Human Substantia Nigra Neurons Encode Reward Expectations.

Dopamine (DA) signals originating from substantia nigra (SN) neurons are centrally involved in the regulation of motor and reward processing. DA signals behaviorally relevant events where reward outcomes differ from expectations (reward prediction errors, RPEs). RPEs play a crucial role in learning optimal courses of action and in determining response vigor when an agent expects rewards. Nevertheless, how reward expectations, crucial for RPE calculations, are conveyed to and represented in the dopaminergic system is not fully understood, especially in the human brain where the activity of DA neurons is difficult to study. One possibility, suggested by evidence from animal models, is that DA neurons explicitly encode reward expectations. Alternatively, they may receive RPE information directly from upstream brain regions. To address whether SN neuron activity directly reflects reward expectation information, we directly examined the encoding of reward expectation signals in human putative DA neurons by performing single-unit recordings from the SN of patients undergoing neurosurgery. Patients played a two-armed bandit decision-making task in which they attempted to maximize reward. We show that neuronal firing rates (FR) of putative DA neurons during the reward expectation period explicitly encode reward expectations. First, activity in these neurons was modulated by previous trial outcomes, such that FR were greater after positive outcomes than after neutral or negative outcome trials. Second, this increase in FR was associated with shorter reaction times, consistent with an invigorating effect of DA neuron activity during expectation. These results suggest that human DA neurons explicitly encode reward expectations, providing a neurophysiological substrate for a signal critical for reward learning.

Awareness and attitude about mental illness in the rural population of India: A mixed method study.

Context: Recent systematic review and meta-analysis of public attitudes have shown that despite improvements in mental health literacy, public attitudes and desire for social distance with mental illnesses have remained stable over time. Aims: To assess the awareness and attitude of the rural community towards mental disorders using the CAMI scale. Materials and Methods: This mixed method study was conducted under the ICMR-STS grant scheme after IEC approval. It included administration of a pre-tested questionnaire adapted from CAMI scale on 196 adults aged 18-60 years from an adopted village in the field practice area of medical college along with 8 in-depth interviews of key people in the same community. Thematic analysis was done for the qualitative part whereas for the quantitative part, Pearson's correlation coefficient, independent t-test, ANOVA and Kruskall-wallis test were used. Results: Age was positively correlated with the attitude of authoritarianism, social restrictiveness, CMHI and showed a negative correlation with attitude of benevolence. Females showed higher scores for authoritarianism and social restrictiveness. There was a statistically significant difference between APL and BPL groups for authoritarianism attitude towards the mentally ill (P value = 0.02) and CMHI (P value = 0.033). It was observed that with increase in the education levels there was a rise in the mean score of the values for the attitude of benevolence but the difference wasn't statistically significant (P > 0.05). Thematic analysis of the key informant interviews suggested various perceptions of the community regarding mental illness, available options for management, current practices of the community and what can be done further to improve facilities for mental health. Conclusions: People in the community have a varied perspective to mental illnesses which has changed for the better over time but community still approaches quacks first which warrants the need for more awareness. For this, feasibility and effectiveness of increasing involvement of females from the community in health-related decisions can be explored further. We recommend further awareness generation in the younger generation with community-based research on perceptions of the community about mental health. This will provide more practical and feasible solutions to complement the national mental health program.

Neural patterns differentiate traumatic from sad autobiographical memories in PTSD.

For people with post-traumatic stress disorder (PTSD), recall of traumatic memories often displays as intrusions that differ profoundly from processing of 'regular' negative memories. These mnemonic features fueled theories speculating a unique cognitive state linked with traumatic memories. Yet, to date, little empirical evidence supports this view. Here we examined neural activity of patients with PTSD who were listening to narratives depicting their own memories. An intersubject representational similarity analysis of cross-subject semantic content and neural patterns revealed a differentiation in hippocampal representation by narrative type: semantically similar, sad autobiographical memories elicited similar neural representations across participants. By contrast, within the same individuals, semantically similar trauma memories were not represented similarly. Furthermore, we were able to decode memory type from hippocampal multivoxel patterns. Finally, individual symptom severity modulated semantic representation of the traumatic narratives in the posterior cingulate cortex. Taken together, these findings suggest that traumatic memories are an alternative cognitive entity that deviates from memory per se.

