hospitalized. Conditional logistic models were fitted in each of the groups to assess the association between vitamin D levels and outcome. An inverse correlation was demonstrated between the level of vitamin D and the risks of SARS-CoV-2 infection and of severe disease in those infected. Patients with very low vitamin D levels (< 30 nmol/L) had the highest risks for SARS-CoV-2 infection and also for severe COVID-19 when infected-OR 1.246 [95% CI 1.210-1.304] and 1.513 [95% CI 1.230-1.861], respectively. In this large observational population study, we show a significant association between vitamin D deficiency and the risks of SARS-CoV-2 infection and of severe disease in those infected.

A model for the fragmentation kinetics of crumpled thin sheets.

As a confined thin sheet crumples, it spontaneously segments into flat facets delimited by a network of ridges. Despite the apparent disorder of this process, statistical properties of crumpled sheets exhibit striking reproducibility. Experiments have shown that the total crease length accrues logarithmically when repeatedly compacting and unfolding a sheet of paper. Here, we offer insight to this unexpected result by exploring the correspondence between crumpling and fragmentation processes. We identify a physical model for the evolution of facet area and ridge length distributions of crumpled sheets, and propose a mechanism for re-fragmentation driven by geometric frustration. This mechanism establishes a feedback loop in which the facet size distribution informs the subsequent rate of fragmentation under repeated confinement, thereby producing a new size distribution. We then demonstrate the capacity of this model to reproduce the characteristic logarithmic scaling of total crease length, thereby supplying a missing physical basis for the observed phenomenon.

Salience and central executive networks track overgeneralization of conditioned-fear in post-traumatic stress disorder.

BACKGROUND: Generalization of conditioned-fear, a core feature of post-traumatic stress disorder (PTSD), has been the focus of several recent neuroimaging studies. A striking outcome of these studies is the frequency with which neural correlates of generalization fall within hubs of well-established functional networks including salience (SN), central executive (CEN), and default networks (DN). Neural substrates of generalization found to date may thus reflect traces of large-scale brain networks that form more expansive neural representations of generalization. The present study includes the first network-based analysis of generalization and PTSD-related abnormalities therein. METHODS: fMRI responses in established intrinsic connectivity networks (ICNs) representing SN, CEN, and DN were assessed during a generalized conditioned-fear task in male combat veterans (N = 58) with wide-ranging PTSD symptom severity. The task included five rings of graded size. Extreme sizes served as conditioned danger-cues (CS+: paired with shock) and safety-cues (CS-), and the three intermediate sizes served as generalization stimuli (GSs) forming a continuum-of-size between CS+ and CS-. Generalization-gradients were assessed as behavioral and ICN response slopes from CS+, through GSs, to CS-. Increasing PTSD symptomatology was predicted to relate to less-steep slopes indicative of stronger generalization. RESULTS: SN, CEN, and DN responses fell along generalization-gradients with levels of generalization within and between SN and CEN scaling with PTSD symptom severity. CONCLUSIONS: Neural substrates of generalized conditioned-fear include large-scale networks that adhere to the functional organization of the brain. Current findings implicate levels of generalization in SN and CEN as promising neural markers of PTSD.

Nondestructive Prediction of the Buckling Load of Imperfect Shells.

From soda cans to space rockets, thin-walled cylindrical shells are abundant, offering exceptional load carrying capacity at relatively low weight. However, the actual load at which any shell buckles and collapses is very sensitive to imperceptible defects and cannot be predicted, which challenges the of such structures. Consequently, probabilistic descriptions in terms of empirical design rules are used and designing reliable structures requires the use of conservative strength estimates. We introduce a nonlinear description where finite-amplitude perturbations trigger buckling. Drawing from the analogy between imperfect shells which buckle and imperfect pipe flow which becomes turbulent, we experimentally show that lateral probing of cylindrical shells reveals their strength nondestructively. A new ridge-tracking method is applied to commercial cylinders with a hole showing that when the location where buckling nucleates is known we can accurately predict the buckling load of each individual shell, within ±5%. Our study provides a new promising framework to understand shell buckling, and more generally, imperfection-sensitive instabilities.

