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The neurocomputational processes underlying bulimia nervosa and its primary symptoms, out-of-control overeating and purging, are poorly understood. Research suggests that the brains of healthy individuals form a dynamic internal model to predict whether control is needed in each moment. This study tested the hypothesis that this computational process of inhibitory control is abnormally affected by metabolic state (being fasted or fed) in bulimia nervosa. A Bayesian ideal observer model was fit to behavioral data acquired from 22 women remitted from bulimia nervosa and 20 group-matched controls who completed a stop-signal task during two counterbalanced functional MRI sessions, one after a 16 h fast and one after a meal. This model estimates participants' trial-by-trial updating of the probability of a stop signal based on their experienced trial history. Neural analyses focused on control-related Bayesian prediction errors, which quantify the direction and degree of "surprise" an individual experiences on any given trial. Regardless of group, metabolic state did not affect behavioral performance on the task. However, metabolic state modulated group differences in neural activation. In the fed state, women remitted from bulimia nervosa had attenuated prediction-error-dependent activation in the left dorsal caudate. This fed-state activation was lower among women with more frequent past binge eating and self-induced vomiting. When they are in a fed state, individuals with bulimia nervosa may not effectively process unexpected information needed to engage inhibitory control. This may explain the difficulties these individuals have stopping eating after it begins.

Objectives:Anorexia nervosa (AN) is associated with altered sensitivity to reward and punishment. Few studies have investigated whether this results in aberrant learning. The ability to learn from rewarding and aversive experiences is essential for flexibly adapting to changing environments, yet individuals with AN tend to demonstrate cognitive inflexibility, difficulty set-shifting and altered decision-making. Deficient reinforcement learning may contribute to repeated engagement in maladaptive behavior.Methods:This study investigated learning in AN using a probabilistic associative learning task that separated learning of stimuli via reward from learning via punishment. Forty-two individuals with Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 restricting-type AN were compared to 38 healthy controls (HCs). We applied computational models of reinforcement learning to assess group differences in learning, thought to be driven by violations in expectations, or prediction errors (PEs). Linear regression analyses examined whether learning parameters predicted BMI at discharge.Results:AN had lower learning rates than HC following both positive and negative PE (p p Conclusions:This is the first study to show lower rates of learning in AN following both positive and negative outcomes, with worse punishment learning predicting less weight gain. An inability to modify expectations about avoiding punishment might explain persistence of restricted eating despite negative consequences, and suggests that treatments that modify negative expectancy might be effective in reducing food avoidance in AN.

Individuals with bulimia nervosa (BN) cycle between periods of binge-eating and compensatory behavior and periods of dietary restraint, suggesting extremes of under and overcontrol that may be metabolic-state related. This study examined the influence of hunger and satiety on impulsivity and neural responding during decision-making. Twenty-three women remitted from BN (RBN) and 20 healthy comparison women (CW) performed a delay discounting task after a 16-hr fast and following a standardized meal during functional neuroimaging. A dual-systems approach examined reward valuation (decision trials where the early reward option was available immediately) and cognitive control (all decision trials). Interactions of Group × Visit (Hungry, Fed) for immediate reward revealed that CW had greater activation when hungry versus fed in the ventral striatum and dorsal caudate, whereas RBN had greater response when fed versus hungry in the dorsal caudate. Compared to CW, RBN showed decreased response when hungry within the left dorsal caudate and ventral striatum and increased response when fed in bilateral dorsal caudate. No differences were found within cognitive control regions or with choice behavior. Reward sensitivity is normally increased when hungry and decreased when fed; our findings in CW provide further support of hunger-based reward sensitivity within the striatum. However, RBN showed no differences for hunger and satiety in the ventral striatum and greater activation in the dorsal caudate when fed compared to hungry. This suggests RBN may be less sensitive to reward when hungry but do not devalue reward when satiated, indicating altered metabolic modulation of self-regulatory control. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

OBJECTIVE:Anorexia nervosa has the highest mortality rate of any psychiatric condition, yet the pathophysiology of this disorder and its primary symptom, extreme dietary restriction, remains poorly understood. In states of hunger relative to satiety, the rewarding value of food stimuli normally increases to promote eating, yet individuals with anorexia nervosa avoid food despite emaciation. This study's aim was to examine potential neural insensitivity to these effects of hunger in anorexia nervosa. METHODS:At two scanning sessions scheduled 24 hours apart, one after a 16-hour fast and one after a standardized meal, 26 women who were in remission from anorexia nervosa (to avoid the confounding effects of malnutrition) and 22 matched control women received tastes of sucrose solution or ionic water while functional MRI data were acquired. Within a network of interest responsible for food valuation and transforming taste signals into motivation to eat, the authors compared groups across conditions on blood-oxygen-level-dependent (BOLD) signal and task-based functional connectivity. RESULTS:Participants in the two groups had similar BOLD responses to sucrose and water tastants. A group-by-condition interaction in the ventral caudal putamen indicated that hunger had opposite effects on tastant response in the control group and the remitted anorexia nervosa group, with an increase and a decrease, respectively, in BOLD response when hungry. Hunger had a similar opposite effect on insula-to-ventral caudal putamen functional connectivity in the remitted anorexia nervosa group compared with the control group. Exploratory analyses indicated that lower caudate response to tastants when hungry was associated with higher scores on harm avoidance among participants in the remitted anorexia nervosa group. CONCLUSIONS:Reduced recruitment of neural circuitry that translates taste stimulation to motivated eating behavior when hungry may facilitate food avoidance and prolonged periods of extremely restricted food intake in anorexia nervosa.

