Digital twins for understanding mechanisms of learning disabilities: Personalized deep neural networks reveal impact of neuronal hyperexcitability.

Learning disabilities affect a significant proportion of children worldwide, with far-reaching consequences for their academic, professional, and personal lives. Here we develop digital twins - biologically plausible personalized Deep Neural Networks (pDNNs) - to investigate the neurophysiological mechanisms underlying learning disabilities in children. Our pDNN reproduces behavioral and neural activity patterns observed in affected children, including lower performance accuracy, slower learning rates, neural hyper-excitability, and reduced neural differentiation of numerical problems. Crucially, pDNN models reveal aberrancies in the geometry of manifold structure, providing a comprehensive view of how neural excitability influences both learning performance and the internal structure of neural representations. Our findings not only advance knowledge of the neurophysiological underpinnings of learning differences but also open avenues for targeted, personalized strategies designed to bridge cognitive gaps in affected children. This work reveals the power of digital twins integrating AI and neuroscience to uncover mechanisms underlying neurodevelopmental disorders.

Space wandering in the rodent default mode network.

The default mode network (DMN) is a large-scale brain network known to be suppressed during a wide range of cognitive tasks. However, our comprehension of its role in naturalistic and unconstrained behaviors has remained elusive because most research on the DMN has been conducted within the restrictive confines of MRI scanners. Here, we use multisite GCaMP (a genetically encoded calcium indicator) fiber photometry with simultaneous videography to probe DMN function in awake, freely exploring rats. We examined neural dynamics in three core DMN nodes-the retrosplenial cortex, cingulate cortex, and prelimbic cortex-as well as the anterior insula node of the salience network, and their association with the rats' spatial exploration behaviors. We found that DMN nodes displayed a hierarchical functional organization during spatial exploration, characterized by stronger coupling with each other than with the anterior insula. Crucially, these DMN nodes encoded the kinematics of spatial exploration, including linear and angular velocity. Additionally, we identified latent brain states that encoded distinct patterns of time-varying exploration behaviors and found that higher linear velocity was associated with enhanced DMN activity, heightened synchronization among DMN nodes, and increased anticorrelation between the DMN and anterior insula. Our findings highlight the involvement of the DMN in collectively and dynamically encoding spatial exploration in a real-world setting. Our findings challenge the notion that the DMN is primarily a "task-negative" network disengaged from the external world. By illuminating the DMN's role in naturalistic behaviors, our study underscores the importance of investigating brain network function in ecologically valid contexts.

Experiences of keratoconus patients attending public eye care facilities in South Africa.

BACKGROUND: Keratoconus (KC) is a progressive condition that usually affects young persons between their first and fourth decades. Myopia and irregular astigmatism are the common presentations which are proceeded by corneal steepening and thinning. Keratoconus is a progressive ectasia of the cornea that presents bilaterally, although often asymmetrical. AIM: To explore the experiences of KC patients attending public eye care facilities in Capricorn District of Limpopo province. SETTING: Capricorn District, Limpopo province, South Africa. METHODS: Descriptive qualitative phenomenology approach was used in the study to explore the lived experiences of patients diagnosed with KC, attending public eye care facilities. Purposive sampling was used to select 16 patients who were diagnosed with KC and referred for contact lens fitting. Data were collected through face-to-face, one-on-one interviews. RESULTS: Patients reported to have developed gradual vision loss which worsened when they grew older. There was lack of knowledge of KC amongst patients and this was exacerbated by limited health literacy and vocabulary barriers. Patients had difficulty performing daily activities where some had dropped out of school while others worked at a slower pace and reduced working distances. CONCLUSION: Patients with KC received inadequate information on their condition due to limited health literacy and vocabulary barriers. Programmes to promote practitioner and patient education are required to improve the perceived service level provided to KC patients.Contribution: The findings of this study will assist to improve the experiences of KC patients on perceived service quality received from public facilities.

Space wandering in the rodent default mode network.

