People with a tobacco use disorder exhibit misaligned Bayesian belief updating by falsely attributing non-drug cues as worse predictors of positive outcomes compared to drug cues.

Adaptive behaviours depend on dynamically updating internal representations of the world based on the ever-changing environmental contingencies. People with a substance use disorder (pSUD) show maladaptive behaviours with high persistence in drug-taking, despite severe negative consequences. We recently proposed a salience misattribution model for addiction (SMMA; Kalhan et al., 2021), arguing that pSUD have aberrations in their updating processes where drug cues are misattributed as strong predictors of positive outcomes, but weaker predictors of negative outcomes. We also argued that conversely, non-drug cues are misattributed as weak predictors of positive outcomes, but stronger predictors of negative outcomes. We tested these hypotheses using a multi-cue reversal learning task, with reversals in whether drug or non-drug cues are relevant in predicting the outcome (monetary win or loss). We show that people with a tobacco use disorder (pTUD), do form misaligned internal representations. We found that pTUD updated less towards learning the drug cue's relevance in predicting a loss. Further, when neither drug nor non-drug cue predicted a win, pTUD updated more towards the drug cue being relevant predictors of that win. Our Bayesian belief updating model revealed that pTUD had a low estimated likelihood of non-drug cues being predictors of wins, compared to drug cues, which drove the misaligned updating. Overall, several hypotheses of the SMMA were supported, but not all. Our results implicate that strengthening the non-drug cue association with positive outcomes may help restore the misaligned internal representation in pTUD, and offers a quantifiable, computational account of these updating processes.

Improved Efficacy of Delayed Treatment with Human Bone Marrow-Derived Stromal Cells Evaluated in Rats with Spinal Cord Injury.

The treatment of spinal cord injury (SCI) with uncultivated human bone marrow-derived stromal cells (bmSCs) prepared by negative selection has been proposed to be therapeutically superior to treatment with stem cells that were expanded in vitro. To explore their use in clinical trials, we studied the functional effects of delayed application at 7 days after SCI by testing different doses of bmSCs. Spinal cord contusion injury was induced in adult male Wistar rats at the thoracic level T9. Human bmSCs were prepared by negative selection without expansion in vitro (NeuroCellsTM). Treatment consisted of one 150 µL injection into the cisterna magna containing 0.5 or 2.5 million fresh bmSCs or 2.5 million bmSCs. The recovery of motor functions was evaluated during a surveillance period of six weeks (6 W), during which spinal cords were assessed histologically. Treatment resulted in a significant, dose-dependent therapeutic effect on the recovery of motor performance. The histological analysis revealed a lower degree of axonal degeneration and better survival of neurons and oligodendrocytes in bmSCs treated rats. Our results support delayed intrathecal application of bmSCs prepared by negative selection without expansion in vitro as a treatment of SCI.

Self-motion induced environmental kinetopsia and pop-out illusion - Insight from a single case phenomenology.

Stable visual perception, while we are moving, depends on complex interactions between multiple brain regions. We report a patient with damage to the right occipital and temporal lobes who presented with a visual disturbance of inward movement of roadside buildings towards the centre of his visual field, that occurred only when he moved forward on his motorbike. We describe this phenomenon as "self-motion induced environmental kinetopsia". Additionally, he was identified to have another illusion, in which objects displayed on the screen, appeared to pop out of the background. Here, we describe the clinical phenomena and the behavioural tasks specifically designed to document and measure this altered visual experience. Using the methods of lesion mapping and lesion network mapping we were able to demonstrate disrupted functional connectivity in the areas that process flow-parsing such as V3A and V6 that may underpin self-motion induced environmental kinetopsia. Moreover, we suggest that altered connectivity to the regions that process environmental frames of reference such as retrosplenial cortex (RSC) might explain the pop-out illusion. Our case adds novel and convergent lesion-based evidence to the role of these brain regions in visual processing.

Sex modulation of faces prediction error in the autistic brain.