ObjectiveThe hippocampus is a key structure in feeding behaviors and weight regulation. Obesity may lead to disruptions in hippocampal structure. In animals, obesity-related factors (e.g., high-fat/sugar foods) are associated with hippocampal insult (e.g., alterations in the blood brain barrier). In humans, individuals with obesity, relative to healthy weight, have smaller hippocampal volumes. Few studies have examined the association between body weight and the hippocampus during adolescence, a critical brain development period. This study examined hippocampal volume and tissue signal intensity in adolescents across the weight spectrum.MethodsStructural magnetic resonance imaging and anthropomorphic data were available for 102 12- to 18-year-old adolescents (53% female; 15.07 [SD1.84] years; standardized BMI [BMIz] scores using the Centers for Disease Control and Prevention growth charts: 0.54 [SD1.17]) from the Pediatric Imaging, Neurocognition, and Genetics database. Linear regression models controlling for age, sex, genetic ancestry, scanner, and household income examined the relationship between BMIz, hippocampal volume, and T2-weighted hippocampal signal intensity.ResultsBMIz was negatively associated with T2-weighted hippocampal signal intensity in the left (t = -3.05; P = 0.003; r = -0.21) and right (t = -2.50; P = 0.01; r = -0.36) hippocampi. BMIz was not significantly associated with hippocampal volume.ConclusionsBMIz is associated with hippocampal tissue characteristics during adolescence, which could impact later brain development.

Introduction: Interoception, defined as the sense of the internal state of one’s body, helps motivate goal-directed behavior. Prior work has shown that methamphetamine (METH) use disorder is associated with altered interoception, and that this may contribute to risky behavior. As people with HIV (PWH) may also experience disrupted bodily sensations (e.g., neuropathy), an important question is whether PWH with a history of METH use disorder might exhibit greater impairment of interoceptive processing. Methods: Eighty-three participants stratified by HIV infection and a past history of methamphetamine use disorder experienced a soft touch paradigm that included slow brush strokes on the left forearm and palm during blood-oxygen level-dependent functional MRI acquisition. To assess differences in interoception and reward, voxelwise analyses were constrained to the insula, a hub for the evaluation of interoceptive cues, and the striatum, which is engaged in reward processing. Results: Overall, individuals with a history of METH use disorder had an attenuated neural response to pleasant touch in both the insula and striatum. Longer abstinence was associated with greater neural response to touch in the insula, suggesting some improvement in responsivity. However, only PWH with no METH use disorder history had lower brain activation in the insula relative to non-using seronegative controls. Conclusions: Our findings suggest that while METH use disorder history and HIV infection independently disrupt the neural processes associated with interoception, PWH with METH use disorder histories do not show significant differences relative to non-using seronegative controls. These findings suggest that the effects of HIV infection and past methamphetamine use might not be additive with respect to interoceptive processing impairment.

BackgroundThe neural mechanisms of anorexia nervosa (AN), a severe and chronic psychiatric illness, are still poorly understood. Altered body state processing, or interoception, has been documented in AN, and disturbances in aversive interoception may contribute to distorted body perception, extreme dietary restriction, and anxiety. As prior data implicate a potential mismatch between interoceptive expectation and experience in AN, we examined whether AN is associated with altered brain activation before, during, and after an unpleasant interoceptive state change.MethodsAdult women remitted from AN (RAN; n = 17) and healthy control women (CW; n = 25) underwent functional magnetic resonance imaging during an inspiratory breathing load paradigm.ResultsDuring stimulus anticipation, the RAN group, relative to CW, showed reduced activation in right mid-insula. In contrast, during the aversive breathing load, the RAN group showed increased activation compared with CW in striatum and cingulate and prefrontal cortices (PFC). The RAN group also showed increased activation in PFC, bilateral insula, striatum, and amygdala after stimulus offset. Time course analyses indicated that RAN responses in interoceptive processing regions during breathing load increased more steeply than those of CW. Exploratory analyses revealed that hyperactivation after breathing load was associated with markers of past AN severity.ConclusionsAnticipatory deactivation with a subsequent exaggerated brain response during and after an aversive body state may contribute to difficulty predicting and adapting to internal state fluctuation. Because eating changes our interoceptive state, restriction may be one method of avoiding aversive, unpredictable internal change in AN.

Bulimia nervosa (BN) is characterized by dysregulated intake of food, which may indicate homeostatic imbalance. Critically important for homeostatic regulation is interoception, or the sensing and processing of body-relevant information. A well-documented link between avoidance of unpleasant body sensations and BN symptoms suggests that aversive interoceptive experiences may be particularly relevant to BN pathophysiology. This study examined whether individuals with a history of BN showaberrant neural processing of aversive interoceptive stimuli. Using a cued inspiratory breathing load paradigm, we compared women remitted from BN (RBN; n = 24; to reduce the confounding effects of active bulimic symptoms) and control women (CW; n = 25). During breathing load anticipation, the RBN group, relative to CW, showed increased activation in mid-insula, superior frontal gyrus, putamen, dorsal anterior cingulate, posterior cingulate, and amygdala. However, over the course of the aversive experience, neural activation in RBN relative to CW showed an aberrant decline in most of these regions. Exploratory analyses indicated that greater activation during breathing load anticipation was associated with past bulimic symptom severity and the duration of symptom remission. An exaggerated anticipatory response and an abnormally decreasing response during aversive homeostatic perturbations may promote hallmark bulimic behaviors-binge eating, dietary restriction, and purging. Our findings support a role for homeostatic instability in BN, and these altered patterns of brainactivation may serve as novel targets for pharmacological, neuromodulatory, and behavioral interventions.