The link between vitamin D deficiency and Covid-19 in a large population

BACKGROUNDRecent studies suggest a link between vitamin D deficiency and Covid-19 infection. In our population we observe major differences in Covid-19 incidence in ethnic groups and genders in each group. METHODSWe carried out a population-based study among 4.6 million members of Clalit Health Services (CHS). We collected results from vitamin D tests performed between 2010 and 2019 and used weighted linear regression to assess the relationship between prevalence of vitamin D deficiency and Covid-19 incidence in 200 localities. Additionally, we matched 52,405 infected patients with 524,050 control individuals of the same sex, age, geographical region and used conditional logistic regression to assess the relationship between baseline vitamin D levels, acquisition of vitamin D supplements in the last 4 months, and positive Covid-19. RESULTSWe observe a highly significant correlation between prevalence of vitamin D deficiency and Covid-19 incidence, and between female-to-male ratio for severe vitamin D deficiency and female-tomale ratio for Covid-19 incidence in localities (P<0.001). In the matched cohort, we found a significant association between low vitamin D levels and the risk of Covid-19, with the highest risk observed for severe vitamin D deficiency. A significant protective effect was observed for members who acquired liquid vitamin D formulations (drops) in the last 4 months. CONCLUSIONIn this large observational population study, we show a strong association between vitamin D deficiency and Covid-19 occurrence. After adjustment for baseline characteristics and prior vitamin D levels, acquisition of liquid vitamin D formulations is associated with decreased risk for Covid-19 infection.

Turbulence generation through an iterative cascade of the elliptical instability.

The essence of turbulent flow is the conveyance of energy through the formation, interaction, and destruction of eddies over a wide range of spatial scales-from the largest scales where energy is injected down to the smallest scales where it is dissipated through viscosity. Currently, there is no mechanistic framework that captures how the interactions of vortices drive this cascade. We show that iterations of the elliptical instability, arising from the interactions between counter-rotating vortices, lead to the emergence of turbulence. We demonstrate how the nonlinear development of the elliptical instability generates an ordered array of antiparallel secondary filaments. The secondary filaments mutually interact, leading to the formation of even smaller tertiary filaments. In experiments and simulations, we observe two and three iterations of this cascade, respectively. Our observations indicate that the elliptical instability could be one of the fundamental mechanisms by which the turbulent cascade develops.

Shear Controls Frictional Aging by Erasing Memory.

We simultaneously measure the static friction and the real area of contact between two solid bodies. These quantities are traditionally considered equivalent, and under static conditions both increase logarithmically in time, a phenomenon coined aging. Here we show that the frictional aging rate is determined by the combination of the aging rate of the real area of contact and two memory-erasure effects that occur when shear is changed (e.g., to measure static friction.) The application of a static shear load accelerates frictional aging while the aging rate of the real area of contact is unaffected. Moreover, a negative static shear-pulling instead of pushing-slows frictional aging, but similarly does not affect the aging of contacts. The origin of this shear effect on aging is geometrical. When shear load is increased, minute relative tilts between the two blocks prematurely erase interfacial memory prior to sliding, negating the effect of aging. Modifying the loading point of the interface eliminates these tilts and as a result frictional aging rate becomes insensitive to shear. We also identify a secondary memory-erasure effect that remains even when all tilts are eliminated and show that this effect can be leveraged to accelerate aging by cycling between two static shear loads.

Geometric frustration induces the transition between rotation and counterrotation in swirled granular media.

