A core component of psychological therapy causes adaptive changes in computational learning mechanisms.

BACKGROUND: Cognitive distancing is an emotion regulation strategy commonly used in psychological treatment of various mental health disorders, but its therapeutic mechanisms are unknown. METHODS: 935 participants completed an online reinforcement learning task involving choices between pairs of symbols with differing reward contingencies. Half (49.1%) of the sample was randomised to a cognitive self-distancing intervention and were trained to regulate or 'take a step back' from their emotional response to feedback throughout. Established computational (Q-learning) models were then fit to individuals' choices to derive reinforcement learning parameters capturing clarity of choice values (inverse temperature) and their sensitivity to positive and negative feedback (learning rates). RESULTS: Cognitive distancing improved task performance, including when participants were later tested on novel combinations of symbols without feedback. Group differences in computational model-derived parameters revealed that cognitive distancing resulted in clearer representations of option values (estimated 0.17 higher inverse temperatures). Simultaneously, distancing caused increased sensitivity to negative feedback (estimated 19% higher loss learning rates). Exploratory analyses suggested this resulted from an evolving shift in strategy by distanced participants: initially, choices were more determined by expected value differences between symbols, but as the task progressed, they became more sensitive to negative feedback, with evidence for a difference strongest by the end of training. CONCLUSIONS: Adaptive effects on the computations that underlie learning from reward and loss may explain the therapeutic benefits of cognitive distancing. Over time and with practice, cognitive distancing may improve symptoms of mental health disorders by promoting more effective engagement with negative information.

A Neuroanatomical Substrate Linking Perceptual Stability to Cognitive Rigidity in Autism.

Overly stable visual perception seen in individuals with autism spectrum disorder (ASD) is related to higher-order core symptoms of the condition. However, the neural basis by which these seemingly different symptoms are simultaneously observed in individuals with ASD remains unclear. Here, we aimed to identify such a neuroanatomical substrate linking perceptual stability to autistic cognitive rigidity, a part of core restricted, repetitive behaviors (RRBs). First, using a bistable visual perception test, we measured the perceptual stability of 22 high-functioning adults with ASD and 22 age-, IQ-, and sex-matched typically developing human individuals and confirmed overstable visual perception in autism. Next, using a spontaneous task-switching (TS) test, we showed that the individuals with ASD were more likely to repeat the same task voluntarily and spontaneously, and such rigid TS behavior was associated with the severity of their RRB symptoms. We then compared these perceptual and cognitive behaviors and found a significant correlation between them for individuals with ASD. Finally, we found that this behavioral link was supported by a smaller gray matter volume (GMV) of the posterior superior parietal lobule (pSPL) in individuals with ASD. Moreover, this smaller GMV in the pSPL was also associated with the RRB symptoms and replicated in two independent datasets. Our findings suggest that the pSPL could be one of the neuroanatomical mediators of cognitive and perceptual inflexibility in autism, which could help a unified biological understanding of the mechanisms underpinning diverse symptoms of this developmental disorder.SIGNIFICANCE STATEMENT Behavioral studies show perceptual overstability in autism spectrum disorder (ASD). However, the neural mechanisms by which such sensory symptoms can coexist and often correlate with seemingly separate core symptoms remain unknown. Here, we have identified such a key neuroanatomical substrate. We have revealed that overstable sensory perception of individuals with ASD is linked with their cognitive rigidity, a part of core restricted, repetitive behavior symptoms, and such a behavioral link is underpinned by a smaller gray matter volume in the posterior superior parietal lobule in autism. These findings uncover a key neuroanatomical mediator of autistic perceptual and cognitive inflexibility and would ignite future studies on how the core symptoms of ASD interact with its unique sensory perception.

ZnT8 Haploinsufficiency Impacts MIN6 Cell Zinc Content and ß-Cell Phenotype via ZIP-ZnT8 Coregulation.

