Closed-loop microstimulations of the orbitofrontal cortex during real-life gaze interaction enhance dynamic social attention.

Neurons from multiple prefrontal areas encode several key variables of social gaze interaction. To explore the causal roles of the primate prefrontal cortex in real-life gaze interaction, we applied weak closed-loop microstimulations that were precisely triggered by specific social gaze events. Microstimulations of the orbitofrontal cortex, but not the dorsomedial prefrontal cortex or the anterior cingulate cortex, enhanced momentary dynamic social attention in the spatial dimension by decreasing the distance of fixations relative to a partner's eyes and in the temporal dimension by reducing the inter-looking interval and the latency to reciprocate the other's directed gaze. By contrast, on a longer timescale, microstimulations of the dorsomedial prefrontal cortex modulated inter-individual gaze dynamics relative to one's own gaze positions. These findings demonstrate that multiple regions in the primate prefrontal cortex may serve as functionally accessible nodes in controlling different aspects of dynamic social attention and suggest their potential for a therapeutic brain interface.

Induction of the plasticity-associated immediate early gene Arc by stress and hallucinogens: role of brain-derived neurotrophic factor.

Exposure to stress and hallucinogens in adulthood evokes persistent alterations in neurocircuitry and emotional behaviour. The structural and functional changes induced by stress and hallucinogen exposure are thought to involve transcriptional alterations in specific effector immediate early genes. The immediate early gene, activity regulated cytoskeletal-associated protein (Arc), is important for both activity and experience dependent plasticity. We sought to examine whether trophic factor signalling through brain-derived neurotrophic factor (BDNF) contributes to the neocortical regulation of Arc mRNA in response to distinct stimuli such as immobilization stress and the hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI). Acute exposure to either immobilization stress or DOI induced Arc mRNA levels within the neocortex. BDNF infusion into the neocortex led to a robust up-regulation of local Arc transcript expression. Further, baseline Arc mRNA expression in the neocortex was significantly decreased in inducible BDNF knockout mice with an adult-onset, forebrain specific BDNF loss. The induction of Arc mRNA levels in response to both acute immobilization stress or a single administration of DOI was significantly attenuated in the inducible BDNF knockout mice. Taken together, our results implicate trophic factor signalling through BDNF in the regulation of cortical Arc mRNA expression, both under baseline conditions and following stress and hallucinogen exposure. These findings suggest the possibility that the regulation of Arc expression via BDNF provides a molecular substrate for the structural and synaptic plasticity observed following stimuli such as stress and hallucinogens.

Cost analyses of obesity in Canada: scope, quality, and implications.

BACKGROUND: Rapid changes in lifestyle have led to a global obesity epidemic. Understanding the economic burden associated with the obesity epidemic is essential to decision making of cost-effective interventions. This study reviewed costs of obesity and intervention programs in Canada, assessed the scope and quality of existing cost analyses, and identified implications for economic evaluations and public health decision makers. METHODS: A systematic search of costs associated with obesity or intervention program in Canada between 1990 and 2011 yielded 10 English language articles eligible for review. RESULTS: The majority of studies was prevalence-based or top-down costing; 40% had excellent quality assessed using the Quality of Health Economic Study scale. The aggregated annual costs of obesity in Canada ranged from 1.27 to 11.08 billion dollars. Direct costs accounted for 37.2% to 54.5% of total annual costs. Between 2.2% and 12.0% of Canada's total health expenditures were attributable to obesity. The average annual physician cost of overweight male ($ 427) and female ($ 578) adults was lower than that of obese male ($ 475) and female ($ 682) adults; this cost differential across weight status groups was comparable to that found in adolescents. The cost for implementation and maintenance of a school-based obesity prevention program was $ 23 per student. CONCLUSIONS: We observed high costs associated with overweight and obesity and modest costs for obesity prevention programs; however, no cost-effectiveness study of obesity interventions has been performed in Canada. Cost-effectiveness analyses of preventive programs that constitute incidence-based life-time modeling of costs and health outcomes from societal perspective are urgently needed.

Detection of Common Cold from Speech Signals using Deep Neural Network.

