Multisensory integration across exteroceptive and interoceptive domains modulates self-experience in the rubber-hand illusion

Identifying with a body is central to being a conscious self. The now classic “rubber hand illusion” demonstrates that the experience of body ownership can be modulated by manipulating the timing of exteroceptive(visual and tactile)body-related feedback. Moreover,the strength of this modulation is related to individual differences in sensitivity to internal bodily signals(interoception). However the interaction of exteroceptive and interoceptive signals in determining the experience of body-ownership within an individual remains poorly understood.Here, we demonstrate that this depends on the online integration of exteroceptive and interoceptive signals by implementing an innovative “cardiac rubber hand illusion” that combined computer-generated augmented-reality with feedback of interoceptive (cardiac) information. We show that both subjective and objective measures of virtual-hand ownership are enhanced by cardio-visual feedback in-time with the actual heartbeat,as compared to asynchronous feedback. We further show that these measures correlate with individual differences in interoceptive sensitivity,and are also modulated by the integration of proprioceptive signals instantiated using real-time visual remapping of finger movements to the virtual hand.Our results demonstrate that interoceptive signals directly influence the experience of body ownership via multisensory integration,and they lend support to models of conscious selfhood based on interoceptive predictive coding

Loss of talin1 in platelets abrogates integrin activation, platelet aggregation, and thrombus formation in vitro and in vivo

Platelet adhesion and aggregation at sites of vascular injury are essential for normal hemostasis but may also lead to pathological thrombus formation, causing diseases such as myocardial infarction or stroke. Heterodimeric receptors of the integrin family play a central role in the adhesion and aggregation of platelets. In resting platelets, integrins exhibit a low affinity state for their ligands, and they shift to a high affinity state at sites of vascular injury. It has been proposed that direct binding of the cytoskeletal protein talin1 to the cytoplasmic domain of the integrin β subunits is necessary and sufficient to trigger the activation of integrins to this high affinity state, but direct in vivo evidence in support of this hypothesis is still lacking. Here, we show that platelets from mice lacking talin1 are unable to activate integrins in response to all known major platelet agonists while other cellular functions are still preserved. As a consequence, mice with talin-deficient platelets display a severe hemostatic defect and are completely resistant to arterial thrombosis. Collectively, these experiments demonstrate that talin is required for inside-out activation of platelet integrins in hemostasis and thrombosis

Emotional orienting during interoceptive threat in orthostatic intolerance: dysautonomic contributions to psychological symptomatology in the postural tachycardia syndrome and vasovagal syncope

Cognitive and emotional processes are influenced by interoception (homeostatic somatic feedback), particularly when physiological arousal is unexpected and discrepancies between predicted and experienced interoceptive signals may engender anxiety. Due to the vulnerability for comorbid psychological symptoms in forms of orthostatic intolerance (OI), this study investigated psychophysiological contributions to emotional symptomatology in 20 healthy control participants (13 females, mean age 36 ± 8 years), 20 postural tachycardia syndrome (PoTS) patients (18 females, mean age 38 ± 13 years) and 20 vasovagal syncope (VVS) patients (15 females, mean age 39 ± 12 years). We investigated indices of emotional orienting responses (OR) to randomly presented neutral, pleasant and unpleasant images in the supine position and during the induced interoceptive threat of symptom provocation of head-up tilt (HUT). PoTS and VVS patients produced greater indices of emotional responsivity to unpleasant images and, to a lesser degree, pleasant images, during interoceptive threat. Our findings are consistent with biased deployment of response-focused emotion regulation (ER) while patients are symptomatic, providing a mechanistic underpinning of how pathological autonomic overexcitation predisposes to anxiogenic traits in PoTS and VVS patients. This hypothesis may improve our understanding of why orthostasis exacerbates cognitive symptoms despite apparently normal cerebral autoregulation, and offer novel therapeutic targets for behavioural interventions aimed at reducing comorbid cognitive-affective symptoms in PoTS and VVS

Which intervention is better for malaria vector control: insecticide mixture long-lasting insecticidal nets or standard pyrethroid nets combined with indoor residual spraying?

BACKGROUND: Malaria control today is threatened by widespread insecticide resistance in vector populations. The World Health Organization (WHO) recommends the use of a mixture of unrelated insecticides for indoor residual spraying (IRS) and long-lasting insecticidal nets (LNs) or as a combination of interventions for improved vector control and insecticide resistance management. Studies investigating the efficacy of these different strategies are necessary. METHODS: The efficacy of Interceptor® G2 LN, a newly developed LN treated with a mixture of chlorfenapyr (a pyrrole) and alpha-cypermethrin (a pyrethroid), was compared to a combined chlorfenapyr IRS and Interceptor® LN (a standard alpha-cypermethrin LN) intervention in experimental huts in Cove Southern Benin, against wild, free-flying, pyrethroid-resistant Anopheles gambiae s.l. A direct comparison was also made with a pyrethroid-only net (Interceptor® LN) alone and chorfenapyr IRS alone. RESULTS: WHO resistance bioassays performed during the trial demonstrated a pyrethroid resistance frequency of >90% in the wild An. gambiae s.l. from the Cove hut site. Mortality in the control (untreated net) hut was 5%. Mortality with Interceptor® LN (24%) was lower than with chlorfenapyr IRS alone (59%, P < 0.001). The combined Interceptor® LN and chlorfenapyr IRS intervention and the mixture net (Interceptor® G2 LN) provided significantly higher mortality rates (73 and 76%, respectively) and these did not differ significantly between both treatments (P = 0.15). Interceptor LN induced 46% blood-feeding inhibition compared to the control untreated net, while chlorfenapyr IRS alone provided none. Both mixture/combination strategies also induced substantial levels of blood-feeding inhibition (38% with combined interventions and 30% with Interceptor® G2 LN). A similar trend of improved mortality of pyrethroid-resistant An. gambiae s.l. from Cove was observed with Interceptor® G2 LN (79%) compared to Interceptor LN (42%, P < 0.001) in WHO tunnel tests. CONCLUSION: The use of chlorfenapyr and alpha-cypermethrin together as a mixture on nets (Interceptor® G2 LN) or a combined chlorfenapyr IRS and pyrethroid LN intervention provides improved control of pyrethroid-resistant malaria vectors by inducing significantly higher levels of mortality through the chlorfenapyr component and providing personal protection through the pyrethroid component. Both strategies are comparable in their potential to improve the control of malaria transmitted by pyrethroid resistant mosquito vectors

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