The zinc transporter ZnT8 (SLC30A8) localises to insulin secretory granules of ß-cells where it facilitates zinc uptake for insulin crystallisation. ZnT8 abundance has been linked to ß-cell survival and functional phenotype. However, the consequences of ZnT8 haploinsufficiency for ß-cell zinc trafficking and function remain unclear. Since investigations in human populations have shown SLC30A8 truncating polymorphisms to decrease the risk of developing Type 2 Diabetes, we hypothesised that ZnT8 haploinsufficiency would improve ß-cell function and maintain the endocrine phenotype. We used CRISPR/Cas9 technology to generate ZnT8 haploinsufficient mouse MIN6 ß-cells and showed that ZnT8 haploinsufficiency is associated with downregulation of mRNAs for Slc39a8 and Slc39a14, which encode for the zinc importers, Znt- and Irt-related proteins 8 (ZIP8) and 14 (ZIP14), and with lowered total cellular zinc content. ZnT8 haploinsufficiency disrupts expression of a distinct array of important ß-cell markers, decreases cellular proliferation via mitogen-activated protein (MAP) kinase cascades and downregulates insulin gene expression. Thus, ZnT8 cooperates with zinc importers of the ZIP family to maintain ß-cell zinc homeostasis. In contrast to the hypothesis, lowered ZnT8 expression reduces MIN6 cell survival by affecting zinc-dependent transcription factors that control the ß-cell phenotype.

Perception and Processing of Faces in the Human Brain Is Tuned to Typical Feature Locations.

UNLABELLED: Faces are salient social stimuli whose features attract a stereotypical pattern of fixations. The implications of this gaze behavior for perception and brain activity are largely unknown. Here, we characterize and quantify a retinotopic bias implied by typical gaze behavior toward faces, which leads to eyes and mouth appearing most often in the upper and lower visual field, respectively. We found that the adult human visual system is tuned to these contingencies. In two recognition experiments, recognition performance for isolated face parts was better when they were presented at typical, rather than reversed, visual field locations. The recognition cost of reversed locations was equal to ∼60% of that for whole face inversion in the same sample. Similarly, an fMRI experiment showed that patterns of activity evoked by eye and mouth stimuli in the right inferior occipital gyrus could be separated with significantly higher accuracy when these features were presented at typical, rather than reversed, visual field locations. Our findings demonstrate that human face perception is determined not only by the local position of features within a face context, but by whether features appear at the typical retinotopic location given normal gaze behavior. Such location sensitivity may reflect fine-tuning of category-specific visual processing to retinal input statistics. Our findings further suggest that retinotopic heterogeneity might play a role for face inversion effects and for the understanding of conditions affecting gaze behavior toward faces, such as autism spectrum disorders and congenital prosopagnosia. SIGNIFICANCE STATEMENT: Faces attract our attention and trigger stereotypical patterns of visual fixations, concentrating on inner features, like eyes and mouth. Here we show that the visual system represents face features better when they are shown at retinal positions where they typically fall during natural vision. When facial features were shown at typical (rather than reversed) visual field locations, they were discriminated better by humans and could be decoded with higher accuracy from brain activity patterns in the right occipital face area. This suggests that brain representations of face features do not cover the visual field uniformly. It may help us understand the well-known face-inversion effect and conditions affecting gaze behavior toward faces, such as prosopagnosia and autism spectrum disorders.

Expression of the ZIP/SLC39A transporters in ß-cells: a systematic review and integration of multiple datasets.