The default mode network (DMN) is a large-scale brain network known to be suppressed during a wide range of cognitive tasks. However, our comprehension of its role in naturalistic and unconstrained behaviors has remained elusive because most research on the DMN has been conducted within the restrictive confines of MRI scanners. Here we use multisite GCaMP fiber photometry with simultaneous videography to probe DMN function in awake, freely exploring rats. We examined neural dynamics in three core DMN nodes- the retrosplenial cortex, cingulate cortex, and prelimbic cortex- as well as the anterior insula node of the salience network, and their association with the rats' spatial exploration behaviors. We found that DMN nodes displayed a hierarchical functional organization during spatial exploration, characterized by stronger coupling with each other than with the anterior insula. Crucially, these DMN nodes encoded the kinematics of spatial exploration, including linear and angular velocity. Additionally, we identified latent brain states that encoded distinct patterns of time-varying exploration behaviors and discovered that higher linear velocity was associated with enhanced DMN activity, heightened synchronization among DMN nodes, and increased anticorrelation between the DMN and anterior insula. Our findings highlight the involvement of the DMN in collectively and dynamically encoding spatial exploration in a real-world setting. Our findings challenge the notion that the DMN is primarily a "task-negative" network disengaged from the external world. By illuminating the DMN's role in naturalistic behaviors, our study underscores the importance of investigating brain network function in ecologically valid contexts.

Learning-induced reorganization of number neurons and emergence of numerical representations in a biologically inspired neural network.

Number sense, the ability to decipher quantity, forms the foundation for mathematical cognition. How number sense emerges with learning is, however, not known. Here we use a biologically-inspired neural architecture comprising cortical layers V1, V2, V3, and intraparietal sulcus (IPS) to investigate how neural representations change with numerosity training. Learning dramatically reorganized neuronal tuning properties at both the single unit and population levels, resulting in the emergence of sharply-tuned representations of numerosity in the IPS layer. Ablation analysis revealed that spontaneous number neurons observed prior to learning were not critical to formation of number representations post-learning. Crucially, multidimensional scaling of population responses revealed the emergence of absolute and relative magnitude representations of quantity, including mid-point anchoring. These learnt representations may underlie changes from logarithmic to cyclic and linear mental number lines that are characteristic of number sense development in humans. Our findings elucidate mechanisms by which learning builds novel representations supporting number sense.

Defining the rate of nutritional and metabolic derangements after pancreatic resection.

BACKGROUND AND AIMS: Pancreatic resection is associated with pancreatic exocrine insufficiency (PEI) leading to nutritional consequences. The Pancreatic Nutrition Clinic was established to diagnose and manage PEI through standardised nutritional assessment. In this prospective observational study, we aimed to define the rate of PEI, diabetes mellitus and nutritional abnormalities in patients who underwent pancreatic resection. METHODS: All Pancreatic Nutrition Clinic patients were included for analysis. Clinical data were prospectively obtained at initial assessment. Biochemical data included micronutrient levels, faecal elastase-1 and haemoglobin A1c. Bone mineral density and nutritional assessment were undertaken. RESULTS: Ninety-eight patients were included. Fifty-nine per cent (58/98) had undergone a pancreatoduodenectomy. Ninety-three patients had a faecal elastase-1 result, 65% (60/93) of which had a faecal elastase-1 less than 200 µg/g of faeces. Seventy-five patients (76%) of the total population required PERT, and thirty-nine (40%) were classified as malnourished using the patient-generated subjective global assessment tool. Seventy-two per cent (70/97) had a biochemical deficiency of one or more micronutrients. Thirty-eight people (39%) had diabetes mellitus. Of the seventy-eight patients with a bone mineral density scan available for analysis, 29% (23/78) had osteoporosis and 49% (38/78) osteopenia. CONCLUSIONS: Pancreatic exocrine insufficiency, micronutrient deficiency, bone disease, diabetes mellitus and malnutrition are highly prevalent in patients who have undergone pancreatic resection.

A Neurodevelopmental Shift in Reward Circuitry from Mother's to Nonfamilial Voices in Adolescence.

