Alterations in amygdala-prefrontal functional connectivity account for excessive worry and autonomic dysregulation in generalized anxiety disorder

Background: Generalized anxiety disorder (GAD) is characterized by the core symptom of uncontrollable worry. Functional magnetic resonance imaging studies link this symptom to aberrant functional connectivity between the amygdala and prefrontal cortex. Patients with GAD also display a characteristic pattern of autonomic dysregulation. Although frontolimbic circuitry is implicated in the regulation of autonomic arousal, no previous study to our knowledge combined functional magnetic resonance imaging with peripheral physiologic monitoring in these patients to test the hypothesis that core symptoms of worry and autonomic dysregulation in GAD arise from a shared underlying neural mechanism. Methods: We used resting-state functional magnetic resonance imaging and the measurement of parasympathetic autonomic function (heart rate variability) in 19 patients with GAD and 21 control subjects to define neural correlates of autonomic and cognitive responses before and after induction of perseverative cognition. Seed-based analyses were conducted to quantify brain changes in functional connectivity with the right and left amygdala. Results: Before induction, patients showed relatively lower connectivity between the right amygdala and right superior frontal gyrus, right paracingulate/anterior cingulate cortex, and right supramarginal gyrus than control subjects. After induction, such connectivity patterns increased in patients with GAD and decreased in control subjects, and these changes tracked increases in state perseverative cognition. Moreover, decreases in functional connectivity between the left amygdala and subgenual cingulate cortex and between the right amygdala and caudate nucleus predicted the magnitude of reduction in heart rate variability after induction. Conclusions: Our results link functional brain mechanisms underlying worry and rumination to autonomic dyscontrol, highlighting overlapping neural substrates associated with cognitive and autonomic responses to the induction of perseverative cognitions in patients with GAD

A conserved lipid-binding loop in the kindlin FERM F1 domain is required for kindlin-mediated aIIbB3 integrin coactivation

The activation of heterodimeric integrin adhesion receptors from low to high affinity states occurs in response to intracellular signals that act on the short cytoplasmic tails of integrin beta subunits. Binding of the talin FERM (four-point-one, ezrin, radixin, moesin) domain to the integrin beta-tail provides one key activation signal, but recent data indicate that the kindlin family of FERM domain proteins also play a central role. Kindlins directly bind integrin beta subunit cytoplasmic domains at a site distinct from the talin-binding site, and target to focal adhesions in adherent cells. However, the mechanisms by which kindlins impact integrin activation remain largely unknown. A notable feature of kindlins is their similarity to the integrin-binding and activating talin FERM domain. Drawing on this similarity, here we report the identification of an unstructured insert in the kindlin F1 FERM domain, and provide evidence that a highly conserved polylysine motif in this loop supports binding to negatively charged phospholipid head groups. We further show that the F1 loop and its membrane-binding motif are required for kindlin-1 targeting to focal adhesions, and for the cooperation between kindlin-1 and -2 and the talin head in aIIbB3 integrin activation, but not for kindlin binding to integrin beta tails. These studies highlight the structural and functional similarities between kindlins and the talin head and indicate that as for talin, FERM domain interactions with acidic membrane phospholipids as well beta-integrin tails contribute to the ability of kindlins to activate integrins

Computerized exposure therapy for Spider Phobia: Effects of cardiac timing and interoceptive ability on subjective and behavioral outcomes

Objective: Spider phobia is a common form of anxiety disorder for which exposure therapy is an effective first-line treatment. Motivated by the observed modulation of threat processing by afferent cardiac signals; we tested the hypothesis that interoceptive information concerning cardiovascular arousal can influence the outcomes of computerised exposure therapy for spider phobia. Method: Fifty-three normal healthy participants with high spider phobia scores underwent one of three modified computerised exposure protocols, defined by the timing of exposure to brief spider stimuli within the cardiac cycle: Systole (during afferent baroreceptor firing); Diastole (during baroreceptor-quiescent interbeat interval); Random (non-contingent on cardiac cycle). Outcomes were judged on phobic and anxiety measures and physiological data (skin conductance). Subjects were also rated on interoceptive accuracy. Results: Mancova analysis showed that timing group affected the outcome measures (F(10,80)=2.405, p=0.015) and there was a group interaction with interoception ability (F(15,110)=1.808, p=0.045). Subjective symptom reduction (SPQ) was greatest in the Systolic group relative to the other two groups (Diastolic (t=3.115, ptukey=0.009); Random (t=2.438, ptukey=0.048), with greatest reductions in those participants with lower interoceptive accuracy. Behavioural aversion (BAT) reduced more in cardiac-contingent groups than the non-contingent (Random) group (Diastolic (t=3.295, ptukey=0.005); Systolic (t=2.602, ptukey=0.032). Physiological (SCR) responses remained strongest for spider stimuli presented at cardiac systole. Conclusion: Interoceptive information influences exposure benefit. The reduction in the subjective expression of fear/phobia is facilitated by ‘bottom-up’ afferent signals; while improvement in the behavioural expression is further dependent on ‘top-down’ representation of Interoceptive effects in spider phobia treatment self-related physiology (heart rhythm). Individual interoceptive differences moderate these effects, suggesting means to personalise therapy