Longing to act: Bayesian inference as a framework for craving in behavioral addiction.

Traditionally, craving is considered a defining feature of drug addiction. Accumulating evidence suggests that craving can also exist in behavioral addictions (e.g., gambling disorder) without drug-induced effects. However, the degree to which mechanisms of craving overlap between classic substance use disorders and behavioral addictions remains unclear. There is, therefore, an urgent need to develop an overarching theory of craving that conceptually integrates findings across behavioral and drug addictions. In this review, we will first synthesize existing theories and empirical findings related to craving in both drug-dependent and -independent addictive disorders. Building on the Bayesian brain hypothesis and previous work on interoceptive inference, we will then propose a computational theory for craving in behavioral addiction, where the target of craving is execution of an action (e.g., gambling) rather than a drug. Specifically, we conceptualize craving in behavioral addiction as a subjective belief about physiological states of the body associated with action completion and is updated based on both a prior belief ("I need to act to feel good") and sensory evidence ("I cannot act"). We conclude by briefly discussing the therapeutic implications of this framework. In summary, this unified Bayesian computational framework for craving generalizes across addictive disorders, provides explanatory power for ostensibly conflicting empirical findings, and generates strong hypotheses for future empirical studies. The disambiguation of the computational components underlying domain-general craving using this framework will lead to a deeper understanding of, and effective treatment targets for, behavioral and drug addictions.

An Interpretable and Predictive Connectivity-Based Neural Signature for Chronic Cannabis Use.

BACKGROUND: Cannabis is one of the most widely used substances in the world, with usage trending upward in recent years. However, although the psychiatric burden associated with maladaptive cannabis use has been well established, reliable and interpretable biomarkers associated with chronic use remain elusive. In this study, we combine large-scale functional magnetic resonance imaging with machine learning and network analysis and develop an interpretable decoding model that offers both accurate prediction and novel insights into chronic cannabis use. METHODS: Chronic cannabis users (n = 166) and nonusing healthy control subjects (n = 124) completed a cue-elicited craving task during functional magnetic resonance imaging. Linear machine learning methods were used to classify individuals into chronic users and nonusers based on whole-brain functional connectivity. Network analysis was used to identify the most predictive regions and communities. RESULTS: We obtained high (∼80% out-of-sample) accuracy across 4 different classification models, demonstrating that task-evoked connectivity can successfully differentiate chronic cannabis users from nonusers. We also identified key predictive regions implicating motor, sensory, attention, and craving-related areas, as well as a core set of brain networks that contributed to successful classification. The most predictive networks also strongly correlated with cannabis craving within the chronic user group. CONCLUSIONS: This novel approach produced a neural signature of chronic cannabis use that is both accurate in terms of out-of-sample prediction and interpretable in terms of predictive networks and their relation to cannabis craving.

Emotional adaptation during a crisis: decline in anxiety and depression after the initial weeks of COVID-19 in the United States.

Crises such as the COVID-19 pandemic are known to exacerbate depression and anxiety, though their temporal trajectories remain under-investigated. The present study aims to investigate fluctuations in depression and anxiety using the COVID-19 pandemic as a model crisis. A total of 1512 adults living in the United States enrolled in this online study beginning April 2, 2020 and were assessed weekly for 10 weeks (until June 4, 2020). We measured depression and anxiety using the Zung Self-Rating Depression scale and State-Trait Anxiety Inventory (state subscale), respectively, along with demographic and COVID-related surveys. Linear mixed-effects models were used to examine factors contributing to longitudinal changes in depression and anxiety. We found that depression and anxiety levels were high in early April, but declined over time. Being female, younger age, lower-income, and previous psychiatric diagnosis correlated with higher overall levels of anxiety and depression; being married additionally correlated with lower overall levels of depression, but not anxiety. Importantly, worsening of COVID-related economic impact and increase in projected pandemic duration exacerbated both depression and anxiety over time. Finally, increasing levels of informedness correlated with decreasing levels of depression, while increased COVID-19 severity (i.e., 7-day change in cases) and social media use were positively associated with anxiety over time. These findings not only provide evidence for overall emotional adaptation during the initial weeks of the pandemic, but also provide insight into overlapping, yet distinct, factors contributing to depression and anxiety throughout the first wave of the pandemic.