The social worlds of young children primarily revolve around parents and caregivers, who play a key role in guiding children's social and cognitive development. However, a hallmark of adolescence is a shift in orientation toward nonfamilial social targets, an adaptive process that prepares adolescents for their independence. Little is known regarding neurobiological signatures underlying changes in adolescents' social orientation. Using functional brain imaging of human voice processing in children and adolescents (ages 7-16), we demonstrate distinct neural signatures for mother's voice and nonfamilial voices across child and adolescent development in reward and social valuation systems, instantiated in nucleus accumbens and ventromedial prefrontal cortex. While younger children showed greater activity in these brain systems for mother's voice compared with nonfamilial voices, older adolescents showed the opposite effect with increased activity for nonfamilial compared with mother's voice. Findings uncover a critical role for reward and social valuative brain systems in the pronounced changes in adolescents' orientation toward nonfamilial social targets. Our approach provides a template for examining developmental shifts in social reward and motivation in individuals with pronounced social impairments, including adolescents with autism.SIGNIFICANCE STATEMENT Children's social worlds undergo a transformation during adolescence. While socialization in young children revolves around parents and caregivers, adolescence is characterized by a shift in social orientation toward nonfamilial social partners. Here we show that this shift is reflected in neural activity measured from reward processing regions in response to brief vocal samples. When younger children hear their mother's voice, reward processing regions show greater activity compared with when they hear nonfamilial, unfamiliar voices. Strikingly, older adolescents show the opposite effect, with increased activity for nonfamilial compared with mother's voice. Findings identify the brain basis of adolescents' switch in social orientation toward nonfamilial social partners and provides a template for understanding neurodevelopment in clinical populations with social and communication difficulties.

A Multinomial Processing Tree Model of the 2-back Working Memory Task.

The n-back task is a widely used behavioral task for measuring working memory and the ability to inhibit interfering information. We develop a novel model of the commonly used 2-back task using the cognitive psychometric framework provided by Multinomial Processing Trees. Our model involves three parameters: a memory parameter, corresponding to how well an individual encodes and updates sequence information about presented stimuli; a decision parameter corresponding to how well participants execute choices based on information stored in memory; and a base-rate parameter corresponding to bias for responding "yes" or "no". We test the parameter recovery properties of the model using existing 2-back experimental designs, and demonstrate the application of the model to two previous data sets: one from social psychology involving faces corresponding to different races (Stelter and Degner, British Journal of Psychology 109:777-798, 2018), and one from cognitive neuroscience involving more than 1000 participants from the Human Connectome Project (Van Essen et al., Neuroimage 80:62-79, 2013). We demonstrate that the model can be used to infer interpretable individual-level parameters. We develop a hierarchical extension of the model to test differences between stimulus conditions, comparing faces of different races, and comparing face to non-face stimuli. We also develop a multivariate regression extension to examine the relationship between the model parameters and individual performance on standardized cognitive measures including the List Sorting and Flanker tasks. We conclude by discussing how our model can be used to dissociate underlying cognitive processes such as encoding failures, inhibition failures, and binding failures.

Neurocognitive modeling of latent memory processes reveals reorganization of hippocampal-cortical circuits underlying learning and efficient strategies.

Efficient memory-based problem-solving strategies are a cardinal feature of expertise across a wide range of cognitive domains in childhood. However, little is known about the neurocognitive mechanisms that underlie the acquisition of efficient memory-based problem-solving strategies. Here we develop, to the best of our knowledge, a novel neurocognitive process model of latent memory processes to investigate how cognitive training designed to improve children's problem-solving skills alters brain network organization and leads to increased use and efficiency of memory retrieval-based strategies. We found that training increased both the use and efficiency of memory retrieval. Functional brain network analysis revealed training-induced changes in modular network organization, characterized by increase in network modules and reorganization of hippocampal-cortical circuits. Critically, training-related changes in modular network organization predicted performance gains, with emergent hippocampal, rather than parietal cortex, circuitry driving gains in efficiency of memory retrieval. Our findings elucidate a neurocognitive process model of brain network mechanisms that drive learning and gains in children's efficient problem-solving strategies.

S100A12 as a marker of worse cardiac output and mortality in pulmonary hypertension.