BACKGROUND: Pancreatic ß-cells require a constant supply of zinc to maintain normal insulin secretory function. Following co-exocytosis with insulin, zinc is replenished via the Zrt- and Irt-like (ZIP; SLC39A) family of transporters. However the ZIP paralogues of particular importance for zinc uptake, and associations with ß-cell function and Type 2 Diabetes remain largely unexplored. We retrieved and statistically analysed publically available microarray and RNA-seq datasets to perform a systematic review on the expression of ß-cell SLC39A paralogues. We complemented results with experimental data on expression profiling of human islets and mouse ß-cell derived MIN6 cells, and compared transcriptomic and proteomic sequence conservation between human, mouse and rat. RESULTS: The 14 ZIP paralogues have 73-98% amino sequence conservation between human and rodents. We identified 18 datasets for ß-cell SLC39A analysis, which compared relative expression to non-ß-cells, and expression in response to PDX-1 activity, cytokines, glucose and type 2 diabetic status. Published expression data demonstrate enrichment of transcripts for ZIP7 and ZIP9 transporters within rodent ß-cells and of ZIP6, ZIP7 and ZIP14 within human ß-cells, with ZIP1 most differentially expressed in response to cytokines and PDX-1 within rodent, and ZIP6 in response to diabetic status in human and glucose in rat. Our qPCR expression profiling data indicate that SLC39A6, -9, -13, and - 14 are the highest expressed paralogues in human ß-cells and Slc39a6 and -7 in MIN6 cells. CONCLUSIONS: Our systematic review, expression profiling and sequence alignment reveal similarities and potentially important differences in ZIP complements between human and rodent ß-cells. We identify ZIP6, ZIP7, ZIP9, ZIP13 and ZIP14 in human and rodent and ZIP1 in rodent as potentially biologically important for ß-cell zinc trafficking. We propose ZIP6 and ZIP7 are key functional orthologues in human and rodent ß-cells and highlight these zinc importers as important targets for exploring associations between zinc status and normal physiology of ß-cells and their decline in Type 2 Diabetes.

The habenula encodes negative motivational value associated with primary punishment in humans.

Learning what to approach, and what to avoid, involves assigning value to environmental cues that predict positive and negative events. Studies in animals indicate that the lateral habenula encodes the previously learned negative motivational value of stimuli. However, involvement of the habenula in dynamic trial-by-trial aversive learning has not been assessed, and the functional role of this structure in humans remains poorly characterized, in part, due to its small size. Using high-resolution functional neuroimaging and computational modeling of reinforcement learning, we demonstrate positive habenula responses to the dynamically changing values of cues signaling painful electric shocks, which predict behavioral suppression of responses to those cues across individuals. By contrast, negative habenula responses to monetary reward cue values predict behavioral invigoration. Our findings show that the habenula plays a key role in an online aversive learning system and in generating associated motivated behavior in humans.

DNA barcoding for biosecurity: case studies from the UK plant protection program.

Since its conception, DNA barcoding has seen a rapid uptake within the research community. Nevertheless, as with many new scientific tools, progression towards the point of routine deployment within diagnostic laboratories has been slow. In this paper, we discuss the application of DNA barcoding in the Defra plant health diagnostic laboratories, where DNA barcoding is used primarily for the identification of invertebrate pests. We present a series of case studies that demonstrate the successful application of DNA barcoding but also reveal some potential limitations to expanded use. The regulated plant pest, Bursephalenchus xylophilus, and one of its vectors, Monochamus alternatus, were found in dining chairs. Some traded wood products are potentially high risk, allowing the movement of longhorn beetles; Trichoferus campestris, Leptura quadrifasciata, and Trichoferus holosericeus were found in a wooden cutlery tray, a railway sleeper, and a dining chair, respectively. An outbreak of Meloidogyne fallax was identified in Allium ampeloprasum and in three weed species. Reference sequences for UK native psyllids were generated to enable the development of rapid diagnostics to be used for monitoring following the release of Aphalara itadori as a biological control agent for Fallopia japonica.

Defining filled and empty space: reassessing the filled space illusion for active touch and vision.

In the filled space illusion, an extent filled with gratings is estimated as longer than an equivalent extent that is apparently empty. However, researchers do not seem to have carefully considered the terms filled and empty when describing this illusion. Specifically, for active touch, smooth, solid surfaces have typically been used to represent empty space. Thus, it is not known whether comparing gratings to truly empty space (air) during active exploration by touch elicits the same illusionary effect. In Experiments 1 and 2, gratings were estimated as longer if they were compared to smooth, solid surfaces rather than being compared to truly empty space. Consistent with this, Experiment 3 showed that empty space was perceived as longer than solid surfaces when the two were compared directly. Together these results are consistent with the hypothesis that, for touch, the standard filled space illusion only occurs if gratings are compared to smooth, solid surfaces and that it may reverse if gratings are compared to empty space. Finally, Experiment 4 showed that gratings were estimated as longer than both solid and empty extents in vision, so the direction of the filled space illusion in vision was not affected by the nature of the comparator. These results are discussed in relation to the dual nature of active touch.

A meta-analysis of cognitive flexibility in autism spectrum disorder.