Variations in the Anatomy of Spinal Accessory Nerve and its Landmarks for Identification in Neck Dissection: A Clinical Study.

PURPOSE: To assess the anatomy of the spinal accessory nerve (SAN), its variations and the landmark of level II B lymph nodes. METHODS: Prospective study included 50 patients from 2016 to 2018.The predictor variables were drawn from demographic details of the patients; SAN was analyzed intraoperatively with the parameters like the nerve relationship with the IJV, SCM muscle, contributions of cervical plexus and a new parameter of length from midpoint of clavicle to entry of nerve in the trapezius muscle in the lower part of neck which was studied for the first time and forms the prime identification landmark to preserve the nerve. Outcome variables were details of anatomic variations and branches and utility of these landmarks in prevention of nerve injury. RESULTS: Sample consisted of 38 (76%) male and 12 (24%) female patients. The SAN with respect to the IJV was dorsal in 42% patients and ventral in 58%. In 54% cases, SAN gave a branch to the SCM without penetrating the muscle and in 46% gave a branch to the SCM penetrating the muscle. SAN received contributions from the C2 root of the cervical plexus in 68%, both C2 and C3 in 54% and C3 in 50% cases. Mean length from measurements recorded between mid-line of clavicle to insertion of SAN to trapezius muscle and entry of SAN into trapezius muscle was 59 mm with variations recorded in gender and short/long neck. CONCLUSION: The result of this study suggests that parameters used are simple clinical tools for identification of the SAN and its variations resulting in no nerve injury. It is prudent for the surgeon to have knowledge of sound anatomical landmarks with the variations in the SAN course which avoids morbidity and improves the quality of life.

Containment of COVID-19: Simulating the impact of different policies and testing capacities for contact tracing, testing, and isolation.

Efficient contact tracing and testing are fundamental tools to contain the transmission of SARS-CoV-2. We used multi-agent simulations to estimate the daily testing capacity required to find and isolate a number of infected agents sufficient to break the chain of transmission of SARS-CoV-2, so decreasing the risk of new waves of infections. Depending on the non-pharmaceutical mitigation policies in place, the size of secondary infection clusters allowed or the percentage of asymptomatic and paucisymptomatic (i.e., subclinical) infections, we estimated that the daily testing capacity required to contain the disease varies between 0.7 and 9.1 tests per thousand agents in the population. However, we also found that if contact tracing and testing efficacy dropped below 60% (e.g. due to false negatives or reduced tracing capability), the number of new daily infections did not always decrease and could even increase exponentially, irrespective of the testing capacity. Under these conditions, we show that population-level information about geographical distribution and travel behaviour could inform sampling policies to aid a successful containment, while avoiding concerns about government-controlled mass surveillance.

A Whole-Brain and Cross-Diagnostic Perspective on Functional Brain Network Dysfunction.

A wide variety of mental disorders have been associated with resting-state functional network alterations, which are thought to contribute to the cognitive changes underlying mental illness. These observations appear to support theories postulating large-scale disruptions of brain systems in mental illness. However, existing approaches isolate differences in network organization without putting those differences in a broad, whole-brain perspective. Using a graph distance approach-connectome-wide similarity-we found that whole-brain resting-state functional network organization is highly similar across groups of individuals with and without a variety of mental diseases. This similarity was observed across autism spectrum disorder, attention-deficit hyperactivity disorder, and schizophrenia. Nonetheless, subtle differences in network graph distance were predictive of diagnosis, suggesting that while functional connectomes differ little across health and disease, those differences are informative. These results suggest a need to reevaluate neurocognitive theories of mental illness, with a role for subtle functional brain network changes in the production of an array of mental diseases. Such small network alterations suggest the possibility that small, well-targeted alterations to brain network organization may provide meaningful improvements for a variety of mental disorders.

Containment of future waves of COVID-19: simulating the impact of different policies and testing capacities for contact tracing, testing, and isolation.