Network abnormalities in generalized anxiety pervade beyond the amygdala-prefrontal cortex circuit: insights from graph theory

Generalized anxiety (GAD) has excessive anxiety and uncontrollable worry as core symptoms. Abnormal cerebral functioning underpins the expression and perhaps pathogenesis of GAD: Studies implicate impaired communication between the amygdala and the pre-frontal cortex (PFC). Our aim was to longitudinally investigate whether such network abnormalities are spatially restricted to this circuit or if the integrity of functional brain networks is globally disrupted in GAD. We acquired resting-state functional magnetic resonance imaging data from 16 GAD patients and 16 matched controls at baseline and after 1 year. Using network modelling and graph-theory, whole-brain connectivity was characterized from local and global perspectives. Overall lower global efficiency, indicating sub-optimal brain-wide organization and integration, was present in patients with GAD compared to controls. The amygdala and midline cortices showed higher betweenness centrality, reflecting functional dominance of these brain structures. Third, lower betweenness centrality and lower degree emerged for PFC, suggesting weakened inhibitory control. Overall, network organization showed impairments consistent with neurobiological models of GAD (involving amygdala, PFC, and cingulate cortex) and further pointed to an involvement of temporal regions. Such impairments tended to progress over time and predict anxiety symptoms. A graph-analytic approach represents a powerful approach to deepen our understanding of GAD

Development of Soft-Hardware Platform for Training System Design of Electrotechnical Complexes and Electric Drives

The article presents the results of the development of software and hardware platform as the equipment for the training of children and youth work skills with robotics, allowing in the future to apply this knowledge in practice, implementing automation system for home use. We consider the problems of existing solutions. The main difference is the integration of the proposed fees and extensions into a single set by connecting the connectors and the ability to connect third-party components from different manufacturers, without limiting users. As well as a simplified method using a visual object-oriented programming allows you to immediately engage in the work. Prepared lessons and tasks in the game style simplifies the information and allows you to understand how you can apply one or another technical solution

Mice carrying a complete deletion of the talin2 coding sequence are viable and fertile

AbstractMice homozygous for several Tln2 gene targeted alleles are viable and fertile. Here we show that although the expression of talin2 protein is drastically reduced in muscle from these mice, other tissues continue to express talin2 albeit at reduced levels. We therefore generated a Tln2 allele lacking the entire coding sequence (Tln2cd). Tln2cd/cd mice were viable and fertile, and the genotypes of Tln2cd/+ intercrosses were at the expected Mendelian ratio. Tln2cd/cd mice showed no major difference in body mass or the weight of the major organs compared to wild-type, although they displayed a mildly dystrophic phenotype. Moreover, Tln2cd/cd mouse embryo fibroblasts showed no obvious defects in cell adhesion, migration or proliferation. However, the number of Tln2cd/cd pups surviving to adulthood was variable suggesting that such mice have an underlying defect

Neurobiological substrates of cognitive rigidity and autonomic inflexibility in generalized anxiety disorder

Generalized anxiety disorder (GAD) is characterized by difficulties in inhibiting both perseverative thoughts (worry and rumination) and autonomic arousal. We investigated the neurobiological substrates of such abnormal inhibitory processes, hypothesizing aberrant functional coupling within ‘default mode’ (DMN) and autonomic brain networks. Functional imaging and heart rate variability (HRV) data were acquired from GAD patients and controls during performance of three tracking tasks interspersed with a perseverative cognition (PC) induction. After detection of infrequent target stimuli, activity within putative DMN hubs was suppressed, consistent with a redirection of attentional resources from internal to external focus. This magnitude of activity change was attenuated in patients and individuals with higher trait PC, but was predicted by individual differences in HRV. Following the induction of PC in controls, this pattern of neural reactivity became closer to that of GAD patients. Results support, at a neural level, the association between cognitive inflexibility and autonomic rigidity

Exogenous sex steroid hormones and asthma in females:protocol for a population-based retrospective cohort study using a UK primary care database

This work was supported by Asthma UK, grant number: AUK-IG-2016-346. BIN, INS, CRS and AS were in addition support by the Farr Institute and Asthma UK Centre for Applied Research. BIN acknowledges the support of Knut and Alice Wallenberg Foundation and the Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden.Peer reviewedPublisher PD

Bose-Einstein condensation for interacting scalar fields in curved spacetime

We consider the model of self-interacting complex scalar fields with a rigid gauge invariance under an arbitrary gauge group $G$. In order to analyze the phenomenon of Bose-Einstein condensation finite temperature and the possibility of a finite background charge is included. Different approaches to derive the relevant high-temperature behaviour of the theory are presented.Comment: 28 pages, LaTe