BACKGROUND AND OBJECTIVE: Molecular biomarkers are needed to refine prognostication and phenotyping of pulmonary hypertension (PH) patients. S100A12 is an emerging biomarker of various inflammatory diseases. This study aims to determine the prognostic value of S100A12 in PH. METHODS: Exploratory microarray analysis performed on peripheral blood mononuclear cells (PBMC) collected from idiopathic pulmonary fibrosis (IPF) patients suggested an association between S100A12 and both PH and mortality. So the current study was designed to evaluate for an association between S100A12 in peripheral blood collected from two well-phenotyped PH cohorts in two other centres to derive and validate an association between S100A12 protein serum concentrations and mortality. RESULTS: The majority of the patients in the discovery and validation cohorts were either World Health Organization (WHO) group 1 (pulmonary arterial hypertension (PAH)) or 3 (lung disease-associated) PH. In the discovery PH cohort, S100A12 was significantly increased in patients with PH (n = 51) compared to controls (n = 22) (29.8 vs 15.7 ng/mL, P < 0.001) and negatively correlated with cardiac output (r = -0.58, P < 0.001) in PH patients. When S100A12 data were pooled from both cohorts, PAH and non-PAH PH patients had higher S100A12 compared to healthy external controls (32.6, 30.9, 15.7 ng/mL; P < 0.001). S100A12 was associated with an increased risk in overall mortality in PH patients in both the discovery (n = 51; P = 0.008) and validation (n = 40; P < 0.001) cohorts. CONCLUSION: S100A12 levels are increased in PH patients and are associated with increased mortality.

Pulmonary arterial hypertension in the setting of scleroderma is different than in the setting of lupus: A review.

Pulmonary hypertension (PH) is a clinical syndrome that is subdivided into five groups per the World Health Organization (WHO) classification, based largely on hemodynamic and pathophysiologic criteria. WHO Group 1 PH, termed pulmonary arterial hypertension (PAH), is a clinically progressive disease that can eventually lead to right heart failure and death, and it is hemodynamically characterized by pre-capillary PH and increased pulmonary vascular resistance in the absence of elevated left ventricular filling pressures. PAH can be idiopathic, heritable, or associated with a variety of conditions. Connective tissue diseases make up the largest portion of these associated conditions, most commonly systemic sclerosis (SSc), followed by mixed connective tissue disease and systemic lupus erythematous. These etiologies (namely SSc and Lupus) have been grouped together as connective tissue disease-associated PAH, however emerging evidence suggests they differ in pathogenesis, clinical course, prognosis, and treatment response. This review highlights the differences between SSc-PAH and Lupus-PAH. After introducing the diagnosis, screening, and pathobiology of PAH, we discuss connective tissue disease-associated PAH as a group, and then explore SSc-PAH and SLE-PAH separately, comparing these 2 PAH etiologies.

Advances in understanding ozone impact on forest trees: messages from novel phytotron and free-air fumigation studies.

Recent evidence from novel phytotron and free-air ozone (O3) fumigation experiments in Europe and America on forest tree species is highlighted in relation to previous chamber studies. Differences in O3 sensitivity between pioneer and climax species are examined and viewed for trees growing at the harsh alpine timberline ecotone. As O3 apparently counteracts positive effects of elevated CO2 and mitigates productivity increases, response is governed by genotype, competitors, and ontogeny rather than species per se. Complexity in O3 responsiveness increased under the influence of pathogens and herbivores. The new evidence does not conflict in principle with previous findings that, however, pointed to a low ecological significance. This new knowledge on trees' O3 responsiveness beyond the juvenile stage in plantations and forests nevertheless implies limited predictability due to complexity in biotic and abiotic interactions. Unravelling underlying mechanisms is mandatory for assessing O3 risks as an important component of climate change scenarios.

Air quality in natural areas: interface between the public, science and regulation.

Natural areas are important interfaces between air quality, the public, science and regulation. In the United States and Canada, national parks received over 315million visits during 2004. Many natural areas have been experiencing decreased visibility, increased ozone (O(3)) levels and elevated nitrogen deposition. Ozone is the most pervasive air pollutant in North American natural areas. There is an extensive scientific literature on O(3) exposure-tree response in chambered environments and, lately, free-air exposure systems. Yet, less is known about O(3) impacts on natural terrestrial ecosystems. To advance scientifically defensible O(3) risk assessment for natural forest areas, species-level measurement endpoints must be socially, economically and ecologically relevant. Exposure-based indices, based on appropriate final endpoints, present an underused opportunity to meet this need. Exposure-plant indices should have a high degree of statistical significance, have high goodness of fit, be biologically plausible and include confidence intervals to define uncertainty. They must be supported by exposure-response functions and be easy to use within an air quality regulation context. Ozone exposure-response indices developed within an ambient air context have great potential for improving risk assessment in natural forest areas and enhancing scientific literacy.