The neurodevelopmental trajectory in individuals with fetal alcohol spectrum disorders (FASD) has not been well characterized. We examined age-related differences in the volume of the corpus callosum, basal ganglia, and cerebellum across adolescence and young adulthood, due to the sensitivity of these regions to prenatal alcohol exposure. T1-weighted anatomical magnetic resonance images (MRI) were acquired from a cross-sectional sample of subjects 13–30 years old who had received an alcohol-related diagnosis (FASD, n = 107) and typically developing controls (CON, n = 56). FreeSurfer v5.3 was used to obtain volumetric data for the corpus callosum, caudate, putamen, pallidum, and cerebellum. Analysis of variance (ANOVA) was used to examine the effects of group (FASD, CON), sex, and age on region volume. Data were analyzed with and without correction for intracranial volume (ICV). All subregions were significantly smaller in the FASD group compared to controls, and these findings persisted even after ICV correction. Furthermore, the FASD and control groups differed in their relationship between age and total volume of the corpus callosum, caudate, and cerebellum. Specifically, older FASD individuals had smaller total volume in these regions; this relationship was not seen in the control group. Control males demonstrated larger volumes than control females in all regions prior to ICV correction; however, sex differences were attenuated in the FASD group in both the pallidum and cerebellum. Sex differences remained after ICV correction in the pallidum and cerebellum. These cross-sectional findings suggest that at least some brain regions may become smaller at an earlier than expected age in individuals with FASD, and that sex is an important factor to consider when examining neural structures in FASD. Further evaluation is necessary using longitudinal methods and including older ages.

Bulimia nervosa (BN) is characterized by dysregulated intake of food, which may indicate homeostatic imbalance. Critically important for homeostatic regulation is interoception, or the sensing and processing of body-relevant information. A well-documented link between avoidance of unpleasant body sensations and BN symptoms suggests that aversive interoceptive experiences may be particularly relevant to BN pathophysiology. This study examined whether individuals with a history of BN show aberrant neural processing of aversive interoceptive stimuli. Using a cued inspiratory breathing load paradigm, we compared women remitted from BN (RBN; n = 24; to reduce the confounding effects of active bulimic symptoms) and control women (CW; n = 25). During breathing load anticipation, the RBN group, relative to CW, showed increased activation in mid-insula, superior frontal gyrus, putamen, dorsal anterior cingulate, posterior cingulate, and amygdala. However, over the course of the aversive experience, neural activation in RBN relative to CW showed an aberrant decline in most of these regions. Exploratory analyses indicated that greater activation during breathing load anticipation was associated with past bulimic symptom severity and the duration of symptom remission. An exaggerated anticipatory response and an abnormally decreasing response during aversive homeostatic perturbations may promote hallmark bulimic behaviors—binge eating, dietary restriction, and purging. Our findings support a role for homeostatic instability in BN, and these altered patterns of brain activation may serve as novel targets for pharmacological, neuromodulatory, and behavioral interventions.

Interoception, or the sensing and integration of bodily state signals, has been implicated in anorexia nervosa (AN), given that the hallmark symptoms involve food restriction and body image disturbance. Here we focus on brain response to the anticipation and experience of affective interoceptive stimuli. Women remitted from AN (RAN; N = 18) and healthy comparison women (CW; N = 26) underwent a pleasant affective touch paradigm consisting of gentle strokes with a soft brush administered to the forearm or palm during functional neuroimaging. RAN had a lower brain response relative to CW during anticipation of touch, but a greater response when experiencing touch in the right ventral mid-insula. In RAN, this reduced anticipatory response was associated with higher levels of harm avoidance. Exploratory analyses in RAN also suggested that lower response during touch anticipation was associated with greater body dissatisfaction and higher perceived touch intensity ratings. This reduced responsivity to the anticipation of pleasant affective interoceptive stimuli in association with higher harm avoidance, along with an elevated response to the experience of touch, suggests an impaired ability in AN to predict and interpret incoming physiological stimuli. Impaired interoception may thus impact one’s sense of self, thereby supporting observations of disturbed body image and avoidance of affective and social stimuli. Therapeutic approaches that help AN to better anticipate and interpret salient affective stimuli or improve tolerance of interoceptive experiences may be an important addition to current interventions.

