Search

Larger portions of food elicit greater intake than smaller portions of food, particularly when foods are high in energy density (kcal/g; ED). The neural mechanisms underlying this effect remain unclear. The present study used fMRI to assess brain activation to food (higher-ED, lower-ED) and non-food (office supplies) images presented in larger and smaller (i.e., age-appropriate) amounts in 61, 7-8-year-olds (29 male, 32 female) without obesity. Larger amounts of food increased activation in bilateral visual and right parahippocampal areas compared to smaller amounts; greater activation to food amount (larger > smaller) in this cluster was associated with smaller increases in food intake as portions increased. Activation to amount (larger > smaller) was stronger for food than office supplies in primary and secondary visual areas, but, for office supplies only, extended into bilateral parahippocampus, inferior parietal cortex, and additional visual areas (e.g., V7). Activation was greater for higher-vs. lower-ED food images in ventromedial prefrontal cortex for both larger and smaller amounts of food; however, this activation extended into left lateral orbital frontal cortex for smaller amounts only. Activation to food cues did not differ by familial risk for obesity. These results highlight potentially distinct neural pathways for encoding food energy content and quantity., Competing Interests: Declaration of competing interest None, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The neural mechanisms underlying susceptibility to eating more in response to large portions (i.e., the portion size effect) remain unclear. Thus, the present study examined how neural responses to portion size relate to changes in weight and energy consumed as portions increase. Associations were examined across brain regions traditionally implicated in appetite control (i.e., an appetitive network) as well as the cerebellum, which has recently been implicated in appetite-related processes. Children without obesity (i.e., BMI-for-age-and-sex percentile < 90; N = 63; 55% female) viewed images of larger and smaller portions of food during fMRI and, in separate sessions, ate four meals that varied in portion size. Individual-level linear and quadratic associations between intake (kcal, grams) and portion size (i.e., portion size slopes) were estimated. The response to portion size in cerebellar lobules IV-VI was associated with the quadratic portion size slope estimated from gram intake; a greater response to images depicting smaller compared to larger portions was associated with steeper increases in intake with increasing portion sizes. Within the appetitive network, neural responses were not associated with portion size slopes. A decreased cerebellar response to larger amounts of food may increase children's susceptibility to overeating when excessively large portions are served.

Deficits in executive functions (EFs), a set of cognitive processes related to self-regulation, are associated with the development of obesity. Prior studies from our group showed that lower food-cue related activation in brain regions implicated in self-regulation was related to a larger portion size effect. We tested the hypothesis that lower EFs in children would be positively related to the portion size effect. Healthy weight children aged 7-8 y (n = 88), who varied by maternal obesity status, participated in a prospective study. At baseline, the parent primarily in charge of feeding completed the Behavior Rating Inventory of Executive Function (BRIEF2) to assess child EFs, including Behavioral (BRI), Emotional (ERI), and Cognitive (CRI) indices. At 4 baseline sessions, children consumed meals in which the portion sizes of foods (pasta, chicken nuggets, broccoli, and grapes) varied by visit (total meal weight of 769, 1011, 1256, or 1492g). Intake increased with increasing portions in a linear trajectory (p < 0.001). EFs moderated the portion size effect such that lower BRI (p = 0.003) and ERI (p = 0.006) were associated with steeper increases in intake as portions increased. As amount of food increased, children in the lowest functioning tertiles for BRI and ERI increased intake by 35% and 36%, respectively, compared to children in the higher tertiles. Increases in intake among children with lower EFs were for higher- but not lower-energy-dense foods. Thus, in healthy weight children who varied by obesity risk, lower parentally reported EFs were associated with a larger portion size effect, and these results were independent of child and parent weight status. Therefore, EFs may be target behaviors that could be strengthened to help children moderate excess intake in response to large portions of energy-dense foods., Competing Interests: Declaration of competinginterest The authors declare that this study was performed in accordance with the Declaration of Helsinki. The protocol was approved by the Institutional Review Board of The Pennsylvania State University STUDY00005357., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Flexible self-regulation has been shown to be an adaptive ability. This study adapted and validated the adult Flexible Regulation of Emotional Expression (FREE) Scale for use with youth (FREE-Y) in community and maltreatment samples. The FREE-Y measures the ability to flexibly enhance and suppress emotion expression across an array of hypothetical social scenarios. Participants ( N = 654, 8-19 years) were included from three studies. Confirmatory factor analysis (CFA) confirmed a theoretically appropriate higher order factor structure. Using multiple-group CFAs, measurement invariance was achieved across maltreatment status, age, and gender. Reliabilities were adequate and construct validity was demonstrated through associations with measures of emotion regulation, psychopathology, IQ, and executive functioning. Group comparisons indicated lower Suppression and Flexibility scores for maltreated versus comparison participants. Findings suggest that the FREE-Y is a valid measure of expressive regulation ability in youth that can be applied across a range of populations.

Data-driven methods for personalizing treatment assignment have garnered much attention from clinicians and researchers. Dynamic treatment regimes formalize this through a sequence of decision rules that map individual patient characteristics to a recommended treatment. Observational studies are commonly used for estimating dynamic treatment regimes due to the potentially prohibitive costs of conducting sequential multiple assignment randomized trials. However, estimating a dynamic treatment regime from observational data can lead to bias in the estimated regime due to unmeasured confounding. Sensitivity analyses are useful for assessing how robust the conclusions of the study are to a potential unmeasured confounder. A Monte Carlo sensitivity analysis is a probabilistic approach that involves positing and sampling from distributions for the parameters governing the bias. We propose a method for performing a Monte Carlo sensitivity analysis of the bias due to unmeasured confounding in the estimation of dynamic treatment regimes. We demonstrate the performance of the proposed procedure with a simulation study and apply it to an observational study examining tailoring the use of antidepressant medication for reducing symptoms of depression using data from Kaiser Permanente Washington., (© 2023 Wiley-VCH GmbH.)

Determining the factors that influence implementation of school-based wellbeing and health programs is essential for achieving desired program effects. Using a convergent mixed-methods, multiple informant design, this study considered factors that influence implementation of health programs for ninth grade students and in what ways implementation is differentially perceived by multiple informants (i.e., participants, instructors, and independent observers). Two types of programs-mindfulness and health education-were implemented with ninth graders (N = 70) in three schools situated in low-resourced urban neighborhoods. Study outcomes were derived from four data sources: (1) focus group participants (N = 45); (2) program instructor fidelity ratings; (3) independent observer fidelity ratings and notes; and (4) instructor open-ended session responses. Using thematic and mixed methods integration analyses, we identified themes related to implementation promoting or challenging factors. Theme names differed when data sources were separately analyzed by informant. Mixed methods integration analysis indicated that four themes were common across all informant groups: (1) competent, attentive, and engaging instructors are essential; (2) programs should involve interactive components (e.g., physical activities, applied learning opportunities); (3) adequate time for program delivery is key for student exposure and engagement; and (4) students' availability and preferences should guide program scheduling. A fifth theme, unique to instructor and observer perspectives, was that program implementation was negatively impacted by distractions from multiple sources, including instructors, students, and settings. Recommendations from students, instructors, and observers for implementation optimization are discussed., (© 2023. Society for Prevention Research.)