This paper presents a deep learning-based analysis and classification of cold speech observed when a person is diagnosed with the common cold. The common cold is a viral infectious disease that affects the throat and the nose. Since speech is produced by the vocal tract after linear filtering of excitation source information, during a common cold, its attributes are impacted by the throat and the nose. The proposed study attempts to develop a deep learning-based classification model that can accurately predict whether a person has a cold or not based on their speech. The common cold-related information is captured using Mel-frequency cepstral coefficients (MFCC) and linear predictive coding (LPC) from the speech signal. The data imbalance is handled using the sampling strategy, SMOTE-Tomek links. Then, utilizing MFCC and LPC features, a deep learning-based model is trained and then used to categorize cold speech. The performance of a deep learning-based method is compared to logistic regression, random forest, and gradient boosted tree classifiers. The proposed model is less complex and uses a smaller feature set while giving comparable results to other state-of-the-art methods. The proposed method gives an UAR of 67.71 % , higher than the benchmark OpenSMILE SVM result of 64 % . The study's success will yield a noninvasive method for cold detection, which can further be extended to detect other speech-affecting pathologies.

Closed-loop microstimulations of the orbitofrontal cortex during real-life gaze interaction enhance dynamic social attention.

The prefrontal cortex is extensively involved in social exchange. During dyadic gaze interaction, multiple prefrontal areas exhibit neuronal encoding of social gaze events and context-specific mutual eye contact, supported by a widespread neural mechanism of social gaze monitoring. To explore causal manipulation of real-life gaze interaction, we applied weak closed-loop microstimulations that were precisely triggered by specific social gaze events to three prefrontal areas in monkeys. Microstimulations of orbitofrontal cortex (OFC), but not dorsomedial prefrontal or anterior cingulate cortex, enhanced momentary dynamic social attention in the spatial dimension by decreasing distance of one's gaze fixations relative to partner monkey's eyes. In the temporal dimension, microstimulations of OFC reduced the inter-looking interval for attending to another agent and the latency to reciprocate other's directed gaze. These findings demonstrate that primate OFC serves as a functionally accessible node in controlling dynamic social attention and suggest its potential for a therapeutic brain interface.

Amygdala connectivity and implications for social cognition and disorders.

The amygdala is a hub of subcortical region that is crucial in a wide array of affective and motivation-related behaviors. While early research contributed significantly to our understanding of this region's extensive connections to other subcortical and cortical regions, recent methodological advances have enabled researchers to better understand the details of these circuits and their behavioral contributions. Much of this work has focused specifically on investigating the role of amygdala circuits in social cognition. In this chapter, we review both long-standing knowledge and novel research on the amygdala's structure, function, and involvement in social cognition. We focus specifically on the amygdala's circuits with the medial prefrontal cortex, the orbitofrontal cortex, and the hippocampus, as these regions share extensive anatomic and functional connections with the amygdala. Furthermore, we discuss how dysfunction in the amygdala may contribute to social deficits in clinical disorders including autism spectrum disorder, social anxiety disorder, and Williams syndrome. We conclude that social functions mediated by the amygdala are orchestrated through multiple intricate interactions between the amygdala and its interconnected brain regions, endorsing the importance of understanding the amygdala from network perspectives.

Social neuroscience: Staying bonded over oxytocin and endocannabinoids.

Oxytocin is known to be critical for the formation of social relationships in prairie voles. A new study further explores the role of oxytocin in maintaining an established social relationship, and in recruiting the endocannabinoid system to do so.

Prefrontal circuits guiding social preference: Implications in autism spectrum disorder.

Although Autism Spectrum Disorder (ASD) is increasing in diagnostic prevalence, treatment options are inadequate largely due to limited understanding of ASD's underlying neural mechanisms. Contributing to difficulties in treatment development is the vast heterogeneity of ASD, from physiological causes to clinical presentations. Recent studies suggest that distinct genetic and neurological alterations may converge onto similar underlying neural circuits. Therefore, an improved understanding of neural circuit-level dysfunction in ASD may be a more productive path to developing broader treatments that are effective across a greater spectrum of ASD. Given the social preference behavioral deficits commonly seen in ASD, dysfunction in circuits mediating social preference may contribute to the atypical development of social cognition. We discuss some of the animal models used to study ASD and examine the function and effects of dysregulation of the social preference circuits, notably the medial prefrontal cortex-amygdala and the medial prefrontal cortex-nucleus accumbens circuits, in these animal models. Using the common circuits underlying similar behavioral disruptions of social preference behaviors as an example, we highlight the importance of identifying disruption in convergent circuits to improve the translational success of animal model research for ASD treatment development.

Widespread implementations of interactive social gaze neurons in the primate prefrontal-amygdala networks.