Cognitive flexibility is a fundamental process that underlies adaptive behaviour in response to environmental change. Studies examining the profile of cognitive flexibility in autism spectrum disorder (ASD) have reported inconsistent findings. To address whether difficulties with cognitive flexibility are characteristic of autism, we conducted a random-effects meta-analysis and employed subgroup analyses and meta-regression to assess the impact of relevant moderator variables such as task, outcomes, and age. Fifty-nine studies were included and comprised of 2122 autistic individuals without intellectual disabilities and 2036 neurotypical controls, with an age range of 4 to 85 years. The results showed that autistic individuals have greater difficulties with cognitive flexibility, with an overall statistically significant small to moderate effect size. Subgroup analyses revealed a significant difference between task outcomes, with perseverative errors obtaining the largest effect size. In summary, the present meta-analysis highlights the existence of cognitive flexibility difficulties in autistic people, in the absence of learning disabilities, but also that this profile is characterised by substantial heterogeneity. Potential contributing factors are discussed.

Towards a Customizable, SLA 3D-Printed Biliary Stent: Optimizing a Commercially Available Resin and Predicting Stent Behavior with Accurate In Silico Testing.

Inflammation of the bile ducts and surrounding tissues can impede bile flow from the liver into the intestines. If this occurs, a plastic or self-expanding metal (SEM) stent is placed to restore bile drainage. United States (US) Food and Drug Administration (FDA)-approved plastic biliary stents are less expensive than SEMs but have limited patency and can occlude bile flow if placed spanning a duct juncture. Recently, we investigated the effects of variations to post-processing and autoclaving on a commercially available stereolithography (SLA) resin in an effort to produce a suitable material for use in a biliary stent, an FDA Class II medical device. We tested six variations from the manufacturer's recommended post-processing and found that tripling the isopropanol (IPA) wash time to 60 min and reducing the time and temperature of the UV cure to 10 min at 40 °C, followed by a 30 min gravity autoclave cycle, yielded a polymer that was flexible and non-cytotoxic. In turn, we designed and fabricated customizable, SLA 3D-printed polymeric biliary stents that permit bile flow at a duct juncture and can be deployed via catheter. Next, we generated an in silico stent 3-point bend test to predict displacements and peak stresses in the stent designs. We confirmed our simulation accuracy with experimental data from 3-point bend tests on SLA 3D-printed stents. Unfortunately, our 3-point bend test simulation indicates that, when bent to the degree needed for placement via catheter (~30°), the peak stress the stents are predicted to experience would exceed the yield stress of the polymer. Thus, the risk of permanent deformation or damage during placement via catheter to a stent printed and post-processed as we have described would be significant. Moving forward, we will test alternative resins and post-processing parameters that have increased elasticity but would still be compatible with use in a Class II medical device.

Defining the habenula in human neuroimaging studies.

Recently there has been renewed interest in the habenula; a pair of small, highly evolutionarily conserved epithalamic nuclei adjacent to the medial dorsal (MD) nucleus of the thalamus. The habenula has been implicated in a range of behaviours including sleep, stress and pain, and studies in non-human primates have suggested a potentially important role in reinforcement processing, putatively via its effects on monoaminergic neurotransmission. Over the last decade, an increasing number of neuroimaging studies have reported functional responses in the human habenula using functional magnetic resonance imaging (fMRI). However, standard fMRI analysis approaches face several challenges in isolating signal from this structure because of its relatively small size, around 30 mm(3) in volume. In this paper we offer a set of guidelines for locating and manually tracing the habenula in humans using high-resolution T1-weighted structural images. We also offer recommendations for appropriate pre-processing and analysis of high-resolution functional magnetic resonance imaging (fMRI) data such that signal from the habenula can be accurately resolved from that in surrounding structures.

A systematic review of the measures that have been used to assess surface characteristics in relation to their impact on walking and falling.