Free-air exposure systems to scale up ozone research to mature trees.

Because seedlings and mature trees do not necessarily respond similarly to O(3) stress, it is critically important that exposure systems be developed that allow exposure of seedlings through to mature trees. Here we describe three different O(3) Free-Air Exposure Systems that have been used successfully for exposure at all growth stages. These systems of spatially uniform O(3) release have been shown to provide reliable O(3) exposure with minimal, if any, impact on the microclimate. This methodology offers a welcome alternative to chamber studies which had severe space constraints precluding stand or community-level studies and substantial chamber effects on the microclimate and, hence physiological tree performance.

New exposure-based metric approach for evaluating O(3) risk to North American aspen forests.

The United States and Canada currently use exposure-based metrics to protect vegetation from O(3). Using 5 years (1999-2003) of co-measured O(3), meteorology and growth response, we have developed exposure-based regression models that predict Populus tremuloides growth change within the North American ambient air quality context. The models comprised growing season fourth-highest daily maximum 8-h average O(3) concentration, growing degree days, and wind speed. They had high statistical significance, high goodness of fit, include 95% confidence intervals for tree growth change, and are simple to use. Averaged across a wide range of clonal sensitivity, historical 2001-2003 growth change over most of the 26 Mha P. tremuloides distribution was estimated to have ranged from no impact (0%) to strong negative impacts (-31%). With four aspen clones responding negatively (one responded positively) to O(3), the growing season fourth-highest daily maximum 8-h average O(3) concentration performed much better than growing season SUM06, AOT40 or maximum 1h average O(3) concentration metrics as a single indicator of aspen stem cross-sectional area growth.

Impacts of greenhouse gases on epicuticular waxes of Populus tremuloides Michx.: results from an open-air exposure and a natural O3 gradient.

Epicuticular waxes of three trembling aspen (Populus tremuloides Michx.) clones differing in O3 tolerance were examined over six growing seasons (1998-2003) at three bioindicator sites in the Lake States region of the USA and at FACTS II (Aspen FACE) site in Rhinelander, WI. Differences in epicuticular wax structure were determined by scanning electron microscopy and quantified by a coefficient of occlusion. Statistically significant increases in stomatal occlusion occurred for the three O3 bioindicator sites, with the higher O3 sites having the most affected stomata for all three clones as well as for all treatments including elevated CO2, elevated O3, and elevated CO2 + O3. We recorded statistically significant differences between aspen clones and between sampling period (spring, summer, fall). We found no statistically significant differences between treatments or aspen clones in stomatal frequency.

Air pollution and forest health: toward new monitoring concepts.

It is estimated that 49% of forests (17 million km(2)) will be exposed to damaging concentrations of tropospheric O(3) by 2100. Global forest area at risk from S deposition may reach 5.9 million km(2) by 2050, despite SO(2) emission reductions of 48% in North America and 25% in Europe. Although SO(2) levels have decreased, emissions of NO(x) are little changed, or have increased slightly. In some regions, the molar SO(4)/NO(3) ratio in precipitation has switched from 2/1 to near 1/1 during the past two decades. Coincidentally, pattern shifts in precipitation and temperature are evident. A number of reports suggest that forests are being affected by air pollution. Yet, the extent to which such effects occur is uncertain, despite the efforts dedicated to monitoring forests. Routine monitoring programmes provide a huge amount of data. Yet in many cases, these data do not fit the conceptual and statistical requirements for detecting status and trends of forest health, nor for cause-effect research. There is a clear need for a re-thinking of monitoring strategies.

Growth responses of Populus tremuloides clones to interacting elevated carbon dioxide and tropospheric ozone.