Background: Childhood maltreatment (CM) can be an impediment to normative development and consistently predicts increased risk for substance misuse and polysubstance use (polySU). Yet, a subset of individuals who experience CM exhibit successful adaptations across the lifespan. Although there is an expansive literature on socioemotional and cognitive protective factors that mitigate impacts of CM, less is known about other, intra-individual resilience-promoting factors (e.g., positive future orientation) known to assuage high-risk SU patterns during adolescence., Method: This study examined heterogeneity in individual-level resilience characteristics in maltreated youth as it related to CM characteristics and SU patterns during adolescence. Participants included maltreated youth from the longitudinal LONGSCAN sample ( N =355; 181 females). Latent Profile Analysis was used to identify subgroups of CM-exposed individuals based on 5 resilience indicator variables (i.e., commitment to goals, engaging in demanding activities, self-reliance, positive future orientation, and externalizing behaviors). Tests for differences in SU patterns and CM characteristics between the resultant profiles were performed., Results: Data models revealed 3 latent profiles based on participants' resilience traits (i.e., Low Resilience, Average Resilience, and High Resilience). There were no profile differences on the basis of CM characteristics. Those in the High Resilience profile were less likely to engage in polySU compared to the Average Resilience profile., Implications: These findings highlight the promise of individual-level resilience factors that are not necessarily dependent upon caregiver or environmental inputs as protective against polySU following CM. This work represents a promising avenue for future preventative intervention efforts targeting emergent SU behaviors in high-risk youth., Competing Interests: Declaration of Interest Statement The authors have no conflicts of interest to declare.

Significant attention has been given to developing data-driven methods for tailoring patient care based on individual patient characteristics. Dynamic treatment regimes formalize this approach through a sequence of decision rules that map patient information to a suggested treatment. The data for estimating and evaluating treatment regimes are ideally gathered through the use of Sequential Multiple Assignment Randomized Trials (SMARTs), though longitudinal observational studies are commonly used due to the potentially prohibitive costs of conducting a SMART. Observational studies are typically powered for simple comparisons of fixed treatment sequences; a priori power or sample size calculations for tailored strategies are rarely if ever undertaken. This has lead to many studies that fail to find a statistically significant benefit to tailoring treatment. We develop power analyses for the estimation of dynamic treatment regimes from observational studies. Our approach uses pilot data to estimate the power for comparing the value of the optimal regime, i.e., the expected outcome if all patients in the population were treated by following the optimal regime, with a known comparison mean. This allows for calculations that ensure a study has sufficient power to detect the need for tailoring, should it be present. Our approach also ensures the value of the estimated optimal treatment regime has a high probability of being within a range of the value of the true optimal regime, set a priori. We examine the performance of the proposed procedure with a simulation study and use it to size a study for reducing depressive symptoms using data from electronic health records., Competing Interests: Conflict of Interest No potential conflict of interest was reported by the author(s).

Background: Earlier substance use (SU) initiation is associated with greater risk for the development of SU disorders (SUDs), while delays in SU initiation are associated with a diminished risk for SUDs. Thus, identifying brain and behavioral factors that are markers of enhanced risk for earlier SU has major public health import. Heightened reward-sensitivity and risk-taking are two factors that confer risk for earlier SU., Materials and Methods: We characterized neural and behavioral factors associated with reward-sensitivity and risk-taking in substance-naïve adolescents ( N = 70; 11.1-14.0 years), examining whether these factors differed as a function of subsequent SU initiation at 18- and 36-months follow-up. Adolescents completed a reward-related decision-making task while undergoing functional MRI. Measures of reward sensitivity (Behavioral Inhibition System-Behavioral Approach System; BIS-BAS), impulsive decision-making (delay discounting task), and SUD risk [Drug Use Screening Inventory, Revised (DUSI-R)] were collected. These metrics were compared for youth who did [Substance Initiators (SI); n = 27] and did not [Substance Non-initiators (SN); n = 43] initiate SU at follow-up., Results: While SI and SN youth showed similar task-based risk-taking behavior, SI youth showed more variable patterns of activation in left insular cortex during high-risk selections, and left anterior cingulate cortex in response to rewarded outcomes. Groups displayed similar discounting behavior. SI participants scored higher on the DUSI-R and the BAS sub-scale., Conclusion: Activation patterns in the insula and anterior cingulate cortex may serve as a biomarker for earlier SU initiation. Importantly, these brain regions are implicated in the development and experience of SUDs, suggesting differences in these regions prior to substance exposure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 McQuaid, Darcey, Patterson, Rose, VanMeter and Fishbein.)

Children show substantial variation in the rate of physical, cognitive, and social maturation as they traverse adolescence and enter adulthood. Differences in developmental paths are thought to underlie individual differences in later life outcomes, however, there remains a lack of consensus on the normative trajectory of cognitive maturation in adolescence. To address this problem, we derive a Cognitive Maturity Index (CMI), to estimate the difference between chronological and cognitive age predicted with latent factor estimates of inhibitory control, risky decision-making and emotional processing measured with standard neuropsychological instruments. One hundred and forty-one children from the Adolescent Development Study (ADS) were followed longitudinally across three time points from ages 11-14, 13-16, and 14-18. Age prediction with latent factor estimates of cognitive skills approximated age within ±10 months ( r = 0.71). Males in advanced puberty displayed lower cognitive maturity relative to peers of the same age; manifesting as weaker inhibitory control, greater risk-taking, desensitization to negative affect, and poor recognition of positive affect., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 El Damaty, Darcey, McQuaid, Picci, Stoianova, Mucciarone, Chun, Laws, Campano, Van Hecke, Ryan, Rose, Fishbein and VanMeter.)

New insights into mechanisms linking obesity to poor health outcomes suggest a role for cellular aging pathways, casting obesity as a disease of accelerated biological aging. Although obesity has been linked to accelerated epigenetic aging in middle-aged adults, the impact during childhood remains unclear. We tested the association between body mass index (BMI) and accelerated epigenetic aging in a cohort of high-risk children. Participants were children (N = 273, aged 8 to 14 years, 82% investigated for maltreatment) recruited to the Child Health Study, an ongoing prospective study of youth investigated for maltreatment and a comparison youth. BMI was measured as a continuous variable. Accelerated epigenetic aging of blood leukocytes was defined as the age-adjusted residuals of several established epigenetic aging clocks (Horvath, Hannum, GrimAge, PhenoAge) along with a newer algorithm, the DunedinPoAm, developed to quantify the pace-of-aging. Hypotheses were tested with generalized linear models. Higher age-and sex- adjusted z-scored BMI was significantly correlated with household income, blood cell counts, and three of the accelerated epigenetic aging measures: GrimAge (r = 0.31, P < .0001), PhenoAge (r = 0.24, P < .0001), and DunedinPoAm (r = 0.38, P < .0001). In fully adjusted models, GrimAge (β = 0.07; P = .0009) and DunedinPoAm (β = 0.0017; P < .0001) remained significantly associated with higher age- and sex-adjusted z-scored BMI. Maltreatment-status was not associated with accelerated epigenetic aging. In a high-risk cohort of children, higher BMI predicted epigenetic aging as assessed by two epigenetic aging clocks. These results suggest the association between obesity and accelerated epigenetic aging begins in early life, with implications for future morbidity and mortality risk., (© 2022. The Author(s).)