Social gaze interaction powerfully shapes interpersonal communication. However, compared with social perception, very little is known about the neuronal underpinnings of real-life social gaze interaction. Here, we studied a large number of neurons spanning four regions in primate prefrontal-amygdala networks and demonstrate robust single-cell foundations of interactive social gaze in the orbitofrontal, dorsomedial prefrontal, and anterior cingulate cortices, in addition to the amygdala. Many neurons in these areas exhibited high temporal heterogeneity for social discriminability, with a selectivity bias for looking at a conspecific compared with an object. Notably, a large proportion of neurons in each brain region parametrically tracked the gaze of self or other, providing substrates for social gaze monitoring. Furthermore, several neurons displayed selective encoding of mutual eye contact in an agent-specific manner. These findings provide evidence of widespread implementations of interactive social gaze neurons in the primate prefrontal-amygdala networks during social gaze interaction.

The dorsomedial prefrontal cortex computes task-invariant relative subjective value for self and other.

Few studies have addressed the neural computations underlying decisions made for others despite the importance of this ubiquitous behavior. Using participant-specific behavioral modeling with univariate and multivariate fMRI approaches, we investigated the neural correlates of decision-making for self and other in two independent tasks, including intertemporal and risky choice. Modeling subjective valuation indicated that participants distinguished between themselves and others with dissimilar preferences. Activity in the dorsomedial prefrontal cortex (dmPFC) and ventromedial prefrontal cortex (vmPFC) was consistently modulated by relative subjective value. Multi-voxel pattern analysis indicated that activity in the dmPFC uniquely encoded relative subjective value and generalized across self and other and across both tasks. Furthermore, agent cross-decoding accuracy between self and other in the dmPFC was related to self-reported social attitudes. These findings indicate that the dmPFC emerges as a medial prefrontal node that utilizes a task-invariant mechanism for computing relative subjective value for self and other.

Stressor-specific regulation of distinct brain-derived neurotrophic factor transcripts and cyclic AMP response element-binding protein expression in the postnatal and adult rat hippocampus.

Stress regulation of brain-derived neurotrophic factor (BDNF) is implicated in the hippocampal damage observed in depression. BDNF has a complex gene structure with four 5' untranslated exons (I-IV) with unique promoters, and a common 3' coding exon (V). To better understand the stress regulation of BDNF, we addressed whether distinct stressors differentially regulate exon-specific BDNF transcripts in the postnatal and adult hippocampus. The early life stress of maternal separation (MS) resulted in a time point-dependent differential upregulation of BDNF transcripts restricted to early postnatal life (P14-BDNF II, P21-BDNF IV, V). In adulthood, distinct stressors regulated BDNF transcripts in a signature manner. Immobilization stress, administered once, decreased all BDNF splice variants but had differing effects on BDNF I/II (increase) and III/IV (decrease) when administered chronically. Although immobilization stress reduced BDNF (V) mRNA, chronic unpredictable stress did not influence total BDNF despite altering specific BDNF transcripts. Furthermore, a prior history of MS altered the signature pattern in which adult-onset stress regulated specific BDNF transcripts. We also examined the expression of cyclic AMP response element-binding protein (CREB), an upstream transcriptional activator of BDNF, and observed a CREB induction in the postnatal hippocampus following MS. As a possible consequence of enhanced CREB and BDNF expression following MS, we examined hippocampal progenitor proliferation and observed a significant increase restricted to early life. These results suggest that alterations in CREB/BDNF may contribute to the generation of individual differences in stress neurocircuitry, providing a substrate for altered vulnerability to depressive disorders.

Differential regulation of multiple brain-derived neurotrophic factor transcripts in the postnatal and adult rat hippocampus during development, and in response to kainate administration.

Brain-derived neurotrophic factor (BDNF) is expressed at high levels in the hippocampus, where it has been implicated in physiological functions such as the modulation of synaptic strength as well as in the pathophysiology of epileptic seizures. BDNF expression is highly regulated and the BDNF gene can generate multiple transcript isoforms by alternate splicing of four 5' exons (exons I-IV) to one 3' exon (exon V). To gain insight into the regulation of different BDNF transcripts in specific hippocampal subfields during postnatal development, exon-specific riboprobes were used. Our data shows that BDNF exon I and exon II mRNAs are regulated in hippocampal subfields during postnatal development, in contrast to BDNF exon III and exon IV mRNA, which remain relatively stable through this period. Further, exons I and II show distinct temporal patterns of expression in the hippocampus: BDNF I mRNA peaks in adulthood in contrast to BDNF II mRNA which peaks at postnatal day 14 (P14). Finally, we have addressed whether kainate treatment in postnatal pups and adults regulates BDNF through the recruitment of the same, or distinct, BDNF promoters. Our data indicates that kainate-induced seizures induce strikingly different expression of distinct BDNF transcripts, both in magnitude as well as spatial patterns in the hippocampal subfields, of pups as compared to adults. These results suggest that kainate-mediated seizures differentially recruit BDNF promoters in the developing postnatal hippocampus in contrast to the adult hippocampus to achieve a hippocampal subfield specific regulation of exon-specific BDNF mRNAs.