Recent research suggests that autistic females may have superior socio-cognitive abilities compared to autistic males, potentially contributing to underdiagnosis in females. However, it remains unclear whether these differences arise from distinct neurophysiological functioning in autistic males and females. This study addresses this question by presenting 41 autistic and 48 non-autistic adults with a spatially filtered faces oddball paradigm. Analysis of event-related potentials from scalp electroencephalography reveal a neurophysiological profile in autistic females that fell between those of autistic males and non-autistic females, highlighting sex differences in autism from the initial stages of face processing. This finding underscores the urgent need to explore neurophysiological sex differences in autism and encourages efforts toward a better comprehension of compensation mechanism and a clearer definition of what is meant by camouflaging.

Neurodesk: an accessible, flexible and portable data analysis environment for reproducible neuroimaging.

Neuroimaging research requires purpose-built analysis software, which is challenging to install and may produce different results across computing environments. The community-oriented, open-source Neurodesk platform ( https://www.neurodesk.org/ ) harnesses a comprehensive and growing suite of neuroimaging software containers. Neurodesk includes a browser-accessible virtual desktop, command-line interface and computational notebook compatibility, allowing for accessible, flexible, portable and fully reproducible neuroimaging analysis on personal workstations, high-performance computers and the cloud.

Are we really Bayesian? Probabilistic inference shows sub-optimal knowledge transfer.

Numerous studies have found that the Bayesian framework, which formulates the optimal integration of the knowledge of the world (i.e. prior) and current sensory evidence (i.e. likelihood), captures human behaviours sufficiently well. However, there are debates regarding whether humans use precise but cognitively demanding Bayesian computations for behaviours. Across two studies, we trained participants to estimate hidden locations of a target drawn from priors with different levels of uncertainty. In each trial, scattered dots provided noisy likelihood information about the target location. Participants showed that they learned the priors and combined prior and likelihood information to infer target locations in a Bayes fashion. We then introduced a transfer condition presenting a trained prior and a likelihood that has never been put together during training. How well participants integrate this novel likelihood with their learned prior is an indicator of whether participants perform Bayesian computations. In one study, participants experienced the newly introduced likelihood, which was paired with a different prior, during training. Participants changed likelihood weighting following expected directions although the degrees of change were significantly lower than Bayes-optimal predictions. In another group, the novel likelihoods were never used during training. We found people integrated a new likelihood within (interpolation) better than the one outside (extrapolation) the range of their previous learning experience and they were quantitatively Bayes-suboptimal in both. We replicated the findings of both studies in a validation dataset. Our results showed that Bayesian behaviours may not always be achieved by a full Bayesian computation. Future studies can apply our approach to different tasks to enhance the understanding of decision-making mechanisms.

Feedforward connectivity patterns from visual areas to the front of the brain contain information about sensory stimuli regardless of awareness or report.

Current theories of consciousness can be categorized to some extent by their predictions about the putative role of the prefrontal cortex (PFC) in conscious perception. One family of the theories proposes that the PFC is necessary for conscious perception. The other postulates that the PFC is not necessary and that other areas (e.g., posterior cortical areas) are more important for conscious perception. No-report paradigms could potentially arbitrate the debate as they disentangle task reporting from conscious perception. While previous no-report paradigms tend to point to a reduction in PFC activity, they have not examined the critical role of the PFC in "monitoring" or "reading out" the patterns of activity in the sensory cortex to generate conscious perception. To address this, we reanalysed electroencephalography (EEG) data from a no-report inattentional blindness paradigm (Shafto & Pitts, 2015). We examined the role of feedforward input patterns to the PFC from sensory cortices. We employed nonparametric spectral Granger causality and quantified the amount of information that reflected the contents of consciousness using multivariate classifiers. Unexpectedly, regardless of whether the stimulus was consciously seen or not, we found that information relating to the current sensory stimulus was present in the pattern of inputs from visual areas to the PFC. In light of these findings, we suggest various theories of consciousness need to be revised to accommodate the fact that the contents of consciousness are decodable from the input patterns from posterior sensory regions to the PFC, regardless of awareness (or report).