Various approaches exist to assess population differences in biological aging. Telomere length (TL) is one such measure, and is associated with disease, disability and early mortality. Yet, issues surrounding precision and reproducibility are a concern for TL measurement. An alternative method to estimate TL using DNA methylation (DNAmTL) was recently developed. Although DNAmTL has been characterized in adult and elderly cohorts, its utility in pediatric populations remains unknown. We examined the comparability of leukocyte TL measurements generated using qPCR (absolute TL; aTL) to those estimated using DNAmTL in a high-risk pediatric cohort ( N = 269; age: 8-13 years, 83% investigated for maltreatment). aTL and DNAmTL measurements were correlated with one another (r = 0.20, p = 0.001), but exhibited poor measurement agreement and were significantly different in paired-sample t -tests (Cohen's d = 0.77, p < 0.001). Shorter DNAmTL was associated with older age (r = -0.25, p < 0.001), male sex (β = -0.27, p = 0.029), and White race (β = -0.74, p = 0.008). By contrast, aTL was less strongly associated with age (r = -0.13, p = 0.040), was longer in males (β = 0.31, p = 0.012), and was not associated with race ( p = 0.820). These findings highlight strengths and limitations of high-throughput measures of TL; although DNAmTL replicated hypothesized associations, aTL measurements were positively skewed and did not replicate associations with external validity measures. These results also extend previous research in adults and suggest that DNAmTL is a sensitive TL measure for use in pediatric populations.

Genetic variants in the opioid receptor mu 1 (OPRM1) and dopamine receptor d2 (DRD2) genes are implicated in behavioral phenotypes related to substance use disorders (SUD). Despite associations among OPRM1 (rs179971) and DRD2 (rs6277) genes and structural alterations in neural reward pathways implicated in SUDs, little is known about the contribution of risk-related gene variants to structural neurodevelopment. In a 3-year longitudinal study of initially SU-naïve adolescents (N = 129; 70 females; 11-14 years old), participants underwent an MRI structural scan at baseline and provided genetic assays for OPRM1 and DRD2 with SU behavior assessed during follow-up visits. Baseline differences in key reward-related brain regions (i.e., bilateral caudate and cingulate cortex) were detected in those with genetic liability for SU in OPRM1 who went onto engage in SU at subsequent waves of data collection. In addition, main effects of OPRM1, DRD2, and SU were related to variability in structure of the putamen, anterior cingulate, and nucleus accumbens, respectively. These data provide preliminary evidence that genetic risk factors interact with future SU to confer structural variability prior to SU in regions commonly implicated in risk for SU and the development of SUDs., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

As championed by the work of Ed Zigler, investing in nurturing environments for all children is a chief tenet of primary prevention that will have far-reaching benefits to the health and welfare of all members of society. Children who endure child maltreatment (CM) are among society's most vulnerable. Prospective longitudinal research aimed at a comprehensive understanding of the mechanisms linking CM to subsequent adverse health consequences is needed to improve outcomes and to strengthen causal inference. This paper outlines the methods of the Child Health Study (CHS), a large, state-wide longitudinal cohort of recently maltreated and nonmaltreated youth aged 8-13 who will be assessed every 2 years. The CHS is designed to include in-depth assessments of multiple environmental, behavioral, neural, physiological, and molecular mechanisms through which CM may impact a broad spectrum of youth development, including behavioral and physical health outcomes. In addition to describing the conceptual framework and methods underlying the CHS, we provide information on valuable "lessons learned" in the hopes of supporting future research efforts facing similar challenges. The ultimate goal of this research is demonstrating how policies regarding CM impact the well-being, resilience and recovery of survivors and that they are worthy of large public investment.

Brain development is exquisitely sensitive to psychosocial experiences, with implications for neurodevelopmental trajectories, for better or worse. The premise of this investigation was that the level of responsibility in adolescence may relate to brain structure and higher-order cognitive functions. In a sample of 108 adolescents, we focused on cortical thickness (using FreeSurfer) as an indicator of neurodevelopment in regions previously implicated in executive functioning (EF) and examined performance on an EF task outside of the scanner, in the context of level of responsibility. We further investigated whether socioeconomic status (SES) and family stress moderated the relationship between responsibility and brain structure or EF. Findings revealed that greater responsibility was related to thinner left precuneus and right middle frontal cortex. In lower SES adolescents, greater responsibility predicted thinner left precuneus and right middle frontal cortex, which have been consistently implicated in EF. Higher SES adolescents did not show structural differences related to responsibility, however, they did exhibit better EF performance. It may be that circumstances surrounding the need for greater responsibility in lower SES households are detrimental to neurodevelopment compared to higher SES households. Alternatively, responsibility may act as a protective factor that bolsters cortical thinning in regions related to EF., (© 2020 Wiley Periodicals LLC.)

Food images are routinely used to investigate the cognitive and neurobiological mechanisms of eating behaviors, but there is a lack of standardized image sets for use in children, which limits cross-study comparisons. To address this gap, we developed a set of age-appropriate images that included 30 high-energy-dense (ED) foods (>2.00 kcal/g), 30 low-ED foods (<1.75 kcal/g), and 30 office supplies photographed in two amounts (i.e., "larger" and "smaller"). Preliminary testing was conducted with children (6-10 years) to assess recognition, emotional valence (1 = very sad, 5 = very happy), and excitability (1 = very bored, 5 = very excited). After the initial testing, 10 images with low recognition were replaced; thus, differences between Image Set 1 and Image Set 2 were analyzed. Thirty ( n = 30, mean age 8.3 ± 1.2 years) children rated Set 1, and a different cohort of 29 children (mean age 8.1 ± 1.1 years) rated Set 2. Changes made between image sets improved recognition of low-ED foods (Set 1 = 88.3 ± 10.5% vs. Set 2 = 95.6 ± 10.6%; p < 0.0001) and office supplies (83.7 ± 10.5 vs. 93.0 ± 10.6%; p < 0.0001). For the revised image set, children recognized more high-ED foods (98.4 ± 10.6%) than low-ED foods (95.6 ± 10.6%; p < 0.05) and office supplies (93.0 ± 10.6%; p < 0.0001). Recognition also improved with age ( p < 0.001). Excitability and emotional valence scores were greater for high-ED foods compared with both low-ED foods and office supplies ( p < 0.0001 for both). However, child fullness ratings influenced the relationship between excitability/emotional valence and category of item ( p < 0.002). At the lowest fullness level, high-ED foods were rated the highest in both excitability and emotional valence, followed by low-ED foods and then office supplies. At the highest fullness level, high-ED foods remained the highest in excitability and emotional valence, but ratings for low-ED foods and office supplies were not different. This suggests that low-ED foods were more exciting and emotionally salient (relative to office supplies) when children were hungry. Ratings of recognition, excitability, and emotional valence did not differ by image amount. This new, freely available, image set showed high recognition and expected differences between image category for emotional valence and excitability. When investigating children's responsiveness to food cues, specifically energy density, it is essential for investigators to account for potential influences of child age and satiety level., (Copyright © 2020 Kling, Pearce, Reynolds, Garavan, Geier, Rolls, Rose, Wilson and Keller.)