The Intergovernmental Panel of Climate Change (IPCC) has concluded that the greenhouse gases carbon dioxide (CO2) and tropospheric ozone (O3) are increasing concomitantly globally. Little is known about the effect of these interacting gases on growth, survival, and productivity of forest ecosystems. In this study we assess the effects of three successive years of exposure to combinations of elevated CO2 and O3 on growth responses in a five trembling aspen (Populus tremuloides) clonal mixture in a regenerating stand. The experiment is located in Rhinelander, Wisconsin, USA (45 degrees N 89 degrees W) and employs free air carbon dioxide and ozone enrichment (FACE) technology. The aspen stand was exposed to a factorial combination of four treatments consisting of elevated CO2 (560 ppm), elevated O3 (episodic exposure-90 microl l(-1) hour(-1)), a combination of elevated CO2 and O3, and ambient control in 30 m treatment rings with three replications. Our overall results showed that our three growth parameters including height, diameter and volume were increased by elevated CO2, decreased by elevated O3, and were not significantly different from the ambient control under elevated CO2 + O3. However, there were significant clonal differences in the responses; all five clones exhibited increased growth with elevated CO2, one clone showed an increase with elevated O3, and two clones showed an increase over the control with elevated CO2 + O3, two clones showed a decrease, and one was not significantly different from the control. Notably. there was a significant increase in current terminal shoot dieback with elevated CO2 during the 1999-2000 dormant season. Dieback was especially prominent in two of the five clones, and was attributed to those clones growing longer into the autumnal season where they were subject to frost. Our results show that elevated O3 negates expected positive growth effects of elevated CO2 in Populus tremuloides in the field, and suggest that future climate model predictions should take into account the offsetting effects of elevated O3 on CO2 enrichment when estimating future growth of trembling aspen stands.

Selection effects of air pollution on gene pools of Norway spruce, European silver fir and European beech.

The effects of industrial pollution on allelic and genotypic structures of Norway spruce. European silver fir and European beech were investigated by means of isozyme analysis. In a mixed Norway spruce-silver fir forest stand in an area heavily polluted by sulphur dioxide and heavy metals in the region of Spis (eastern Slovakia), pairs of neighbouring damaged and apparently healthy trees were selected in two replicates (44 and 69 pairs in a heavily and moderately damaged stand, respectively). Pairwise sampling of trees with contrasting vitality was applied to reduce potential effects of site heterogeneity on the vitality of sampled trees. No significant differences in allelic and genotypic frequencies were found between sets of healthy and declining trees. There were differences in the single-locus heterozygosities, but these were not consistent between the replicates. However, the set of damaged trees exhibited higher levels of genetic multiplicity and diversity, possibly due to the deleterious effect of rare alleles under the conditions of air pollution. Consequently. following the decline of pollutant-sensitive trees, the remaining stand will be depleted of a part of alleles with unknown adaptive value to future selection pressures.

Environmental influences on the development of spruce needle cuticles.

Seedlings of Norway [Picea abies (L.) Karst.], red (P. rubens Sarg.), black [P. mariana (Mill) B.S.P.] and white [P. glauca (Moench.) Voss] spruce were grown from bud break to bud set outdoors, in the greenhouse, and in controlled environment chambers. The outdoor and greenhouse treatments also included adjacent shaded (50%) seedlings. The effects of growth environment on needle epicuticular wax production and morphology, and on needle wettability were investigated. Red and black spruce exhibited free growth in addition to determinate growth, but only in the greenhouse. Although relative growth rate was significantly lower for seedlings grown outdoors, there were no differences in wax morphology between outdoor- and greenhouse-grown seedlings, Wax deposits on controlled environment seedlings were significantly more crystalline. Wax tubes were crystallized in 'tufts'. There were significant differences in wax amounts recovered between species and treatments. Wax amounts relative to needle dry weights decreased in the order greenhouse > outdoors > controlled environment. Shaded red and black spruce produced significantly more wax than unshaded. Needles from seedlings grown in controlled environment chambers had the largest needle/droplet contact angles. These data indicate that seedling growth environment affects needle epicuticular wax characteristics and wettability. Studies designed to investigate factors determined by needle surface phystcochemical characteristics should include a consideration of growth environment.