Temporal stability of Bayesian belief updating in perceptual decision-making.

Bayesian inference suggests that perception is inferred from a weighted integration of prior contextual beliefs with current sensory evidence (likelihood) about the world around us. The perceived precision or uncertainty associated with prior and likelihood information is used to guide perceptual decision-making, such that more weight is placed on the source of information with greater precision. This provides a framework for understanding a spectrum of clinical transdiagnostic symptoms associated with aberrant perception, as well as individual differences in the general population. While behavioral paradigms are commonly used to characterize individual differences in perception as a stable characteristic, measurement reliability in these behavioral tasks is rarely assessed. To remedy this gap, we empirically evaluate the reliability of a perceptual decision-making task that quantifies individual differences in Bayesian belief updating in terms of the relative precision weighting afforded to prior and likelihood information (i.e., sensory weight). We analyzed data from participants (n = 37) who performed this task twice. We found that the precision afforded to prior and likelihood information showed high internal consistency and good test-retest reliability (ICC = 0.73, 95% CI [0.53, 0.85]) when averaged across participants, as well as at the individual level using hierarchical modeling. Our results provide support for the assumption that Bayesian belief updating operates as a stable characteristic in perceptual decision-making. We discuss the utility and applicability of reliable perceptual decision-making paradigms as a measure of individual differences in the general population, as well as a diagnostic tool in psychiatric research.

Bayesian accounts of perceptual decisions in the nonclinical continuum of psychosis: Greater imprecision in both top-down and bottom-up processes.

Neurocomputational accounts of psychosis propose mechanisms for how information is integrated into a predictive model of the world, in attempts to understand the occurrence of altered perceptual experiences. Conflicting Bayesian theories postulate aberrations in either top-down or bottom-up processing. The top-down theory predicts an overreliance on prior beliefs or expectations resulting in aberrant perceptual experiences, whereas the bottom-up theory predicts an overreliance on current sensory information, as aberrant salience is directed towards objectively uninformative stimuli. This study empirically adjudicates between these models. We use a perceptual decision-making task in a neurotypical population with varying degrees of psychotic-like experiences. Bayesian modelling was used to compute individuals' reliance on prior relative to sensory information. Across two datasets (discovery dataset n = 363; independent replication in validation dataset n = 782) we showed that psychotic-like experiences were associated with an overweighting of sensory information relative to prior expectations, which seem to be driven by decreased precision afforded to prior information. However, when prior information was more uncertain, participants with greater psychotic-like experiences encoded sensory information with greater noise. Greater psychotic-like experiences were associated with aberrant precision in the encoding both prior and likelihood information, which we suggest may be related to generally heightened perceptions of task instability. Our study lends empirical support to notions of both weaker bottom-up and weaker (rather than stronger) top-down perceptual processes, as well as aberrancies in belief updating that extend into the non-clinical continuum of psychosis.

Reward prediction-errors weighted by cue salience produces addictive behaviours in simulations, with asymmetrical learning and steeper delay discounting.

Dysfunction in learning and motivational systems are thought to contribute to addictive behaviours. Previous models have suggested that dopaminergic roles in learning and motivation could produce addictive behaviours through pharmacological manipulations that provide excess dopaminergic signalling towards these learning and motivational systems. Redish (2004) suggested a role based on dopaminergic signals of value prediction error, while (Zhang et al., 2009) suggested a role based on dopaminergic signals of motivation. However, both models present significant limitations. They do not explain the reduced sensitivity to drug-related costs/negative consequences, the increased impulsivity generally found in people with a substance use disorder, craving behaviours, and non-pharmacological dependence, all of which are key hallmarks of addictive behaviours. Here, we propose a novel mathematical definition of salience, that combines aspects of dopamine's role in both learning and motivation within the reinforcement learning framework. Using a single parameter regime, we simulated addictive behaviours that the (Zhang et al., 2009; Redish, 2004) models also produce but we went further in simulating the downweighting of drug-related negative prediction-errors, steeper delay discounting of drug rewards, craving behaviours and aspects of behavioural/non-pharmacological addictions. The current salience model builds on our recently proposed conceptual theory that salience modulates internal representation updating and may contribute to addictive behaviours by producing misaligned internal representations (Kalhan et al., 2021). Critically, our current mathematical model of salience argues that the seemingly disparate learning and motivational aspects of dopaminergic functioning may interact through a salience mechanism that modulates internal representation updating.