As social robots continue to show promise as assistive technologies, the exploration of appropriate and impactful robot behaviors is key to their eventual success. Teens are a unique population given their vulnerability to stress leading to both mental and physical illness. Much of teen stress stems from school, making the school environment an ideal location for a stress reducing technology. The goal of this mixed-methods study was to understand teens' operation of, and responsiveness to, a robot only capable of movement compared to a robot only capable of speech. Stemming from a human-centered approach, we introduce a Participatory Wizard of Oz (PWoz) interaction method that engaged teens as operators, users, and witnesses in a uniquely transparent interaction. In this paper, we illustrate the use of the PWoz interaction method as well as how it helps identify engaging robot interactions. Using this technique, we present results from a study with 62 teens that includes details of the complexity of teen stress and a significant reduction in negative attitudes toward robots after interactions. We analyzed the teens' interactions with both the verbal and non-verbal robots and identified strong themes of (1) authenticity, (2) empathy, (3) emotional engagement, and (4) imperfection creates connection. Finally, we reflect on the benefits and limitations of the PWoz method and our study to identify next steps toward the design and development of our social robot., (Copyright © 2020 Björling, Thomas, Rose and Cakmak.)

[This corrects the article DOI: 10.3389/fpsyt.2019.00399.]., (Copyright © 2020 Rose, Picci and Fishbein.)

Studies of substance misuse prevention generally focus on characteristics that typify risk, with the assumption that the prevalence of the problem will be optimally reduced by identifying, targeting, and reducing or eliminating risk factors. However, this risk-centered approach neglects variations in individual-level and environmental characteristics that portend differential pathways that are distinguishable by timing of substance use initiation (e.g., early versus delayed), the likelihood of use escalation versus eventual desistance, and enduring abstinence, despite exposure to significant risk factors. Considering the various underpinnings of these distinct substance use trajectories is critical to a more nuanced understanding of the effects, potency, and malleability of factors that are known to increase risk or confer protection. Here, we discuss three pathways relative to substance use patterns and predictors in the context of adversity, a well-known, highly significant influence on propensity for substance misuse. The first pathway is designated as "high risk" based on early onset of substance use, rapid escalation, and proneness to substance use disorders. Individuals who defy all odds and eventually exhibit adaptive developmental outcomes despite an initial maladaptive reaction to adversity, are referred to as "resilient." However, another categorization that has not been adequately characterized is "resistant." Resistant individuals include those who do not exhibit problematic substance use behaviors (e.g., early onset and escalation) and do not develop substance use disorders or other forms of psychopathology, despite significant exposure to factors that normally increase the propensity for such outcomes (e.g. trauma and/or adversity). In this paper, we apply this conceptualization of risk, resistance, and resilience for substance misuse to a more fine-grained analysis of substance use pathways and their corresponding patterns (e.g., non-use, initiation, escalation, desistance). The significance of the progression of neurocognitive functioning over the course of development is discussed as well as how this knowledge may be translated to make a science-based determination of intervention targets. This more encompassing theoretical model has direct implications for primary prevention and clinical approaches to disrupt risk pathways and to optimize long-term outcomes.

The relative impact of chronic vs acute cocaine on dependence-related variability in reward processing in cocaine-dependent individuals (CD) is not well understood, despite the relevance of such effects to long-term outcomes. To dissociate these effects, CD (N=15) and healthy controls (HC; N=15) underwent MRI two times while performing a monetary incentive delay task. Both scans were identical across subjects/groups, except that, in a single-blind, counterbalanced design, CD received intravenous cocaine (30 mg/70 kg) before one session (CD+cocaine) and saline in another (CD+saline). Imaging analyses focused on activity related to anticipatory valence (gain/loss), anticipatory magnitude (small/medium/large), and reinforcing outcomes (successful/unsuccessful). Drug condition (cocaine vs saline) and group (HC vs CD+cocaine or CD+saline) did not influence valence-related activity. However, compared with HC, magnitude-related activity for gains was reduced in CD in the left cingulate gyrus post-cocaine and in the left putamen in the abstinence/saline condition. In contrast, magnitude-dependent activity for losses increased in CD vs HC in the right inferior parietal lobe post-cocaine and in the left superior frontal gyrus post-saline. Across outcomes (ie, successful and unsuccessful) activity in the right habenula decreased in CD in the abstinence/saline condition vs acute cocaine and HC. Cocaine-dependent variability in outcome- and loss-magnitude activity correlated negatively with ratings of cocaine craving and positively with how high subjects felt during the scanning session. Collectively, these data suggest dissociable effects of acute cocaine on non-drug reward processes, with cocaine consumption partially ameliorating dependence-related insensitivity to reinforcing outcomes/'liking', but having no discernible effect on dependence-related alterations in incentive salience/'wanting'. The relationship of drug-related affective sequelae to non-drug reward processing suggests that CD experience a general alteration of reward function and may be motivated to continue using cocaine for reasons beyond desired drug-related effects. This may have implications for individual differences in treatment efficacy for approaches that rely on reinforcement strategies (eg, contingency management) and for the long-term success of treatment.