We used multi-agent simulations to estimate the testing capacity required to find and isolate a number of infections sufficient to break the chain of transmission of SARS-CoV-2. Depending on the mitigation policies in place, a daily capacity between 0.7 to 3.6 tests per thousand was required to contain the disease. However, if contact tracing and testing efficacy dropped below 60% (e.g. due to false negatives or reduced tracing capability), the number of infections kept growing exponentially, irrespective of any testing capacity. Under these conditions, the population's geographical distribution and travel behaviour could inform sampling policies to aid a successful containment.

Clinical outcomes of endoscopic vs retromandibular approach for the treatment of condylar fractures-a randomized clinical trial.

OBJECTIVE: Condylar fractures remain the most controversial topic in maxillofacial trauma. Open reduction and internal fixation (ORIF) with use of an extraoral approach has certain benefits over the nonsurgical treatment. Concerns, however, remain about the risk of facial nerve injury, postoperative facial nerve weakness, and facial scarring when operating in this region despite the various extraoral approaches that have been developed. The recently popularized endoscope-assisted open reduction and internal fixation (EAORIF) is claimed to provide better results because it is minimally invasive, provides excellent visibility, and eliminates surgical scarring and the risk of facial nerve injury. This study, therefore, aims to compare the retromandibular (extraoral) approach and EAORIF for the treatment of condylar fractures. STUDY DESIGN: A prospective analysis of 32 cases of condylar fractures that reported to the SDM Craniofacial Centre (Dharwad, India) was carried out. Sixteen patients had been treated with the retromandibular (RM) approach, and 16 had undergone EAORIF in the period from 2012-2017. Patients were evaluated for clinical parameters, such as fracture site, displacement, and surgical duration, as well as for functional parameters, such as occlusion, maximum interincisal opening, deviation of mouth on lateral movements, temporomandibular joint (TMJ) pain and clicking, and facial nerve weakness. Statistical significance was elicited with P < .05. RESULTS: The patients subjected to either approach had suffered fractures of the low condylar neck and the subcondyle. Maximum interincisal opening, mandibular deviation, occlusion, and TMJ function at postoperative month 6 were comparable between the groups. Although no permanent facial nerve injury was seen in this study, the incidence of transient facial nerve weakness was higher in the RM group (56.25%) compared with the EAORIF group (6.25%) (P = .036). The surgical time was longer in the EAORIF group (RM: 107+/- 19.7 minutes and EAORIF: 155 +/- 18.2 minutes) (P = .04). The rest of the parameters were comparable between both groups. CONCLUSIONS: Although there is consensus on closed reduction in pediatric and adult condylar head fractures, the role of a surgical approach to treatment of displaced condylar neck and subcondylar fractures remains controversial. In our study, both surgical approaches were found to be suitable for the treatment of these fractures.

Mapping the human brain's cortical-subcortical functional network organization.

Understanding complex systems such as the human brain requires characterization of the system's architecture across multiple levels of organization - from neurons, to local circuits, to brain regions, and ultimately large-scale brain networks. Here we focus on characterizing the human brain's large-scale network organization, as it provides an overall framework for the organization of all other levels. We developed a highly principled approach to identify cortical network communities at the level of functional systems, calibrating our community detection algorithm using extremely well-established sensory and motor systems as guides. Building on previous network partitions, we replicated and expanded upon well-known and recently-identified networks, including several higher-order cognitive networks such as a left-lateralized language network. We expanded these cortical networks to subcortex, revealing 358 highly-organized subcortical parcels that take part in forming whole-brain functional networks. Notably, the identified subcortical parcels are similar in number to a recent estimate of the number of cortical parcels (360). This whole-brain network atlas - released as an open resource for the neuroscience community - places all brain structures across both cortex and subcortex into a single large-scale functional framework, with the potential to facilitate a variety of studies investigating large-scale functional networks in health and disease.

The Human Brain Traverses a Common Activation-Pattern State Space Across Task and Rest.