Smart stimuli sensitive nanogels in cancer drug delivery and imaging: a review.

Nanogels are nanosized hydrogel particles formed by physical or chemical cross-linked polymer networks. The advantageous properties of nanogels related to the ability of retaining considerable amount of water, the biocompatibility of the polymers used, the ability to encapsulate and protect a large quantity of payload drugs within the nanogel matrix, the high stability in aqueous media, their stimuli responsively behavior potential, and the versatility in release drugs in a controlled manner make them very attractive for use in the area of drug delivery. The materials used for the preparation of nanogels ranged from natural polymers like ovalbumin, pullulan, hyaluronic acid, methacrylated chondroitin sulfate and chitosan, to synthetic polymers like poly (N-isopropylacrylamide), poly (Nisopropylacrylamide- co-acrylic acid) and poly (ethylene glycol)-b-poly (methacrylic acid). The porous nanogels have been finding application as anti-cancer drug and imaging agent reservoirs. Smart nanogels responding to external stimuli such as temperature, pH etc can be designed for diverse therapeutic and diagnostic applications. The nanogels have also been surface functionalized with specific ligands aiding in targeted drug delivery. This review focus on stimuli-sensitive, multi-responsive, magnetic and targeted nanogels providing a brief insight on the application of nanogels in cancer drug delivery and imaging in detail.

Development and evaluation of 5-fluorouracil loaded chitin nanogels for treatment of skin cancer.

This study focuses on development and evaluation of 5-fluorouracil (5-FU) loaded chitin nanogels (FCNGs). It formed good, stable aqueous dispersion with spherical particles in 120-140 nm size range and showed pH responsive swelling and drug release. The FCNGs showed toxicity on melanoma (A375) in a concentration range of 0.4-2.0mg/mL, but less toxicity toward human dermal fibroblast (HDF) cells by MTT assay. Confocal analysis revealed uptake of FCNGs by both cells. From skin permeation experiments, FCNGs showed almost same steady state flux as that of control 5-FU but the retention in the deeper layers of skin was found to be 4-5 times more from FCNGs. Histopathological evaluation revealed loosening of the horny layer of epidermis by interaction of cationically charged chitin, with no observed signs of inflammation and so FCNGs can be a good option for treatment of skin cancers.

Synthesis, characterization and in vitro cytocompatibility studies of chitin nanogels for biomedical applications.

In this work we developed biodegradable chitin nanogels (CNGs) of size 65nm by controlled regeneration method and characterized. The CNGs showed higher swelling and degradation in acidic pH. The in vitro cytocompatibility was analyzed on an array of cell lines and cell uptake studies were done by conjugating CNGs with the rhodamine-123 dye (rhodamine-123-CNGs), which showed retention of nanogels inside the cells. Our preliminary studies reveal that these nanogels could be useful for the delivery of drugs, growth factors for drug delivery and tissue engineering.

Curcumin loaded chitin nanogels for skin cancer treatment via the transdermal route.

In this study, curcumin loaded chitin nanogels (CCNGs) were developed using biocompatible and biodegradable chitin with an anticancer curcumin drug. Chitin, as well as curcumin, is insoluble in water. However, the developed CCNGs form a very good and stable dispersion in water. The CCNGs were analyzed by DLS, SEM and FTIR and showed spherical particles in a size range of 70-80 nm. The CCNGs showed higher release at acidic pH compared to neutral pH. The cytotoxicity of the nanogels were analyzed on human dermal fibroblast cells (HDF) and A375 (human melanoma) cell lines and the results show that CCNGs have specific toxicity on melanoma in a concentration range of 0.1-1.0 mg mL(-1), but less toxicity towards HDF cells. The confocal analysis confirmed the uptake of CCNGs by A375. The apoptotic effect of CCNGs was analyzed by a flow-cytometric assay and the results indicate that CCNGs at the higher concentration of the cytotoxic range showed comparable apoptosis as the control curcumin, in which there was negligible apoptosis induced by the control chitin nanogels. The CCNGs showed a 4-fold increase in steady state transdermal flux of curcumin as compared to that of control curcumin solution. The histopathology studies of the porcine skin samples treated with the prepared materials showed loosening of the horny layer of the epidermis, facilitating penetration with no observed signs of inflammation. These results suggest that the formulated CCNGs offer specific advantage for the treatment of melanoma, the most common and serious type of skin cancer, by effective transdermal penetration.