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r g =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρ genetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

Background: Advances in treatment of sarcoma patients has prolonged survival but has led to increased disease- or treatment-related complications resulting in greater number of admissions to the intensive care unit (ICU). Survival and long-term outcome information about such critically ill patients with sarcoma is unknown., Methods: The primary objective of the study was to determine the ICU and post-ICU survival rates of critically ill sarcoma patients. Secondary objectives included determining the modifiable and non-modifiable predictors of poor survival. We performed a retrospective chart review of sarcoma patients admitted to the ICU at The University of Texas MD Anderson Cancer Center between January 1, 2005, and December 31, 2012. Main outcome measures were ICU mortality, in-hospital mortality and 1, 2, and 6-month survival rates. Covariates such as histological diagnosis, disease characteristics, chemotherapy use, Charlson comorbidity index, Sequential Organ Failure Assessment (SOFA) scores, and clinical findings leading to ICU admission were analyzed for their effects on survival., Results: We identified 172 admissions over the 8-year study period hat met our inclusion criteria. The study population was 45.9 % males with a median age of 52 years. The most common sarcoma subgroups were high-grade unclassified sarcoma (25 %) and bone tumors (17.4 %). The ICU mortality rate was 23.3 % (95 % confidence interval [CI], 16.9-29.6 %), and an additional 6.4 % of patients died before hospital discharge (95 % CI, 22.9-37.1 %). 6-month OS rates were 41 %. The median SOFA scores on admission were 6 (inter quartile range (IQR), 3.5-9) in ICU survivors and 10 (IQR, 6.5-14) in ICU non-survivors. Increase in SOFA scores ≥6 led to poor outcomes (ICU survival 13.3 %, OS 6.7 %). Charlson comorbidity index (HR 1.139, 95 % CI 1.023-1.268, p = 0.02) and discharge SOFA scores (HR 1.210, 95 % CI 1.141-1.283, p < 0.0001) correlated with overall survival., Conclusions: Our results suggest that patients that are admitted to the ICU for respiratory failure, cardiac arrest, septic shock, acute renal failure or acidosis and also have a high SOFA score with subsequent worsening in the ICU have poor prognosis. Based on the retrospective data which needs further validation we can recommend that judicious approach should be taken in patients with predictors of poor survival before subjecting them to aggressive treatment.

Neurocognitive and emotional regulatory deficits in substance users are often attributed to misuse; however most studies do not include a substance-naïve baseline to justify that conclusion. The etiological literature suggests that pre-existing deficits may contribute to the onset and escalation of use that are then exacerbated by subsequent use. To address this, there is burgeoning interest in conducting prospective, longitudinal neuroimaging studies to isolate neurodevelopmental precursors and consequences of adolescent substance misuse, as reflected in recent initiatives such as the NIH-led Adolescent Brain Cognitive Development (ABCD) study and the National Consortium on Alcohol and Neurodevelopment (NCANDA). To distinguish neurodevelopmental precursors from the consequences of adolescent substance use specifically, prospective, longitudinal neuroimaging studies with substance-naïve pre-adolescents are needed. The exemplar described in this article-i.e., the ongoing Adolescent Development Study (ADS)-used a targeted recruitment strategy to bolster the numbers of pre-adolescent individuals who were at increased risk of substance use (i.e., "high-risk") in a sample that was relatively small for longitudinal studies of similar phenomena, but historically large for neuroimaging (i.e., N = 135; 11-13 years of age). At baseline participants underwent MRI testing and a large complement of cognitive and behavioral assessments along with genetics, stress physiology and interviews. The study methods include repeating these measures at three time points (i.e., baseline/Wave 1, Wave 2 and Wave 3), 18 months apart. In this article, rather than outlining specific study outcomes, we describe the breadth of the numerous complexities and challenges involved in conducting this type of prospective, longitudinal neuroimaging study and "lessons learned" for subsequent efforts are discussed. While these types of large longitudinal neuroimaging studies present a number of logistical and scientific challenges, the wealth of information obtained about the precursors and consequences of adolescent substance use provides unique insights into the neurobiological bases for adolescent substance use that will lay the groundwork for targeted interventions.

This study investigated the differences in the quality of park play spaces between an affluent and a non-affluent community in a large US Southeastern metropolitan area. Two cities were purposefully selected to reflect differences in household income and race/ethnicity characteristics. Using the Playable Space Quality Assessment Tool (PSQAT), all parks (n = 11, with six in the affluent city, and five in the non-affluent city) in these two cities were evaluated. The data were analyzed across three aspects of environmental features of the PSQAT: Location, Play Value and Care and Maintenance between parks in the two cities. The Mann-Whitney U test was used to test the study hypotheses. Results indicated significant differences between parks in the two cities in all three aspects of the PSQAT with p-values ≤ 0.03 and effect sizes of > 0.65, suggesting that the affluent city had parks of a higher quality than the non-affluent city. Significant disparity in Play Value (p = 0.009) in parks between these two communities suggests that children and young people are likely to have different experiences of the play spaces in their locality and therefore may experience different physical and psychological health benefits.

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

The micro RNA 137 (miR-137) variant rs1625579 has been identified as a genome-wide significant risk variant for schizophrenia. miR-137 has an established role in neurodevelopment and may mediate cognitive dysfunction in schizophrenia. This role of miR-137 may be related to changes in brain morphology for risk-related genotypes; however this has not yet been delineated. Here we considered whether rs1625579 genotype was predictive of indices of brain structure in patients with schizophrenia and healthy controls. Structural magnetic resonance imaging (sMRI) data (i.e. 3T T1-TFE or 1.5T T1-MPRAGE) were acquired from 150 healthy controls and 163 schizophrenic patients. Two volumetric analyses that considered the impact of miR-137/rs1625579 genotype were carried out on sMRI data. In the first analysis, voxel based morphometry was employed to consider genotype-related variability in local grey and white matter across the entire brain volume. Our secondary analysis utilized the FIRST protocol in FSL to consider the volume of subcortical structures (i.e. bilateral accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus). Several brain regions in both analyses demonstrated the expected main effect of participant group (i.e. schizophrenics < controls), yet there were no regions where we observed an impact of rs1635579 genotype on brain volume. Our analyses suggest that the mechanism by which miR-137 confers risk for schizophrenia and impacts upon cognitive function may not be mediated by changes in local brain volume. However, it remains to be determined whether or not alternative measures of brain structure are related to these functions of miR-137., (© 2014 Wiley Periodicals, Inc.)