Prenatal alcohol exposure can adversely affect brain development, although little is known about the effects of prenatal alcohol exposure on gyrification. Gyrification reflects cortical folding complexity and is a process by which the surface of the brain creates sulci and gyri. Prior studies have shown that prenatal alcohol exposure is associated with reduced gyrification in childhood, but no studies have examined adolescents. Subjects (12-16 years) comprised two age-equivalent groups: 30 adolescents with histories of heavy prenatal alcohol exposure (AE) and 19 non-exposed controls (CON). A T1-weighted image was obtained for all participants. Local gyrification index (LGI) was estimated using FreeSurfer. General linear models were used to determine between group differences in LGI controlling for age and sex. Age-by-group interactions were also investigated while controlling for sex. The AE group displayed reduced LGI relative to CON in the bilateral superior parietal region, right postcentral region, and left precentral and lateral occipital regions (ps

This study investigated the temporal pattern of brain response to emotional stimuli during 28 days of alprazolam treatment among patients with generalized anxiety disorder (GAD) randomized 2:1 to drug or placebo in a double-blind design. Functional magnetic resonance imaging scans obtained during an emotion face matching task (EFMT) and an affective stimulus expectancy task (STIMEX) were performed at baseline, one hour after initial drug administration and 28 days later. Alprazolam significantly reduced scores on the Hamilton Anxiety Scale and the Penn State Worry Questionnaire after one week and 28 days of treatment. Brain activation in the amygdala during the EFMT and in the insula during the STIMEX was reduced one hour after alprazolam administration but returned to baseline levels at Day 28. Exploratory analyses revealed significant treatment differences in brain activity during the STIMEX on Day 28 in frontal lobe, caudate nucleus, middle temporal gyrus, secondary visual cortex, and supramarginal gyrus. These results are consistent with the notion that the neural mechanisms supporting sustained treatment effects of benzodiazepines in GAD differ from those underlying their acute effects.

Individuals prenatally exposed to alcohol often have impaired spatial working memory (SWM). This study examines functional connections of frontal and parietal regions that support SWM in children with and without prenatal alcohol exposure. Children ages 10 to 16 with histories of heavy prenatal alcohol exposure (AE group; n=18) and controls (CON group; n=19) underwent functional magnetic resonance imaging (fMRI) while performing a SWM task. Whole brain task-related functional connectivity of bilateral dorsolateral prefrontal cortex (DLPFC) and posterior parietal cortex (PPC) seed regions were estimated for each participant using a psychophysiological interaction approach. Children in the AE group were less accurate than children in the CON group when performing the SWM task (p=0.008). Positive coupling between bilateral DLPFC seeds and regions within the fronto-parietal network was observed in the CON group, whereas the AE group showed negative connectivity. In contrast to the CON group, the AE group showed positive connectivity between PPC seeds and frontal lobe regions. Across seeds, decreased negative coupling with regions outside the fronto-parietal network (e.g., left middle occipital gyrus) were observed in the AE group relative to the CON group. Functional data clusters were considered significant at p&nbsp

BackgroundChronic methamphetamine use may lead to changes in reward-related function of the ventral striatum and caudate nucleus. Whether methamphetamine-dependent individuals show heightened reactivity to positively valenced stimuli (i.e. positive reinforcement mechanisms), or an exaggerated response to negatively valenced stimuli (i.e. driven by negative reinforcement mechanisms) remains unclear. This study investigated neural functioning of expectancy and receipt for gains and losses in adults with (METH+) and without (METH-) histories of methamphetamine dependence.MethodsParticipants (17 METH+; 23 METH-) performed a probabilistic feedback expectancy task during blood-oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI). Participants were given visual cues probabilistically associated with monetary gain, loss, or neutral outcomes. General linear models examined the BOLD response to: (1) anticipation of gains and losses, and (2) gain and loss monetary outcomes.ResultsMETH+ had less BOLD response to loss anticipation than METH- in the ventral striatum and posterior caudate. METH+ also showed more BOLD response to loss outcomes than to gain outcomes in the anterior and posterior caudate, whereas METH- did not show differential responses to the valence of outcomes.DiscussionMETH+ individuals showed attenuated neural response to anticipated gains and losses, but their response to loss outcomes was greater than to gain outcomes. A decreased response to loss anticipation, along with a greater response to loss outcomes, suggests an altered ability to evaluate future risks and benefits based upon prior experience, which may underlie suboptimal decision-making in METH+ individuals that increases the likelihood of risky behavior.

Adults recovered from Anorexia nervosa (AN) have altered reward modulation within striatal limbic regions associated with the emotional significance of stimuli, and executive regions concerned with planning and consequences. We hypothesized that adolescents with AN would show similar disturbed reward modulation within the striatum and the anterior cingulate cortex, a region connected to the striatum and involved in reward-guided action selection. Using functional magnetic resonance imaging, twenty-two adolescent females (10 restricting-type AN, 12 healthy volunteers) performed a monetary guessing task. Time series data associated with monetary wins and losses within striatal and cingulate regions of interest were subjected to a linear mixed effects analysis. All participants responded more strongly to wins versus losses in limbic and anterior executive striatal territories. However, AN participants exhibited an exaggerated response to losses compared to wins in posterior executive and sensorimotor striatal regions, suggesting altered function in circuitry responsible for coding the affective context of stimuli and action selection based upon these valuations. As AN individuals are particularly sensitive to criticism, failure, and making mistakes, these findings may reflect the neural processes responsible for a bias in those with AN to exaggerate negative consequences.