IκB kinase-α coordinates BRD4 and JAK/STAT signaling to subvert DNA damage-based anticancer therapy.

Activation of the IκB kinase (IKK) complex has recurrently been linked to colorectal cancer (CRC) initiation and progression. However, identification of downstream effectors other than NF-κB has remained elusive. Here, analysis of IKK-dependent substrates in CRC cells after UV treatment revealed that phosphorylation of BRD4 by IKK-α is required for its chromatin-binding at target genes upon DNA damage. Moreover, IKK-α induces the NF-κB-dependent transcription of the cytokine LIF, leading to STAT3 activation, association with BRD4 and recruitment to specific target genes. IKK-α abrogation results in defective BRD4 and STAT3 functions and consequently irreparable DNA damage and apoptotic cell death upon different stimuli. Simultaneous inhibition of BRAF-dependent IKK-α activity, BRD4, and the JAK/STAT pathway enhanced the therapeutic potential of 5-fluorouracil combined with irinotecan in CRC cells and is curative in a chemotherapy-resistant xenograft model. Finally, coordinated expression of LIF and IKK-α is a poor prognosis marker for CRC patients. Our data uncover a functional link between IKK-α, BRD4, and JAK/STAT signaling with clinical relevance.

Evidence for adaptive myelination of subcortical shortcuts for visual motion perception in healthy adults.

Conscious visual motion information follows a cortical pathway from the retina to the lateral geniculate nucleus (LGN) and on to the primary visual cortex (V1) before arriving at the middle temporal visual area (MT/V5). Alternative subcortical pathways that bypass V1 are thought to convey unconscious visual information. One flows from the retina to the pulvinar (PUL) and on to medial temporal visual area (MT); while the other directly connects the LGN to MT. Evidence for these pathways comes from non-human primates and modest-sized studies in humans with brain lesions. Thus, the aim of the current study was to reconstruct these pathways in a large sample of neurotypical individuals and to determine the degree to which these pathways are myelinated, suggesting information flow is rapid. We used the publicly available 7T (N = 98; 'discovery') and 3T (N = 381; 'validation') diffusion magnetic resonance imaging datasets from the Human Connectome Project to reconstruct the PUL-MT (including all subcompartments of the PUL) and LGN-MT pathways. We found more fibre tracts with greater density in the left hemisphere. Although the left PUL-MT path was denser, the bilateral LGN-MT tracts were more heavily myelinated, suggesting faster signal transduction. We suggest that this apparent discrepancy may be due to 'adaptive myelination' caused by more frequent use of the LGN-MT pathway that leads to greater myelination and faster overall signal transmission.

Neurodesk: An accessible, flexible, and portable data analysis environment for reproducible neuroimaging.

Neuroimaging data analysis often requires purpose-built software, which can be challenging to install and may produce different results across computing environments. Beyond being a roadblock to neuroscientists, these issues of accessibility and portability can hamper the reproducibility of neuroimaging data analysis pipelines. Here, we introduce the Neurodesk platform, which harnesses software containers to support a comprehensive and growing suite of neuroimaging software (https://www.neurodesk.org/). Neurodesk includes a browser-accessible virtual desktop environment and a command line interface, mediating access to containerized neuroimaging software libraries on various computing platforms, including personal and high-performance computers, cloud computing and Jupyter Notebooks. This community-oriented, open-source platform enables a paradigm shift for neuroimaging data analysis, allowing for accessible, flexible, fully reproducible, and portable data analysis pipelines.