Much of our lives are spent in unconstrained rest states, yet cognitive brain processes are primarily investigated using task-constrained states. It may be possible to utilize the insights gained from experimental control of task processes as reference points for investigating unconstrained rest. To facilitate comparison of rest and task functional magnetic resonance imaging data, we focused on activation amplitude patterns, commonly used for task but not rest analyses. During rest, we identified spontaneous changes in temporally extended whole-brain activation-pattern states. This revealed a hierarchical organization of rest states. The top consisted of two competing states consistent with previously identified "task-positive" and "task-negative" activation patterns. These states were composed of more specific states that repeated over time and across individuals. Contrasting with the view that rest consists of only task-negative states, task-positive states occurred 40% of the time while individuals "rested," suggesting task-focused activity may occur during rest. Together our results suggest that brain activation dynamics form a general hierarchy across task and rest, with a small number of dominant general states reflecting basic functional modes and a variety of specific states potentially reflecting a wide variety of cognitive processes.

Cognitive task information is transferred between brain regions via resting-state network topology.

Resting-state network connectivity has been associated with a variety of cognitive abilities, yet it remains unclear how these connectivity properties might contribute to the neurocognitive computations underlying these abilities. We developed a new approach-information transfer mapping-to test the hypothesis that resting-state functional network topology describes the computational mappings between brain regions that carry cognitive task information. Here, we report that the transfer of diverse, task-rule information in distributed brain regions can be predicted based on estimated activity flow through resting-state network connections. Further, we find that these task-rule information transfers are coordinated by global hub regions within cognitive control networks. Activity flow over resting-state connections thus provides a large-scale network mechanism for cognitive task information transfer and global information coordination in the human brain, demonstrating the cognitive relevance of resting-state network topology.

Preparation and characterization of maghemite nanoparticles from mild steel for magnetically guided drug therapy.

Maghemite (γ-Fe 2 O 3) nanoparticles for therapeutic applications are prepared from mild steel but the existing synthesis technique is very cumbersome. The entire process takes around 100 days with multiple steps which lack proper understanding. In the current work, maghemite nanoparticles of cuboidal and spheroidal morphologies were prepared from mild steel chips by a novel cost effective oil reduction technique for magnetically guided intravascular drug delivery. The technique developed in this work yields isometric sized γ-Fe 2 O 3 nanoparticles in 6 h with higher saturation magnetization as compared to the existing similar solid state synthesis route. Mass and heat flow kinetics during the heating and quenching steps were studied with the help of Finite element simulations. Qualitative and quantitative analysis of the γ-Fe 2 O 3 phase is performed with the help of x-ray diffraction, transmission electron microscope and x-ray photoelectron spectroscopy. Mechanism for the α-Fe 2 O 3 (haematite) to γ-Fe 2 O 3 (maghemite) phase evolution during the synthesis process is also investigated. Maghemite (γ-Fe2O3) nanoparticles were prepared bya novel cost effective oil reduction technique as mentioned below in the figure. The raw materials included mild steel chips which is one of the most abundant engineering materials. These particles can be used as ideal nanocarriers for targeted drug delivery through the vascular network.

Gender-dependent differences in uridine 5'-diphospho-glucuronosyltransferase have implications in metabolism and clearance of xenobiotics.

INTRODUCTION: Gender differences have a significant impact on absorption, disposition and overall systemic bioavailability of various xenobiotics in rodents as well as humans. Over the past few years, significant research has explored and investigated the effects of gender differences on the expression profiles of uridine 5'-diphospho-glucuronosyltransferases (or UGTs) in rodents but no data is available that could effectively help predict the metabolic clearance or systemic bioavailability of xenobiotics predominantly metabolized by UGT enzymes in vivo. AREAS COVERED: This review highlights and explains the unique features of the metabolic clearance reactions catalyzed by UGTs (metabolite formation) and its intricate interactions with the efflux transporters that will transport hydrophilic glucuronides out of cell in vivo. In addition, the article reviews the gender differences in hepatic and extrahepatic UGT isoforms and efflux transporter expression profiles in rodents. Furthermore, the article highlights the implications of sex hormone differences on metabolic clearance and thereby oral bioavailability of xenobiotics that are predominantly metabolized by UGTs in vivo. Finally, the article reviews the impact of plasma sex hormone level differences on UGT enzyme and efflux transporter expression profiles using in situ and in vivo models. EXPERT OPINION: The authors believe that the article demonstrates that gender, and perhaps more importantly the differences in plasma sex hormone levels in female species, will drive the gender-dependent differences in expression profiles of UGT enzymes and efflux transporters. These differences significantly affect the metabolic clearance and the systemic bioavailability of compounds eliminated via this disposition pathway.