Objective: A recent study of ill individuals with anorexia nervosa (AN) reported microstructural alterations in white matter integrity including lower fractional anisotropy and higher mean diffusivity. This study was designed to determine whether such alterations exist in longterm recovered AN individuals and to examine potential associations with underlying AN traits. Method: Twelve adult women recovered from restricting-type AN and 10 control women were studied using diffusion tensor imaging. Results: Overall, there was no significant fractional anisotropy alteration in recovered AN, in contrast to a prior study reporting lower fractional anisotropy in ill AN. Further, recovered AN showed lower mean diffusivity in frontal, parietal and cingulum white matter relative to control women, contrary to elevated mean diffusivity previously reported in ill AN. Lower longitudinal diffusivity in recovered AN was associated with higher harm avoidance. However, more severe illness history was associated with worse white matter integrity after recovery in the same direction as reported in prior work. Discussion: Our findings suggest that fractional anisotropy in recovered AN is not different from controls, however, a novel pattern of lower mean diffusivity was evidenced in recovered AN, and this alteration was associated with harm avoidance. Notably, severity of illness history may have long-term consequences, emphasizing the importance of aggressive treatment.

Is starvation in anorexia nervosa (AN) or overeating in bulimia nervosa (BN) a form of addiction? Alternatively, why are individuals with BN more vulnerable and individuals with AN protected from substance abuse? Such questions have been generated by recent studies suggesting that there are overlapping neural circuits for foods and drugs of abuse. To determine whether a shared neurobiology contributes to eating disorders and substance abuse, this review focused on imaging studies that investigated response to tastes of food and tasks designed to characterize reward and behavioral inhibition in AN and BN. BN and those with substance abuse disorders may share dopamine D2 receptor-related vulnerabilities, and opposite findings may contribute to "protection" from substance abuse in AN. Moreover, imaging studies provide insights into executive corticostriatal processes related to extraordinary inhibition and self-control in AN and diminished inhibitory self-control in BN that may influence the rewarding aspect of palatable foods and likely other consummatory behaviors. AN and BN tend to have premorbid traits, such as perfectionism and anxiety that make them vulnerable to using extremes of food ingestion, which serve to reduce negative mood states. Dysregulation within and/or between limbic and executive corticostriatal circuits contributes to such symptoms. Limited data support the hypothesis that reward and inhibitory processes may contribute to symptoms in eating disorders and addictive disorders, but little is known about the molecular biology of such mechanisms in terms of shared or independent processes.

The hippocampus is a key structure implicated in food motivation and intake. Research has shown that the hippocampus is vulnerable to the consumption of a western diet (i.e., high saturated fat and simple carbohydrates). Studies of patients with obesity (OB), compared with healthy weight (HW), show changes in hippocampal volume and response to food cues. Moreover, evidence suggests that OB children, relative to HW, have greater hippocampal response to taste. However, no study has examined the association of hippocampal volume with taste functioning in children. We hypothesized that OB children, relative to HW, would show a significant reduction in hippocampal volume and that decreased volume would be significantly associated with greater activation to taste. Finally, we explored whether hippocampal activation would be associated with measures on eating and eating habits.Twenty-five 8-12-year-old children (i.e., 13 HW, 12 OB) completed a magnetic resonance imaging scan while participating in a taste paradigm (i.e., 1 ml of 10% sucrose or ionic water delivered pseudorandomly every 20 s).Children with OB, relative to HW, showed reduced left hippocampal volume (t=1.994, P=0.03, 95% confidence interval (CI)=-40.23, 755.42), and greater response to taste in three clusters within the left hippocampus (z=3.3, P=0.001, 95% CI=-0.241, -0.041; z=3.3, P=0.001, 95% CI=-0.2711, -0.0469; z=2.7, P=0.007, 95% CI=-0.6032, -0.0268). Activation within the hippocampus was associated with eating in the absence of hunger (EAH%; t=2.408, P=0.025, 95% CI= 1.751708, 23.94109) and two subscales on a measure of eating behaviors (Food responsiveness, t=2.572, P=0.017, 95% CI= 0.9565195, 9.043440; Food enjoyment, t=2.298, P=0.032, 95% CI=0.2256749, 4.531298).As hypothesized, OB children, relative to HW, had significantly reduced hippocampal volume, and greater hippocampal activation to taste. Moreover, hippocampal activation was associated with measures of eating. These results contribute to research on the relationship between OB, overeating and cognitive impairment.

Background: Chronic methamphetamine use may lead to changes in reward-related function of the ventral striatum and caudate nucleus. Whether methamphetamine-dependent individuals show heightened reactivity to positively valenced stimuli (i.e. positive reinforcement mechanisms), or an exaggerated response to negatively valenced stimuli (i.e. driven by negative reinforcement mechanisms) remains unclear. This study investigated neural functioning of expectancy and receipt for gains and losses in adults with (METH+) and without (METH−) histories of methamphetamine dependence. Methods: Participants (17 METH+; 23 METH−) performed a probabilistic feedback expectancy task during blood-oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI). Participants were given visual cues probabilistically associated with monetary gain, loss, or neutral outcomes. General linear models examined the BOLD response to: (1) anticipation of gains and losses, and (2) gain and loss monetary outcomes. Results: METH+ had less BOLD response to loss anticipation than METH− in the ventral striatum and posterior caudate. METH+ also showed more BOLD response to loss outcomes than to gain outcomes in the anterior and posterior caudate, whereas METH− did not show differential responses to the valence of outcomes. Discussion: METH+ individuals showed attenuated neural response to anticipated gains and losses, but their response to loss outcomes was greater than to gain outcomes. A decreased response to loss anticipation, along with a greater response to loss outcomes, suggests an altered ability to evaluate future risks and benefits based upon prior experience, which may underlie suboptimal decision-making in METH+ individuals that increases the likelihood of risky behavior.

