Single-Dose P2 X4R Single-Chain Fragment Variable Antibody Permanently Reverses Chronic Pain in Male Mice

Non-opioid single-chain variable fragment (scFv) small antibodies were generated as pain-reducing block of P2X4R receptor (P2X4R). A panel of scFvs targeting an extracellular peptide sequence of P2X4R was generated followed by cell-free ribosome display for recombinant antibody selection. After three rounds of bio-panning, a panel of recombinant antibodies was isolated and characterized by ELISA, cross-reactivity analysis, and immunoblotting/immunostaining. Generated scFv antibodies feature binding activity similar to monoclonal antibodies but with stronger affinity and increased tissue penetrability due to their ~30% smaller size. Two anti-P2X4R scFv clones (95, 12) with high specificity and affinity binding were selected for in vivo testing in male and female mice with trigeminal nerve chronic neuropathic pain (FRICT-ION model) persisting for several months in untreated BALBc mice. A single dose of P2X4R scFv (4 mg/kg, i.p.) successfully, completely, and permanently reversed chronic neuropathic pain-like measures in male mice only, providing retention of baseline behaviors indefinitely. Untreated mice retained hypersensitivity, and developed anxiety- and depression-like behaviors within 5 weeks. In vitro P2X4R scFv 95 treatment significantly increased the rheobase of larger-diameter (>25 µm) trigeminal ganglia (TG) neurons from FRICT-ION mice compared to controls. The data support use of engineered scFv antibodies as non-opioid biotherapeutic interventions for chronic pain.

Inflammatory Biomarkers and Sex Hormones Interact to Predict Ecologically-Assessed Cognitive Performance

Inflammatory biomarkers and sex hormones have been investigated as independent risk and resilience factors for cognitive decline in older adults. Many sex hormones are anti-inflammatory and there is emerging evidence that sex hormones may buffer the risk for cognitive decline associated with higher inflammation. However, few studies have included concurrent examination of inflammation and sex hormones in studies of cognitive performance and cognitive aging. A diverse sample of older adults (N = 245; 65% female, 42% Black, 13% Hispanic; mean age = 76.8 years) had blood drawn before and after a two-week measurement burst that included three cognitive tests (6x per day) assessing working spatial memory, perceptual speed, and feature binding. Testosterone, estradiol, estrone, and six basal cytokine concentrations were quantified. Composite scores of basal inflammation were calculated. Multilevel modeling indicated that heightened inflammation related to poorer spatial working memory performance (B = 0.213, 95%CI[0.11, 0.414], p = .040). In addition, sex hormones moderated the association of cytokine concentration with perceptual speed (e.g., basal cytokines x testosterone: B = 0.13, [-0.24, -0.03], p = 0.013; similar effects evident for estrogens). Decomposition these interactions revealed that heightened inflammation predicted poorer performance, but only among individuals with lower sex-hormone concentrations. This study provides evidence of immune and hormonal-by-immune associations with performance in two cognitive domains in older adults. Examining the functional crosstalk between immune and sex hormone functioning will improve understanding of risk and resilience factors related to cognitive performance and help predict cognitive decline in older adults.

Additional Resources for Sparse Theories of Phenomenal Consciousness

The phenomenal overflow debate is a debate about the richness of phenomenal consciousness. There are two candidate views: the rich view and the sparse view. The rich view says phenomenal consciousness outstrips access consciousness and the contents of working memory. The sparse view denies this. Moreover, according to some conceptions of the sparse view, the subjective impression of richness depends on scene statistics and the refrigerator-light illusion. The purpose of this paper is to show there are additional resources available to the sparse view in accommodating intuitions of richness that have yet to be fully appreciated by participants in the debate. To this end, research pertaining to feature binding and activity-silent working memory will be discussed.

Across-Area Synchronization Supports Feature Integration in a Biophysical Network Model of Working Memory

Working memory function is severely limited. One key limitation that constrains the ability to maintain multiple items in working memory simultaneously is so-called swap errors. These errors occur when an inaccurate response is in fact accurate relative to a non-target stimulus, reflecting the failure to maintain the appropriate association or “binding” between the features that define one object (e.g., color and location). The mechanisms underlying feature binding in working memory remain unknown. Here, we tested the hypothesis that features are bound in memory through synchrony across feature-specific neural assemblies. We built a biophysical neural network model composed of two one-dimensional attractor networks – one for color and one for location – simulating feature storage in different cortical areas. Within each area, gamma oscillations were induced during bump attractor activity through the interplay of fast recurrent excitation and slower feedback inhibition. As a result, different memorized items were held at different phases of the network’s oscillation. These two areas were then reciprocally connected via weak cortico-cortical excitation, accomplishing binding between color and location through the synchronization of pairs of bumps across the two areas. Encoding and decoding of color-location associations was accomplished through rate coding, overcoming a long-standing limitation of binding through synchrony. In some simulations, swap errors arose: “color bumps” abruptly changed their phase relationship with “location bumps.” This model, which leverages the explanatory power of similar attractor models, specifies a plausible mechanism for feature binding and makes specific predictions about swap errors that are testable at behavioral and neurophysiological levels.

The Association between the Binding Processes of Working Memory and Vascular Risk Profile in Adults

Episodic buffer (EB), a key component of working memory, seems to have a rather complicated function as part of binding processes. Recent papers on the field claim that binding processes of working memory (WM) are assisted by attention and executive functions. On the same page, vascular pathology is gaining more ground as the main underlying cause for many brain pathologies. Hypercholesterolemia, hypertension, obesity, diabetes, lack of exercise and smoking are the most common risk factors that people of all ages suffer from and constitute the main vascular risk factors responsible for a possible decline in executive functions and attention. Thus, this research is an attempt to examine the relation between the binding functions of WM and the existence of vascular risk factors via a computerized test focusing on feature binding. The study comprised adults (n = 229) with and without vascular risk factors. The main tools used were a biomarker questionnaire and a feature binding test (FBT). The results showed that participants who report suffering from one or more vascular risk factors had significantly lower performance on specific subtasks of the FBT in comparison to the participants who were healthy. This allows us to assume that there might be a positive association between feature binding and a vascular risk profile in adults, and such a test could be a useful diagnostic tool for early cognitive impairment due to incipient vascular pathology.

The role of transient attention in crowding and feature binding

Crowding refers to the failure to identify a peripheral object due to nearby objects (flankers). A hallmark of crowding is the inner-outer asymmetry, i.e., the outer flanker (more peripheral) produces stronger interference than the inner one. Here, by manipulating attention, we tested the predictions of two competing accounts: the attentional account, which predicts a positive attentional effect on the asymmetry (i.e., attention to the outer flanker will increase the asymmetry), and the receptive field size account, which predicts a negative attentional effect. In Experiment 1, observers estimated a Gabor target orientation. A peripheral pre-cue draws attention to one of three locations: target, inner or outer flanker. Probabilistic mixture modeling demonstrated the asymmetry by showing that observers often misreported the outer flanker orientation as the target. Interestingly, the outer cue led to a higher misreport rate of the outer flanker, and the inner cue led to a lower misreport rate of the outer flanker. Experiment 2 tested the effect of asymmetry and attention on binding errors (e.g., reporting the tilt of one presented item with the color of another item). Observers reported both the tilt and color of the target. Attention increased target reports in both dimensions and led to a decrease in target binding. However, attention did not lead to a decrease in flanker biding errors. The results are consistent with the attentional account of crowding and suggest that the locus of spatial attention plays an essential role in crowding and the inner-outer asymmetry.