We investigated whether an impediment to progress in understanding the environmental factors that cause falls may be the difficulty in comparing results across studies because walking surfaces are poorly defined and underspecified. We conducted a systematic review of 384 studies from 370 articles that tested how different surfaces influenced human walking and falling. For each study, we report which categories of surfaces were used (indoor, outdoor, treadmill, virtual reality and qualitative), the nature of each surface (stairs, slopes, slippery, compliant, rough or default) and how information about each surface was measured. We found that minimal information was provided for many surfaces, making it impossible to meaningfully compare results for different types of surfaces across studies. We conclude that most published studies of walking and falling provide insufficient data to describe the surfaces that they used and we provide recommendations about how to improve the reporting of walking surfaces.

Transdiagnostic computations of uncertainty: towards a new lens on intolerance of uncertainty.

People radically differ in how they cope with uncertainty. Clinical researchers describe a dispositional characteristic known as "intolerance of uncertainty", a tendency to find uncertainty aversive, reported to be elevated across psychiatric and neurodevelopmental conditions. Concurrently, recent research in computational psychiatry has leveraged theoretical work to characterise individual differences in uncertainty processing. Under this framework, differences in how people estimate different forms of uncertainty can contribute to mental health difficulties. In this review, we briefly outline the concept of intolerance of uncertainty within its clinical context, and we argue that the mechanisms underlying this construct may be further elucidated through modelling how individuals make inferences about uncertainty. We will review the evidence linking psychopathology to different computationally specified forms of uncertainty and consider how these findings might suggest distinct mechanistic routes towards intolerance of uncertainty. We also discuss the implications of this computational approach for behavioural and pharmacological interventions, as well as the importance of different cognitive domains and subjective experiences in studying uncertainty processing.

Uncertainty as a driver of the youth mental health crisis.

Mental health problems in young people have been on the rise for over a decade, with that trend accelerating during the pandemic. This review proposes that the catalyst effect of the pandemic offers insights into a key driver of increases in youth depression and anxiety: greater uncertainty. Uncertainty about many aspects of everyday life, including social connections, education, job security and health, increased during the pandemic, and this coincided with increasing rates of depression and anxiety. Lab-based developmental cognitive and clinical neuroscience research on tolerance of uncertainty and adolescent mental health shows that when adolescents fail to show age-typical tolerance of uncertainty, they are at greater risk of mental health problems. Avenues for future research to understand and promote tolerance of uncertainty in adolescents are proposed.

Dietary protein, lipid and insect meal on growth, plasma biochemistry and hepatic immune expression of lake whitefish (Coregonus clupeaformis).

Studies are lacking that investigate the dietary nutrient requirements of lake whitefish (Coregonus clupeaformis), a newly farmed fish species in Ontario, Canada. Dietary levels of protein and lipid must be optimized to ensure high growth performance for the commercial success of this species. Additionally, the inclusion of insect meal in the diet may improve growth and immune response. The objective of this study was to evaluate the effects of dietary protein:lipid ratios and insect meal as a feed additive on the growth performance and hepatic immune function of juvenile lake whitefish (301 ± 10 g). A 16-week (112 day) trial was performed with five diets including a commercial control diet (BCC), and four experimental diets with high or low levels of protein (54 and 48%, respectively) and lipid (18 and 12%, respectively). The high protein dietary groups contained 5% of full-fat black soldier fly larvae (Hermetia illucens). Fish weights, viscera, liver, and blood were collected for further analysis. Specific growth rate, thermal growth coefficient and weight gain were significantly higher in fish fed with the BCC and high protein high lipid (HPHL) diets. However, viscerosomatic index was found to be significantly higher in fish fed the BCC diet, thus HPHL is more optimal for non-visceral weight gain. Higher levels of plasma phosphorus, aspartate aminotransferase and potassium indicated poor growth and stress in fish fed low lipid diets. Relative expression of HSP70, involved in cellular repair, was significantly downregulated in fish fed high lipid diets, and no effects were found on the expression of innate immune and oxidative stress genes. Also, IL8 (CXCL8) and catalase were upregulated (non-significant) in fish fed the HPHL diet with the largest weight gain. No effects of insects were found on growth, plasma biochemistry or gene expression, which suggests 5% dietary inclusion was too low. Overall, we recommend a HPHL diet for the cultivation of lake whitefish based on improved growth performance, low viscera weight, improved plasma biochemistry and downregulation of cellular repair genes.