Anxiety attenuates learning advantages conferred by statistical stability and induces loss of volatility-attuning in brain activity.

Anxiety can alter an individual's perception of their external sensory environment. Previous studies suggest that anxiety can increase the magnitude of neural responses to unexpected (or surprising) stimuli. Additionally, surprise responses are reported to be boosted during stable compared to volatile environments. Few studies, however, have examined how learning is impacted by both threat and volatility. To investigate these effects, we used threat-of-shock to transiently increase subjective anxiety in healthy adults while they performed an auditory oddball task under stable and volatile environments and while undergoing functional Magnetic Resonance Imaging (fMRI) scanning. We then used Bayesian Model Selection (BMS) mapping to identify the brain areas where different models of anxiety displayed the highest evidence. Behaviourally, we found that threat-of-shock eliminated the accuracy advantage conferred by environmental stability over volatility. Neurally, we found that threat-of-shock led to attenuation and loss of volatility-attuning of brain activity evoked by surprising sounds across most subcortical and limbic regions including the thalamus, basal ganglia, claustrum, insula, anterior cingulate, hippocampal gyrus and the superior temporal gyrus. Taken together, our findings suggest that threat eliminates learning advantages conferred by statistical stability compared to volatility. Thus, we propose that anxiety disrupts behavioural adaptation to environmental statistics, and that multiple subcortical and limbic regions are implicated in this process.

Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy.

A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased. We determine that CT accumulation in CAFs intensifies TGF-beta activity, leading to the production of multiple factors enhancing cancer aggressiveness. We establish periostin as a stromal marker of chemotherapeutic activity intrinsically upregulated in consensus molecular subtype 4 (CMS4) tumors and highly expressed before and/or after treatment in patients unresponsive to therapy. Collectively, our study underscores the ability of CT-retaining CAFs to support cancer progression and resistance to treatment.

Novel variant in HHAT as a cause of different sex development with partial gonadal dysgenesis associated with microcephaly, eye defects, and distal phalangeal hypoplasia of both thumbs: Case report.

The palmitoylation of the Hedgehog (Hh) family of morphogens, named sonic hedgehog (SHH), desert hedgehog (DHH), and Indian hedgehog (IHH), is crucial for effective short- and long-range signaling. The hedgehog acyltransferase (HHAT) attaches the palmitate molecule to the Hh; therefore, variants in HHAT cause a broad spectrum of phenotypes. A missense HHAT novel variant c.1001T>A/p.(Met334Lys) was described in a patient first referred for a 46,XY different sexual development with partial gonadal dysgenesis but with microcephaly, eye defects, and distal phalangeal hypoplasia of both thumbs. The in silico analysis of the variant predicted an affectation of the nearest splicing site. Thus, in vitro minigene studies were carried out, which demonstrated that the variant does not affect the splicing. Subsequent protein in silico studies supported the pathogenicity of the variant, and, in conclusion, this was considered the cause of the patient's phenotype.

Integrin alpha9 emerges as a key therapeutic target to reduce metastasis in rhabdomyosarcoma and neuroblastoma.

The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis. This is a paradox, since more than 90% of cancer deaths are attributable to metastatic progression. Integrin alpha9 (ITGA9) has been previously described as playing an essential role in metastasis; however, little is known about the mechanism that links this protein to this process, being one of the less studied integrins. We have now deciphered the importance of ITGA9 in metastasis and provide evidence demonstrating its essentiality for metastatic dissemination in rhabdomyosarcoma and neuroblastoma. However, the most translational advance of this study is to reveal, for the first time, the possibility of reducing metastasis by pharmacological inhibition of ITGA9 with a synthetic peptide simulating a key interaction domain of ADAM proteins, in experimental metastasis models, not only in childhood cancers but also in a breast cancer model.

Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors.