Background: Processing the emotional content of faces is recognised as a key deficit of schizophrenia, associated with poorer functional outcomes and possibly contributing to the severity of clinical symptoms such as paranoia. At the neural level, fMRI studies have reported altered limbic activity in response to facial stimuli. However, previous studies may be limited by the use of cognitively demanding tasks and static facial stimuli. To address these issues, the current study used a face processing task involving both passive face viewing and dynamic social stimuli. Such a task may (1) lack the potentially confounding effects of high cognitive demands and (2) show higher ecological validity., Methods: Functional MRI was used to examine neural activity in 25 patients with a DSM-IV diagnosis of schizophrenia/schizoaffective disorder and 21 age- and gender-matched healthy controls while they participated in a face processing task, which involved viewing videos of angry and neutral facial expressions, and a non-biological baseline condition., Results: While viewing faces, patients showed significantly weaker deactivation of the medial prefrontal cortex, including the anterior cingulate, and decreased activation in the left cerebellum, compared to controls. Patients also showed weaker medial prefrontal deactivation while viewing the angry faces relative to baseline., Discussion: Given that the anterior cingulate plays a role in processing negative emotion, weaker deactivation of this region in patients while viewing faces may contribute to an increased perception of social threat. Future studies examining the neurobiology of social cognition in schizophrenia using fMRI may help establish targets for treatment interventions., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A single nucleotide polymorphism (SNP rs1625579) within the micro-RNA 137 (MIR137) gene recently achieved strong genome-wide association with schizophrenia (SZ). However, the mechanisms by which SZ risk may be mediated by this variant are unknown. As miRNAs have the potential to influence oligodendrocyte development, we investigated whether this SNP was associated with variability in white matter (WM) microstructure. Diffusion tensor imaging (DTI) was conducted on 123 healthy participants genotyped for rs1625579. The analysis consisted of whole-brain tract-based spatial statistics and atlas-based tractography analysis of six major WM tracts known to be affected in SZ - the inferior longitudinal fasciculus, the uncinate fasciculus, the inferior fronto-occipital fasciculus, the anterior thalamic radiation, the cingulum bundle and the corpus callosum. No significant differences in either whole-brain fractional anisotropy or mean diffusivity between MIR137 genotype groups were observed (p>0.05). Similarly, atlas-based tractography of particular tracts implicated in SZ failed to reveal any significant differences between MIR137 genotype groups on measures of WM connectivity (p>0.05). In the absence of WM effects comparable to those reported for other SZ associated genes, these data suggest that MIR137 alone may not confer variability in these WM measures and therefore may not act in isolation for any effects that the variant may have on WM microstructure in SZ samples., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Cocaine dependence impacts drug-related, dopamine-dependent reward processing, yet its influence on non-drug reward processing is unclear. Here, we investigated cocaine-mediated effects on reward learning using a natural food reinforcer. Cocaine-dependent subjects (N = 14) and healthy controls (N = 14) learned to associate a visual cue with a juice reward. In subsequent functional imaging sessions they were exposed to trials where juice was received as learned, withheld (negative temporal difference error (NTDE)), or received unexpectedly (positive temporal difference error (PTDE)). Subjects were scanned twice in sessions that were identical, except that cocaine-dependent participants received cocaine or saline 10 min before task onset. In the insula, precentral and postcentral gyri NTDE signals were greater, and PTDE-related function was reduced in cocaine-dependent subjects. Compared with healthy controls, in the cocaine-dependent group PTDE signals were also reduced in medial frontal gyrus and reward-related function, irrespective of predictability, was reduced in the putamen. Group differences in error-related activity were predicted by the time as last self-administered cocaine use, but TDE function was not influenced by acute cocaine. Thus, cocaine dependence seems to engender increased responsiveness to unexpected negative outcomes and reduced sensitivity to positive events in dopaminergic reward regions. Although it remains to be established if these effects are a consequence of or antecedent to cocaine dependence, they likely have implications for the high-cocaine use recidivism rates by contributing to the drive to consume cocaine, perhaps via influence on dopamine-related reward computations. The fact that these effects do not acquiesce to acute cocaine administration might factor in binge-related escalated consumption.

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.

Background: MIR137 is implicated in brain development and encodes a microRNA that regulates neuronal maturation and adult neurogenesis. Recently, a common genetic variant within MIR137 showed genome wide evidence of association with schizophrenia, and with altered amygdala activation in those at genetic risk for schizophrenia. Following this evidence, we investigated the effects of MIR137 genotype on neuronal activity during face processing., Methods: By grouping 81 healthy participants as carrier or non-carriers of the MIR137 rs1625579 risk allele associated with schizophrenia, we investigated MIR137's effects on altered cortical response during an fMRI face processing task and altered functional connectivity using the amygdala as a seed region., Results: Homozygous carriers of the risk allele were observed to show relatively increased functional connectivity between the right amygdala and frontal regions that play a key role in emotion processing and regulation (e.g. the cingulate and prefrontal cortex)., Conclusions: Our findings provide the first evidence that the rs1625579 variant affects fronto-amygdala functional connectivity, providing further evidence that MIR137 may contribute to forms of psychosis in which affective symptoms are more prominent., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: A single nucleotide polymorphism (rs7914558) within the cyclin M2 (CNNM2) gene was recently identified as a common risk variant for schizophrenia. The mechanism by which CNNM2 confers risk is unknown., Aims: To determine the impact of the rs7914558 risk 'G' allele [corrected] on measures of neurocognition, social cognition and brain structure., Method: Patients with schizophrenia (n = 400) and healthy controls (n = 160) completed measures of neuropsychological function and social cognition. Structural magnetic resonance imaging data were also acquired from an overlapping sample of Irish healthy controls (n = 159) and an independent sample of Italian patients (n = 82) and healthy controls (n = 39)., Results: No effects of genotype on neuropsychological test performance were observed. However, a dosage effect of the risk allele was found for an index of social cognition (i.e. attributional style), such that risk status was associated with reduced self-serving bias across groups (GG>AG>AA, P<0.05). Using voxel-based morphometry to investigate neuroanatomical regions putatively supporting social cognition, risk carriers had relatively increased grey matter volume in the right temporal pole and right anterior cingulate cortex (Pcorrected<0.05) in the Irish healthy controls sample; neuroanatomical associations between CNNM2 and grey matter volume in anterior cingulate cortex were also observed in the Italian schizophrenia and healthy controls samples., Conclusions: Although the biological role of CNNM2 in schizophrenia remains unknown, these data suggest that this CNNM2 risk variant rs7914558 may have an impact on neural systems relevant to social cognition. How such effects may mediate the relationship between genotype and disease risk remains to be established.

The single nucleotide polymorphism rs10503253 within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2 has been identified as genome-wide significant for schizophrenia (SZ). This gene is of unknown function but has been implicated in multiple neurodevelopmental disorders that impact upon cognition, leading us to hypothesize that an effect on brain structure and function underlying cognitive processes may be part of the mechanism by which CMSD1 increases illness risk. To test this hypothesis, we investigated this CSMD1 variant in vivo in healthy participants in a magnetic resonance imaging (MRI) study comprised of both fMRI of spatial working memory (N = 50) and a voxel-based morphometry investigation of grey and white matter (WM) volume (N = 150). Analyses of these data indicated that the risk "A" allele was associated with comparatively reduced cortical activations in BA18, that is, middle occipital gyrus and cuneus; posterior brain regions that support maintenance processes during performance of a spatial working memory task. Conversely, there was an absence of significant structural differences in brain volume (i.e., grey or WM). In accordance with previous evidence, these data suggest that CSMD1 may mediate brain function related to cognitive processes (i.e., executive function); with the relatively deleterious effects of the identified "A" risk allele on brain activity possibly constituting part of the mechanism by which CSMD1 increases schizophrenia risk., (Copyright © 2013 Wiley Periodicals, Inc.)