Methamphetamine (Meth) use is frequent among HIV-infected persons. Combined HIV and Meth insults may exacerbate neural injury in vulnerable neuroanatomic structures or circuitries in the brain, leading to increased behavioral disturbance and cognitive impairment. While acute and chronic effects of Meth in humans and animal models have been studied for decades, the neurobehavioral effects of Meth in the context of HIV infection are much less explored. In-depth understanding of the scope of neurobehavioral phenotypes and mechanisms in HIV/Meth intersection is needed. The present report summarizes published research findings, as well as unpublished data, in humans and animal models with regard to neurobehavioral disturbance, neuroimaging, and neuropathology, and in vitro experimental systems, with an emphasis on findings emerging from the National Institute on Drug Abuse (NIDA) funded Translational Methamphetamine AIDS Research Center (TMARC). Results from human studies and animal (primarily HIV-1 gp120 transgenic mouse) models thus far suggest that combined HIV and Meth insults increase the likelihood of neural injury in the brain. The neurobehavioral effects include cognitive impairment and increased tendencies toward impaired behavioral inhibition and social cognition. These impairments are relevant to behaviors that affect personal and social risks, e.g. worse medication adherence, riskier behaviors, and greater likelihood of HIV transmission. The underlying mechanisms may include electrochemical changes in neuronal circuitries, injury to white matter microstructures, synaptodendritic damage, and selective neuronal loss. Utilization of research methodologies that are valid across species is instrumental in generating new knowledge with clinical translational value.

Objective Functional neuroimaging studies have led to a significantly deeper understanding of the underlying neural correlates and the development of several mature models of depression in adults. In contrast, our current understanding of the underlying neural substrates of adolescent depression is very limited. Although numerous studies have consistently demonstrated a hyperactive amygdala in depressed adults, the few published pediatric studies have reported opposite results in the amygdala. Thus, the main purpose of this study was to further our knowledge of the underlying neural substrates of adolescent depression by examining the bilateral amygdala specifically and the whole brain in depressed adolescents compared to healthy controls. Method Twelve unmedicated adolescents diagnosed with current major depressive disorder without a comorbid psychiatric disorder and 12 well-matched controls ages 13 to 17 years performed a facial-emotion matching task during functional magnetic resonance imaging at 3 T. Results Region-of-interest analyses demonstrated: (1) significant bilateral amygdala activation in depressed and healthy adolescents, and (2) significantly greater left amygdala activation in depressed adolescents compared to controls. Whole-brain analysis revealed areas of significantly different brain activity in depressed adolescents compared to controls. Conclusions These results suggest that (1) depressed adolescents without a comorbid psychiatric disorder exhibit an abnormally hyperactive amygdala compared to healthy controls; (2) models of adult depression might be extended to include depressed adolescents; and (3) neuropsychiatric interventions that have been developed in depressed adults should be further examined in adolescents.

It is possible that disturbances of systems modulating reward may contribute to a vulnerability to develop an eating disorder.This hypothesis was tested by assessing functional magnetic resonance brain imaging response to a monetary reward task known to activate the anterior ventral striatum (AVS), a region implicated in motivational aspects toward stimuli. To avoid the confounding effects of malnutrition, 10 women who had recovered from bulimia nervosa (BN) were compared with 10 healthy comparison women (CW).For the AVS, CW distinguished positive and negative feedback, whereas recovered BN women had similar responses to both conditions. In addition, these groups had similar patterns of findings for the dorsal caudate.We have previously shown that individuals recovered from anorexia nervosa (AN) also had altered striatal responses and difficulties in differentiating positive and negative feedback. Thus BN and AN individuals may share a difficulty in discriminating the emotional significance of a stimulus.

Recent adult studies suggest that the subgenual anterior cingulate cortex (sgACC) is involved in fundamental mental operations such as affective processing and inhibitory control. However, little is known about inhibition-associated sgACC function in adolescents, and there are no published data regarding whether personality characteristics are related to inhibition-associated sgACC brain activity in adolescents. This study examined the relationship between personality and inhibition-associated sgACC response in healthy adolescents. Seventeen adolescents of 13–17 years of age underwent functional magnetic resonance imaging while performing a parametric stop-signal task. Greater harm avoidance levels were significantly associated with increased inhibition-related sgACC activity. These results establish, for the first time, a link between personality and differential sgACC activation in adolescents.

Emotions have been conceptualized as representations of bodily responses to a stimulus that critically involves the autonomic nervous system (ANS). An association between amygdala activation and ANS activity has been shown in adults. However, to date, no studies have demonstrated this association in adolescents. Examining the interaction between the ANS and amygdala in healthy adolescents may provide information about age-related changes in the association between amygdala activation and ANS measures. Therefore, the aim of this study was to examine the relationship between amygdala activation and heart rate in normal adolescents. Eighteen 12- to 17-year old adolescents participated. Heart rate data was collected during functional magnetic resonance imaging while subjects performed a facial expression matching task that reliably activates the amygdala. Adolescents showed significant amygdala activation for all facial expressions relative to the shape-matching, control task. Moreover, the degree of activation in the right amygdala for Fearful faces was significantly correlated with heart rate (Spearman’s rho = 0.55, p = 0.018, two-tailed). This study shows that amygdala activity is related to heart rate in healthy adolescents. Thus, similar to adults, adolescents show a coupling between processing emotional events and adjusting the ANS accordingly. Furthermore, this study confirms previous adolescent studies showing amygdala activation to Fearful, Angry, and Happy faces. Finally, the results of the present study lay the foundation for future research to investigate whether adolescents with mood or anxiety disorders show an altered coupling between processing emotionally salient events and ANS activity.