Effects of estrogen and estrus cycle on pharmacokinetics, absorption, and disposition of genistein in female Sprague-Dawley rats.

Genistein is an active soy isoflavone with anticancer activities, but it is unknown why it has a higher oral bioavailability in female than in male rats. Our study determined the effects of estrus cycle on genistein's oral bioavailability. Female rats with various levels of estrogen were orally administered with genistein or used in a four-site rat intestinal perfusion experiment. Rats in "proestrus" group (with elevated estrogen) had significantly reduced (57% decrease, p < 0.05) oral bioavailability of total genistein (aglycone + conjugates) than those in "metoestrus" group (with basal level of estrogen). Female ovariectomized rats, due to lack of estrogen, showed oral bioavailability of total genistein similar to the "metoestrus" group but higher (155% increase, p < 0.05) than the "proestrus" group. On the basis of intestinal perfusion studies, the increased bioavailability was partially attributed to the higher (>100% increase, p < 0.05) hepatic disposition via glucuronidation and possibly more efficient enterohepatic recycling of genistein in the "metoestrus" group. Furthermore, chronic exogenous supplementation of estradiol in ovariectomized rats significantly reduced (77%, p < 0.05) the oral bioavailability of total genistein, mostly via increased sulfation (>10-fold) in liver, to a level comparable to those in the "proestrus" group. In conclusion, the oral bioavailability of total genistein was inversely proportional to elevated estrogen levels in female rats, which is partially mediated through the regulation of hepatic enzymes responsible disposition of genistein.

Bioavailability and pharmacokinetics of genistein: mechanistic studies on its ADME.

Genistein, one of the most active natural flavonoids, exerts various biological effects including chemoprevention, antioxidation, antiproliferation and anticancer. More than 30 clinical trials of genistein with various disease indications have been conducted to evaluate its clinical efficacy. Based on many animals and human pharmacokinetic studies, it is well known that the most challenge issue for developing genistein as a chemoprevention agent is the low oral bioavailability, which may be the major reason relating to its ambiguous therapeutic effects and large interindividual variations in clinical trials. In order to better correlate pharmacokinetic to pharmacodynamics results in animals and clinical studies, an in-depth understanding of pharmacokinetic behavior of genistein and its ADME properties are needed. Numerous in vitro/in vivo ADME studies had been conducted to reveal the main factors contributing to the low oral bioavailability of genistein. Therefore, this review focuses on summarizing the most recent progress on mechanistic studies of genistein ADME and provides a systemic view of these processes to explain genistein pharmacokinetic behaviors in vivo. The better understanding of genistein ADME property may lead to development of proper strategy to improve genistein oral bioavailability via mechanism-based approaches.

First-pass metabolism via UDP-glucuronosyltransferase: a barrier to oral bioavailability of phenolics.

Glucuronidation mediated by UDP-glucuronosyltransferases (UGTs) is a significant metabolic pathway that facilitates efficient elimination of numerous endobiotics and xenobiotics, including phenolics. UGT genetic deficiency and polymorphisms or inhibition of glucuronidation by concomitant use of drugs are associated with inherited physiological disorders or drug-induced toxicities. Moreover, extensive glucuronidation can be a barrier to oral bioavailability as the first-pass glucuronidation (or premature clearance by UGTs) of orally administered agents usually results in the poor oral bioavailability and lack of efficacies. This review focused on the first-pass glucuronidation of phenolics including natural polyphenols and pharmaceuticals. The complexity of UGT-mediated metabolism of phenolics is highlighted with species-, gender-, organ- and isoform-dependent specificity, as well as functional compensation between UGT1A and 2B subfamily. In addition, recent advances are discussed with respect to the mechanisms of enzymatic actions, including the important properties such as binding pocket size and phosphorylation requirements.