About 50% of human epidermal growth factor receptor 2 (HER2)+ breast cancer patients do not benefit from HER2-targeted therapy and almost 20% of them relapse after treatment. Here, we conduct a detailed analysis of two independent cohorts of HER2+ breast cancer patients treated with trastuzumab to elucidate the mechanisms of resistance to anti-HER2 monoclonal antibodies. In addition, we develop a fully humanized immunocompetent model of HER2+ breast cancer recapitulating ex vivo the biological processes that associate with patients' response to treatment. Thanks to these two approaches, we uncover a population of TGF-beta-activated cancer-associated fibroblasts (CAF) specific from tumors resistant to therapy. The presence of this cellular subset related to previously described myofibroblastic (CAF-S1) and podoplanin+ CAF subtypes in breast cancer associates with low IL2 activity. Correspondingly, we find that stroma-targeted stimulation of IL2 pathway in unresponsive tumors restores trastuzumab anti-cancer efficiency. Overall, our study underscores the therapeutic potential of exploiting the tumor microenvironment to identify and overcome mechanisms of resistance to anti-cancer treatment.

Diverse mutations and structural variations contribute to Notch signaling deregulation in paediatric T-cell lymphoblastic lymphoma.

BACKGROUND: T-cell lymphoblastic lymphoma (T-LBL) is an aggressive neoplasm closely related to T-cell acute lymphoblastic leukaemia (T-ALL). Despite their similarities, and contrary to T-ALL, studies on paediatric T-LBL are scarce and, therefore, its molecular landscape has not yet been fully elucidated. Thus, the aims of this study were to characterize the genetic and molecular heterogeneity of paediatric T-LBL and to evaluate novel molecular markers differentiating this entity from T-ALL. PROCEDURE: Thirty-three paediatric T-LBL patients were analyzed using an integrated approach, including targeted next-generation sequencing, RNA-sequencing transcriptome analysis and copy-number arrays. RESULTS: Copy number and mutational analyses allowed the detection of recurrent homozygous deletions of 9p/CDKN2A (78%), trisomy 20 (19%) and gains of 17q24-q25 (16%), as well as frequent mutations of NOTCH1 (62%), followed by the BCL11B (23%), WT1 (19%) and FBXW7, PHF6 and RPL10 genes (15%, respectively). This genetic profile did not differ from that described in T-ALL in terms of mutation incidence and global genomic complexity level, but unveiled virtually exclusive 17q25 gains and trisomy 20 in T-LBL. Additionally, we identified novel gene fusions in paediatric T-LBL, including NOTCH1-IKZF2, RNGTT-SNAP91 and DDX3X-MLLT10, the last being the only one previously described in T-ALL. Moreover, clinical correlations highlighted the presence of Notch pathway alterations as a factor related to favourable outcome. CONCLUSIONS: In summary, the genomic landscape of paediatric T-LBL is similar to that observed in T-ALL, and Notch signaling pathway deregulation remains the cornerstone in its pathogenesis, including not only mutations but fusion genes targeting NOTCH1.

Surprising Threats Accelerate Conscious Perception.

The folk psychological notion that "we see what we expect to see" is supported by evidence that we become consciously aware of visual stimuli that match our prior expectations more quickly than stimuli that violate our expectations. Similarly, "we see what we want to see," such that more biologically-relevant stimuli are also prioritised for conscious perception. How, then, is perception shaped by biologically-relevant stimuli that we did not expect? Here, we conducted two experiments using breaking continuous flash suppression (bCFS) to investigate how prior expectations modulated response times to neutral and fearful faces. In both experiments, we found that prior expectations for neutral faces hastened responses, whereas the opposite was true for fearful faces. This interaction between emotional expression and prior expectations was driven predominantly by participants with higher trait anxiety. Electroencephalography (EEG) data collected in Experiment 2 revealed an interaction evident in the earliest stages of sensory encoding, suggesting prediction errors expedite sensory encoding of fearful faces. These findings support a survival hypothesis, where biologically-relevant fearful stimuli are prioritised for conscious access even more so when unexpected, especially for people with high trait anxiety.