Human neuroimaging studies of reward processing typically involve tasks that engage decision-making processes in the dorsal striatum or focus upon the ventral striatum’s response to feedback expectancy. These studies are often compared to the animal literature; however, some animal studies include both feedback and nonfeedback events that activate the dorsal striatum during feedback expectancy. Differences in task parameters, movement complexity, and motoric effort to attain rewards may partly explain ventral and dorsal striatal response differences across species. We, therefore, used a target capture task during functional neuroimaging that was inspired by a study of single cell modulation in the internal globus pallidus during reward-cued, rotational arm movements in nonhuman primates. In this functional magnetic resonance imaging study, participants used a fiberoptic joystick to make a rotational response to an instruction stimulus that indicated both a target location for a capture movement and whether or not the trial would end with feedback indicating either a small financial gain or a neutral outcome. Portions of the dorsal striatum and pallidum demonstrated greater neural activation to visual cues predicting potential gains relative to cues with no associated outcome. Furthermore, both striatal and pallidal regions displayed a greater response to financial gains relative to neutral outcomes. This reward-dependent modulation of dorsal striatal and pallidal activation in a target-capture task is consistent with findings from reward studies in animals, supporting the use of motorically complex tasks as translational paradigms to investigate the neural substrates of reward expectancy and outcome in humans. (JINS, 2015, 21, 399–411)

Amphetamine, likely via action on the brain's dopaminergic systems, induces anorectic eating behavior and blunts dopaminergic midbrain activation to rewards. Past work has hypothesized that this blunted reward responsivity is a result of increasing tonic over phasic DA activity. We sought to extend past findings to sweet taste during fMRI following single-blind administration of dextroamphetamine and placebo in 11 healthy women. We hypothesized that neural response in both limbic and cognitive sweet taste circuits would mirror past work with monetary rewards by effectively blunting sweet taste reward, and 'equalizing' it's rewarding taste with receipt of water. Behavioral results showed that amphetamine reduced self-reported hunger (supporting the existence of amphetamine anorexia) and increased self-report euphoria. In addition, region of Interest analysis revealed significant treatment by taste interactions in the middle insula and dorsal anterior cingulate confirming the 'equalizing' hypothesis in the cingulate, but unlike monetary reinforcers, the insula actually evinced enhanced separation between tastes on the amphetamine day. These results suggest a divergence from prior research using monetary reinforcers when extended to primary reinforcers, and may hint that altering dopaminergic signaling in the insula and anterior cingulate may be a target for pharmacological manipulation of appetite, and the treatment of obesity.

HIV-associated cognitive impairments are prevalent, and are consistent with injury to both frontal cortical and subcortical regions of the brain. The current study aimed to assess the association of HIV infection with functional connections within the frontostriatal network, circuitry hypothesized to be highly vulnerable to HIV infection. Fifteen HIV-positive and 15 demographically matched control participants underwent 6 min of resting-state functional magnetic resonance imaging (RS-fMRI). Multivariate group comparisons of age-adjusted estimates of connectivity within the frontostriatal network were derived from BOLD data for dorsolateral prefrontal cortex (DLPFC), dorsal caudate and mediodorsal thalamic regions of interest. Whole-brain comparisons of group differences in frontostriatal connectivity were conducted, as were pairwise tests of connectivity associations with measures of global cognitive functioning and clinical and immunological characteristics (nadir and current CD4 count, duration of HIV infection, plasma HIV RNA). HIV – associated reductions in connectivity were observed between the DLPFC and the dorsal caudate, particularly in younger participants (N=9). Seropositive participants also demonstrated reductions in dorsal caudate connectivity to frontal and parietal brain regions previously demonstrated to be functionally connected to the DLPFC. Cognitive impairment, but none of the assessed clinical/immunological variables, was also associated with reduced frontostriatal connectivity. In conclusion, our data indicate that HIV is associated with attenuated intrinsic frontostriatal connectivity. Intrinsic connectivity of this network may therefore serve as a marker of the deleterious effects of HIV infection on the brain, possibly via HIV-associated dopaminergic abnormalities. These findings warrant independent replication in larger studies. (JINS, 2015, 21, 1–11)

HIV-associated cognitive impairments are prevalent, and are consistent with injury to both frontal cortical and subcortical regions of the brain. The current study aimed to assess the association of HIV infection with functional connections within the frontostriatal network, circuitry hypothesized to be highly vulnerable to HIV infection. Fifteen HIV-positive and 15 demographically matched control participants underwent 6 min of resting-state functional magnetic resonance imaging (RS-fMRI). Multivariate group comparisons of age-adjusted estimates of connectivity within the frontostriatal network were derived from BOLD data for dorsolateral prefrontal cortex (DLPFC), dorsal caudate and mediodorsal thalamic regions of interest. Whole-brain comparisons of group differences in frontostriatal connectivity were conducted, as were pairwise tests of connectivity associations with measures of global cognitive functioning and clinical and immunological characteristics (nadir and current CD4 count, duration of HIV infection, plasma HIV RNA). HIV - associated reductions in connectivity were observed between the DLPFC and the dorsal caudate, particularly in younger participants (