Genetic variants associated with increased risk for schizophrenia (SZ) are hypothesized to be more penetrant at the level of brain structure and function than at the level of behavior. However, to date the relative sensitivity of imaging vs cognitive measures of these variants has not been quantified. We considered effect sizes associated with cognitive and imaging studies of 9 robust SZ risk genes (DAOA, DISC1, DTNBP1, NRG1, RGS4, NRGN, CACNA1C, TCF4, and ZNF804A) published between January 2005-November 2011. Summary data was used to calculate estimates of effect size for each significant finding. The mean effect size for each study was categorized as small, medium, or large and the relative frequency of each category was compared between modalities and across genes. Random effects meta-analysis was used to consider the impact of experimental methodology on effect size. Imaging studies reported mostly medium or large effects, whereas cognitive investigations commonly reported small effects. Meta-analysis confirmed that imaging studies were associated with larger effects. Effect size estimates were negatively correlated with sample size but did not differ as a function of gene nor imaging modality. These observations support the notion that SZ risk variants show larger effects, and hence greater penetrance, when characterized using indices of brain structure and function than when indexed by cognitive measures. However, it remains to be established whether this holds true for individual risk variants, imaging modalities, or cognitive functions, and how such effects may be mediated by a relationship with sample size and other aspects of experimental variability.

The single-nucleotide polymorphism (SNP) rs10503253, located within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2, was recently identified as genome-wide significant for schizophrenia (SZ), but is of unknown function. We investigated the neurocognitive effects of this CSMD1 variant in vivo in patients and healthy participants using behavioral and imaging measures of brain structure and function. We compared carriers and non-carriers of the risk 'A' allele on measures of neuropsychological performance typically impaired in SZ (general cognitive ability, episodic and working memory and attentional control) in independent samples of Irish patients (n = 387) and controls (n = 171) and German patients (205) and controls (n = 533). Across these groups, the risk 'A' allele at CSMD1 was associated with deleterious effects across a number of neurocognitive phenotypes. Specifically, the risk allele was associated with poorer performance on neuropsychological measures of general cognitive ability and memory function but not attentional control. These effects, while significant, were subtle, and varied between samples. Consistent with previous evidence suggesting that CSMD1 may be involved in brain mechanisms related to memory and learning, these data appear to reflect the deleterious effects of the identified 'A' risk allele on neurocognitive function, possibly as part of the mechanism by which CSMD1 is associated with SZ risk., (© 2013 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.)

Background: Dopaminergic activity plays a role in mediating the rewarding aspects of abused drugs, including nicotine. Nicotine modulates the reinforcing properties of other motivational stimuli, yet the mechanisms of this interaction are poorly understood. This study aimed to ascertain the impact of nicotine exposure on neuronal activity associated with reinforcing outcomes in dependent smokers., Methods: Smokers (n = 28) and control subjects (n = 28) underwent functional imaging during performance of a monetary incentive delay task. Using a randomized, counterbalanced design, smokers completed scanning after placement of a nicotine or placebo patch; nonsmokers were scanned twice without nicotine manipulation. In regions along dopaminergic pathway trajectories, we considered event-related activity for valence (reward/gain vs. punishment/loss), magnitude (small, medium, large), and outcome (successful vs. unsuccessful)., Results: Both nicotine and placebo patch conditions were associated with reduced activity in regions supporting anticipatory valence, including ventral striatum. In contrast, relative to controls, acute nicotine increased activity in dorsal striatum for anticipated magnitude. Across conditions, anticipatory valence-related activity in the striatum was negatively associated with plasma nicotine concentration, whereas the number of cigarettes daily correlated negatively with loss anticipation activity in the medial prefrontal cortex only during abstinence., Conclusions: These data suggest a partial dissociation in the state- and trait-specific effects of smoking and nicotine exposure on magnitude- and valence-dependent anticipatory activity within discrete reward processing brain regions. Such variability may help explain, in part, nicotine's impact on the reinforcing properties of nondrug stimuli and speak to the continued motivation to smoke and cessation difficulty., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

A single nucleotide polymorphism rs12807809 located upstream of the neurogranin (NRGN) gene has been identified as a risk variant for schizophrenia in recent genome-wide association studies. To date, there has been little investigation of the endophenotypic consequences of this variant, and our own investigations have suggested that the effects of this gene are not apparent at the level of cognitive function in patients or controls. Because the impact of risk variants may be more apparent at the level of brain, the aim of this investigation was to delineate whether NRGN genotype predicted variability in brain structure and/or function. Healthy individuals participated in structural (N = 140) and/or functional (N = 36) magnetic resonance imaging (s/fMRI). Voxel-based morphometry was used to compare gray and white matter volumes between carriers of the non-risk C allele (i.e., CC/CT) and those who were homozygous for the risk T allele. Functional imaging data were acquired during the performance of a spatial working memory task, and were also analyzed with respect to the difference between C carriers and T homozygotes. There was no effect of the NRGN variant rs12807809 on behavioral performance or brain structure. However, there was a main effect of genotype on brain activity during performance of the working memory task, such that while C carriers exhibited a load-independent decrease in left superior frontal gyrus/BA10, TT individuals failed to show a similar decrease in activity. The failure to disengage this ventromedial prefrontal region, despite preserved performance, may be indicative of a reduction in processing efficiency in healthy TT carriers. Although it remains to be established whether this holds true in larger samples and in patient cohorts, if valid, this suggests a potential mechanism by which NRGN variability might contribute to schizophrenia risk.

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).

In light of observed changes in connectivity in schizophrenia and the highly heritable nature of the disease, neural connectivity may serve as an important intermediate phenotype for schizophrenia. However, how individual variants confer altered connectivity and which measure of brain connectivity is more proximal to the underlying genetic architecture (i.e., functional or structural) has not been well delineated. In this review we consider these issues and the relative sensitivity of imaging methodologies to schizophrenia-related changes in connectivity. We searched PubMed for studies considering schizophrenia risk genes AND functional or structural connectivity. Where data was available, summary statistics were used to determine an estimate of effect size (i.e., Cohen's d). A random-effects meta-analysis was used to consider (1) the largest effect and (2) all significant effects between functional and structural studies. Schizophrenia risk variants involved in neurotransmission, neurodevelopment and myelin function were found to be associated with altered neural connectivity. On average, schizophrenia risk genes had a large effect on functional (mean d = 0.76) and structural connectivity (mean d = 1.04). The examination of the largest effect size indicated that the outcomes of functional and structural studies were comparable (Q = 2.17, p > 0.05). Conversely, consideration of effect size estimates for all significant effects suggest that reported effect sizes in structural connectivity studies were more variable than in functional connectivity studies, and that there was a significant lack of homogeneity across the modalities (Q = 6.928, p = 0.008). Given the more variable profile of effect sizes associated with structural connectivity, these data may suggest that structural imaging methods are more sensitive to a wider range of effects, as opposed to functional studies which may only be able to determine large effects. These conclusions are limited by methodological considerations, and require further investigation involving larger samples, multiple genes, and novel analysis techniques for confirmation.