Granular material in a swirled container exhibits a curious transition as the number of particles is increased: At low densities, the particle cluster rotates in the same direction as the swirling motion of the container, while at high densities it rotates in the opposite direction. We investigate this phenomenon experimentally and numerically using a corotating reference frame in which the system reaches a statistical steady state. In this steady state, the particles form a cluster whose translational degrees of freedom are stationary, while the individual particles constantly circulate around the cluster's center of mass, similar to a ball rolling along the wall within a rotating drum. We show that the transition to counterrotation is friction dependent. At high particle densities, frictional effects result in geometric frustration, which prevents particles from cooperatively rolling and spinning. Consequently, the particle cluster rolls like a rigid body with no-slip conditions on the container wall, which necessarily counterrotates around its own axis. Numerical simulations verify that both wall-disk friction and disk-disk friction are critical for inducing counterrotation.

A Sequence of Developmental Events Occurs Underneath Growing Bacillus subtilis Pellicles.

Biofilms are structured communities of bacteria that exhibit complex spatio-temporal dynamics. In liquid media, Bacillus subtilis produces an opaque floating biofilm, or a pellicle. Biofilms are generally associated with an interface, but the ability of Bacillus subtilis to swim means the bacteria are additionally able to reside within the liquid phase. However, due to imaging complications associated with the opacity of pellicles, the extent to which bacteria coexist within the liquid bulk as well as their behavior in the liquid is not well studied. We therefore develop a high-throughput imaging system to image underneath developing pellicles. Here we report a well-defined sequence of developmental events that occurs underneath a growing pellicle. Comparison with bacteria deficient in swimming and chemotaxis suggest that these properties enable collective bacterial swimming within the liquid phase which facilitate faster surface colonization. Furthermore, comparison to bacteria deficient in exopolymeric substances (EPS) suggest that the lack of a surface pellicle prevents further developmental steps from occurring within the liquid phase. Our results reveal a sequence of developmental events during pellicle growth, encompassing adhesion, conversion, growth, maturity, and detachment on the interface, which are synchronized with the bacteria in the liquid bulk increasing in density until the formation of a mature surface pellicle, after which the density of bacteria in the liquid drops.

Incident gout and chronic Kidney Disease: healthcare utilization and survival.

BACKGROUND: Uncontrolled gout can cause significant joint and organ damage and has been associated with impairments in quality of life and high economic cost. Gout has also been associated with other comorbid diseases, such as chronic kidney disease. The current study explored if healthcare resource utilization (HRU) and survival differs between patients with incident gout in the presence or absence of chronic kidney disease (CKD). METHODS: Clalit Health Services (CHS) data were used to conduct a retrospective population-based cohort study of incident gout between 1/1/2006-31/12/2009. Incident cases of gout were identified and stratified by CKD status and by age group (< 55 and 55+ years). CKD status was defined as a pre-existing diagnosis of chronic kidney disease, chronic renal failure, kidney transplantation, or dialysis at index date. Demographic and clinical characteristics, as well as healthcare resource use, were reported. RESULTS: A total of 12,940 incident adult gout patients, with (n = 8286) and without (n = 4654) CKD, were followed for 55,206 person-years. Higher rates of HRU were observed for gout patients with CKD than without. Total annual hospital admissions for patients with gout and CKD were at least 3 times higher for adults < 55 (mean = 0.51 vs 0.13) and approximately 1.5 times higher for adults 55+ (mean = 0.46 vs 0.29) without CKD. Healthcare utilization rates from year 1 to year 5 remained similar for gout patients < 55 years irrespective of CKD status, however varied according to healthcare utilization by CKD status for gout patients 55+ years. The 5-year all-cause mortality was higher among those with CKD compared to those without CKD for both age groups (HR< 55 years = 1.65; 95% CI 1.01-2.71; HR55+ years = 1.50; 95% CI 1.37-1.65). CONCLUSIONS: The current study suggests important differences exist in patient characteristics and outcomes among patients with gout and CKD. Healthcare utilization differed between sub-populations, age and comorbidities, over the study period and the 5-year mortality risk was higher for gout patients with CKD, regardless of age. Future work should explore factors associated with these outcomes and barriers to gout control in order to enhance patient management among this high-risk subgroup.