Changes in "top-down" connectivity underlie repetition suppression in the ventral visual pathway.

Repetition of the same stimulus leads to a reduction in neural activity known as repetition suppression (RS). In functional magnetic resonance imaging (fMRI), RS is found for multiple object categories. One proposal is that RS reflects locally based "within-region" changes, such as neural fatigue. Thus, if a given region shows RS across changes in stimulus size or view, then it is inferred to hold size- or view-invariant representations. An alternative hypothesis characterizes RS as a consequence of "top-down" between-region modulation. Differentiating between these accounts is central to the correct interpretation of fMRI RS data. It is also unknown whether the same mechanisms underlie RS to identical stimuli and RS across changes in stimulus size or view. Using fMRI, we investigated RS within a body-sensitive network in human visual cortex comprising the extrastriate body area (EBA) and the fusiform body area (FBA). Both regions showed RS to identical images of the same body that was unaffected by changes in body size or view. Dynamic causal modeling demonstrated that changes in backward, top-down (FBA-to-EBA) effective connectivity play a critical role in RS. Furthermore, only repetition of the identical image showed additional changes in forward connectivity (EBA-to-FBA). These results suggest that RS is driven by changes in top-down modulation, whereas the contribution of "feedforward" changes in connectivity is dependent on the precise nature of the repetition. Our results challenge previous interpretations regarding the underlying nature of neural representations made using fMRI RS paradigms.

Transgenerational effects of zinc in zebrafish following early life stage exposure.

Although toxic effects of zinc (Zn) have been well established in the different developmental stages in fish, long-lasting effects of Zn exposure during embryonic development have not been explored. Exposure to an environmentally relevant Zn concentration of 10 µM (650 µg/L) during the first five days after fertilization did not affect survival, body weight, malformations or overall hatching success of F0 and F1 larvae. Zn exposure did, however, result in delayed hatching in both the F0 and F1 generations and caused significant changes in homeostasis of Zn and selenium (Se) in F0 and F1 fish. This was especially pronounced when F1 embryos from Zn-exposed parents were treated with 30 µM (2000 µg/L) Zn. In the F0 generation, skewed sex ratio towards males and changes in homeostasis of Zn, Se and manganese (Mn) in the brain, gill, liver and gonad of adult fish were also observed. These changes were associated with altered expression of Zn- and Mn-regulatory genes and sex differentiation genes in F0 and F1 fish. The present study suggests that fish may carry memory from embryo-larval Zn exposure into adulthood and further to the next generation. The present study shows that ecotoxicological risk of an exposure to Zn during embryo-larval development may persist long after recovery and may also manifest in the F1 generation.

Perceptual decision-making in autism as assessed by "spot the difference" visual cognition tasks.

Discriminating between similar figures proves to be a remarkably demanding task due to the limited capacity of our visual cognitive processes. Here we examine how perceptual inference and decision-making are modulated by differences arising from neurodiversity. A large sample of autistic (n = 140) and typical (n = 147) participants completed two forced choice similarity judgement tasks online. Each task consisted of "match" (identical figures) and "mismatch" (subtle differences between figures) conditions. Signal detection theory analyses indicated a response bias by the autism group during conditions of uncertainty. More specifically, autistic participants were more likely to choose the "mismatch" option, thus leading to more hits on the "mismatch" condition, but also more false alarms on the "match" condition. These results suggest differences in response strategies during perceptual decision-making in autism.

The rubber hand illusion in a mirror.

In the rubber hand illusion (RHI) one's hand is hidden, and a fake hand is visible. We explored the situation in which visual information was available indirectly in a mirror. In the mirror condition, compared to the standard condition (fake hand visible directly), we found no reduction of the RHI following synchronised stimulation, as measured by crossmanual pointing and by a questionnaire. We replicated the finding with a smaller mirror that prevented visibility of the face. The RHI was eliminated when a wooden block replaced the fake hand, or when the hand belonged to another person or mannequin. We conclude that awareness of the reflection is the critical variable, despite the distant visual localisation of the hand in a mirror and the third-person perspective. Stimuli seen in a mirror activate the same response as stimuli seen in peripersonal space, through knowledge that they are near one's body.