A common polymorphism within the nitric oxide sythanse-1 (NOS1) gene (rs6490121), initially identified as risk variant for schizophrenia, has been associated with variation in working memory and IQ. Here we investigated how this variation might be mediated at the level of brain structure and function. In healthy individuals (N=157), voxel based morphometry was used to compare grey matter (GM) volume between homozygous and heterozygous carriers of the 'G' allele (i.e. the allele associated with impaired cognition and schizophrenia risk) and homozygous carriers of the non-risk 'A' allele. Functional brain imaging data were also acquired from 48 participants during performance of a spatial working memory (SWM) task, and analysed to determine any effect of NOS1 risk status. An a priori region-of-interest analysis identified a significant reduction in ventromedial prefrontal GM volume in 'G' allele carriers. Risk carriers also exhibited altered patterns of activation in the prefrontal cortex, caudate, and superior parietal lobe, which were characteristic of abnormal increases in activation in frontoparietal working memory networks and a failure to disengage regions of the default mode network. These functional changes suggest a NOS1-mediated processing inefficiency, which may contribute to cognitive dysfunction in schizophrenia. While the mechanisms by which NOS1 may influence brain structure and/or function have not yet been well delineated, these data provide further evidence for a role of NOS1 in risk for schizophrenia via an impact upon cognitive function., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The reinforcing effects of nicotine are mediated by brain regions that also support temporal difference error (TDE) processing; yet, the impact of nicotine on TDE is undetermined., Methods: Dependent smokers (n = 21) and matched control subjects (n = 21) were trained to associate a juice reward with a visual cue in a classical conditioning paradigm. Subjects subsequently underwent functional magnetic resonance imaging sessions in which they were exposed to trials where they either received juice as temporally predicted or where the juice was withheld (negative TDE) and later received unexpectedly (positive TDE). Subjects were scanned in two sessions that were identical, except that smokers had a transdermal nicotine (21 mg) or placebo patch placed before scanning. Analysis focused on regions along the trajectory of mesocorticolimbic and nigrostriatal dopaminergic pathways., Results: There was a reduction in TDE-related function in smokers in the striatum, which did not differ as a function of patch manipulation but was predicted by the duration (years) of smoking. Activation in midbrain regions was not impacted by group or drug condition., Conclusions: These data suggest a differential effect of smoking status on the neural substrates of reward in distinct dopaminergic pathway regions, which may be partially attributable to chronic nicotine exposure. The failure of transdermal nicotine to alter reward-related functional processes, either within smokers or between smokers and control subjects, implies that acute nicotine patch administration is insufficient to modify reward processing, which has been linked to abstinence-induced anhedonia in smokers and may play a critical role in smoking relapse., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Psychosis has been associated with aberrant brain activity concurrent with both the anticipation and integration of monetary outcomes. The extent to which abnormal reward-related neural signals can be observed in chronic, medicated patients with schizophrenia (SZ), however, is not clear. In an fMRI study involving 17 chronic outpatients with SZ and 17 matched controls, we used a monetary incentive delay (MID) task, in which different-colored shapes predicted gains, losses, or neutral outcomes. Subjects needed to respond to a target within a time window in order to receive the indicated gain or avoid the indicated loss. Group differences in blood-oxygen-level-dependent responses to cues and outcomes were assessed through voxel-wise whole-brain analyses and regions-of-interest analyses in the neostriatum and prefrontal cortex (PFC). Significant group by outcome valence interactions were observed in the medial and lateral PFC, lateral temporal cortex, and amygdalae, such that controls, but not patients, showed greater activation for gains, relative to losses. In the striatum, neural activity was modulated by outcome magnitude in both groups. Additionally, we found that ratings of negative symptoms in patients correlated with sensitivity to obtained losses in medial PFC, obtained gains in lateral PFC, and anticipated gains in left ventral striatum. Sensitivity to obtained gains in lateral PFC also correlated with positive symptom scores in patients. Our findings of systematic relationships between clinical symptoms and neural responses to stimuli associated with rewards and punishments offer promise that reward-related neural responses may provide sensitive probes of the effectiveness of treatments for negative symptoms.

Rationale: Nicotine influences many cognitive processes, especially those requiring high attentional loads, yet the impact of nicotine on all aspects of information processing has not been well delineated., Objective: The aim of the study was to determine the relative behavioral and functional effects of nicotine on dissociable aspects of information processing (i.e., selective attention and motor intention)., Methods: Adult smokers (N = 25) and healthy controls (N = 23) performed the intention/attention task (IAT) twice, during functional magnetic resonance imaging. The IAT assesses the relative differences in performance evoked by prime stimuli that provide information regarding either the correct hand with which to respond (i.e., intentional primes) or the likely location of a target stimulus (i.e., attentional primes). Smokers were scanned 2 h after nicotine (21 mg) or placebo patch placement. The order of nicotine and placebo sessions was randomized and counter-balanced. Controls were also scanned twice, with no patch placement in either session., Results: While drug condition had no significant effect on reaction time, smokers were overall more accurate than controls. Moreover, nicotine significantly increased the response to intentional primes in brain regions known to mediate response readiness, e.g., inferior parietal lobe, supramarginal gyrus, and striatum., Conclusions: While limited to participant accuracy, these data suggest that the behavioral effects of nicotine in smokers are not only limited to information processing input (i.e., selective attention) but are also generalizable to output functions (i.e., motor intention). Moreover, nicotine's effects on intention appear to be mediated by a facilitation of function in brain regions associated with information processing output.

One prevalent theory of learning states that dopamine neurons signal mismatches between expected and actual outcomes, called temporal difference errors (TDEs). Evidence indicates that dopamine system dysfunction is involved in negative symptoms of schizophrenia (SZ), including avolition and anhedonia. As such, we predicted that brain responses to TDEs in dopamine midbrain nuclei and target areas would be abnormal in SZ. A total of 18 clinically stable patients with chronic SZ and 18 controls participated in an fMRI study, which used a passive conditioning task. In the task, the delivery of a small amount of juice followed a light stimulus by exactly 6 s on approximately 75% of 78 total trials, and was further delayed by 4-7 s on the remaining trials. The delayed juice delivery was designed to elicit the two types of TDE signals, associated with the recognition that a reward was omitted at the expected time, and delivered at an unexpected time. Main effects of TDE valence and group differences in the positive-negative TDE contrast (unexpected juice deliveries-juice omissions) were assessed through whole-brain and regions of interest (ROI) analyses. Main effects of TDE valence were observed for the entire sample in the midbrain, left putamen, left cerebellum, and primary gustatory cortex, bilaterally. Whole-brain analyses revealed group differences in the positive-negative TDE contrast in the right putamen and left precentral gyrus, whereas ROI analyses revealed additional group differences in the midbrain, insula, and parietal operculum, on the right, the putamen and cerebellum, on the left, and the frontal operculum, bilaterally. Further, these group differences were generally driven by attenuated responses in patients to positive TDEs (unexpected juice deliveries), whereas responses to negative TDEs (unexpected juice omissions) were largely intact. Patients also showed reductions in responses to juice deliveries on standard trials, and more blunted reinforcer responses in the left putamen corresponded to higher ratings of avolition. These results provide evidence that SZ patients show abnormal brain responses associated with the processing of a primary reinforcer, which may be a source of motivational deficits.