Postnatal serotonin type 2 receptor blockade prevents the emergence of anxiety behavior, dysregulated stress-induced immediate early gene responses, and specific transcriptional changes that arise following early life stress.

BACKGROUND: Early life adverse experience contributes to an enhanced vulnerability for adult psychopathology. Recent evidence indicates that serotonin type 2 (5-HT(2)) receptor function, implicated in the pathophysiology of mood and anxiety disorders, is significantly enhanced in the maternal separation model of early life stress. We examined whether postnatal 5-HT(2) receptor blockade would prevent the consequences of maternal separation on anxiety behavior and dysregulated gene expression. METHODS: Control and maternally separated litters received treatment with the 5-HT(2) receptor antagonist, ketanserin, or vehicle during postnatal life and were examined for effects on adult anxiety behavior, adult stress-induced immediate early gene expression responses, and transcriptional changes within the prefrontal cortex during postnatal life and in adulthood. RESULTS: Treatment with ketanserin during postnatal life blocked the long-lasting effects of maternal separation on anxiety behavior in the open field test and the elevated plus maze. Further, the dysregulated adult stress-induced expression pattern of the immediate early gene, Arc, observed in maternally separated animals was also prevented by postnatal ketanserin treatment. Ketanserin treatment normalized the alterations in the expression of specific genes in the prefrontal cortex of maternally separated animals, including changes in serotonin type 2A receptor messenger RNA expression during postnatal life and in genes associated with G-protein signaling in adulthood. CONCLUSIONS: Postnatal treatment with the 5-HT(2) receptor antagonist, ketanserin, blocked specific consequences of maternal separation, including anxiety behavior and dysregulated gene expression in the prefrontal cortex. Our results suggest that enhanced 5-HT(2) receptor function may contribute to the emergence of anxiety behavior and perturbed stress responses following early life stress.

Posterior cingulate cortex mediates outcome-contingent allocation of behavior.

Adaptive decision making requires selecting an action and then monitoring its consequences to improve future decisions. The neuronal mechanisms supporting action evaluation and subsequent behavioral modification, however, remain poorly understood. To investigate the contribution of posterior cingulate cortex (CGp) to these processes, we recorded activity of single neurons in monkeys performing a gambling task in which the reward outcome of each choice strongly influenced subsequent choices. We found that CGp neurons signaled reward outcomes in a nonlinear fashion and that outcome-contingent modulations in firing rate persisted into subsequent trials. Moreover, firing rate on any one trial predicted switching to the alternative option on the next trial. Finally, microstimulation in CGp following risky choices promoted a preference reversal for the safe option on the following trial. Collectively, these results demonstrate that CGp directly contributes to the evaluative processes that support dynamic changes in decision making in volatile environments.

Cognitive influences on risk-seeking by rhesus macaques.

Humans and other animals are idiosyncratically sensitive to risk, either preferring or avoiding options having the same value but differing in uncertainty. Many explanations for risk sensitivity rely on the non-linear shape of a hypothesized utility curve. Because such models do not place any importance on uncertainty per se, utility curve-based accounts predict indifference between risky and riskless options that offer the same distribution of rewards. Here we show that monkeys strongly prefer uncertain gambles to alternating rewards with the same payoffs, demonstrating that uncertainty itself contributes to the appeal of risky options. Based on prior observations, we hypothesized that the appeal of the risky option is enhanced by the salience of the potential jackpot. To test this, we subtly manipulated payoffs in a second gambling task. We found that monkeys are more sensitive to small changes in the size of the large reward than to equivalent changes in the size of the small reward, indicating that they attend preferentially to the jackpots. Together, these results challenge utility curve-based accounts of risk sensitivity, and suggest that psychological factors, such as outcome salience and uncertainty itself, contribute to risky decision-making.