Performance of automated methods to isolate brain from nonbrain tissues in magnetic resonance (MR) structural images may be influenced by MR signal inhomogeneities, type of MR image set, regional anatomy, and age and diagnosis of subjects studied. The present study compared the performance of four methods: Brain Extraction Tool (BET; Smith [2002]: Hum Brain Mapp 17:143–155); 3dIntracranial (Ward [1999] Milwaukee: Biophysics Research Institute, Medical College of Wisconsin; in AFNI); a Hybrid Watershed algorithm (HWA, Segonne et al. [2004] Neuroimage 22:1060–1075; in FreeSurfer); and Brain Surface Extractor (BSE, Sandor and Leahy [1997] IEEE Trans Med Imag 16:41–54; Shattuck et al. [2001] Neuroimage 13:856 – 876) to manually stripped images. The methods were applied to uncorrected and bias-corrected datasets; Legacy and Contemporary T1-weighted image sets; and four diagnostic groups (depressed, Alzheimer’s, young and elderly control). To provide a criterion for outcome assessment, two experts manually stripped six sagittal sections for each dataset in locations where brain and nonbrain tissue are difficult to distinguish. Methods were compared on Jaccard similarity coefficients, Hausdorff distances, and an Expectation-Maximization algorithm. Methods tended to perform better on contemporary datasets; bias correction did not significantly improve method performance. Mesial sections were most difficult for all methods. Although AD image sets were most difficult to strip, HWA and BSE were more robust across diagnostic groups compared with 3dIntracranial and BET. With respect to specificity, BSE tended to perform best across all groups, whereas HWA was more sensitive than other methods. The results of this study may direct users towards a method appropriate to their T1-weighted datasets and improve the efficiency of processing for large, multisite neuroimaging studies.

The primary defining characteristic of a diagnosis of an eating disorder (ED) is the “disturbance of eating or eating-related behavior that results in the altered consumption or absorption of food” (DSM V; American Psychiatric Association, 2013). There is a spectrum, ranging from those who severely restrict eating and become emaciated on one end to those who binge and overconsume, usually accompanied by some form of compensatory behaviors, on the other. How can we understand reasons for such extremes of food consummatory behaviors? Recent work on obesity and substance use disorders has identified behaviors and neural pathways that play a powerful role in human consummatory behaviors. That is, corticostriatal limbic and dorsal cognitive neural circuitry can make drugs and food rewarding, but also engage self-control mechanisms that may inhibit their use. Importantly, there is considerable evidence that alterations of these systems also occur in ED. This paper explores the hypothesis that an altered balance of reward and inhibition contributes to altered extremes of response to salient stimuli, such as food. We will review recent studies that show altered sensitivity to reward and punishment in ED, with evidence of altered activity in corticostriatal and insula processes with respect to monetary gains or losses, and tastes of palatable foods. We will also discuss evidence for a spectrum of extremes of inhibition and dysregulation behaviors in ED supported by studies suggesting that this is related to top-down self-control mechanisms. The lack of a mechanistic understanding of ED has thwarted efforts for evidence-based approaches to develop interventions. Understanding how ED behavior is encoded in neural circuits would provide a foundation for developing more specific and effective treatment approaches.

Representation of sequential structure can occur with respect to the order of perceptual events or the order in which actions are linked. Neural correlates of sequence retrieval associated with the order of motor responses were identified in a variant of the serial reaction time task in which training occurred with a spatially incompatible mapping between stimuli and finger responses. After transfer to a spatially compatible version of the task, performance enhancements indicative of learning were only present in subjects required to make finger movements in the same order used during training. In contrast, a second group of subjects performed the compatible task using an identical sequence of stimuli (and different order of finger movements) as in training. They demonstrated no performance benefit, indicating that learning was response based. Analysis was restricted to subjects demonstrating low recall of the sequence structure to rule out effects of explicit awareness. The interaction of group (motor vs. perceptual transfer) with sequence retrieval (sequencing vs. rest) revealed significantly greater activation in the bilateral supplementary motor area, cingulate motor area, ventral premotor cortex, left caudate, and inferior parietal lobule for subjects in the motor group (illustrating successful sequence retrieval at the response level). Retrieval of sequential responses occurs within mesial motor areas and related motor planning areas.

A number of functional hypotheses have recently been advanced to account for how the cerebellum may contribute to cognition. Neuropsychological studies suggest the cerebellum is involved in switching attentional set. We present evidence that fails to support this hypothesis. Rather, we propose that in such tasks, the cerebellum is involved with the remapping of response alternatives to different types of stimuli. In our experiment, participants fixated on the center of a screen onto which a random presentation of four visual stimuli was presented. The stimuli were grouped along two dimensions (color: red square or blue square; shape: white circle or white triangle). Participants were instructed to respond with a button press only to presented stimuli for a particular dimension (e.g., red squares), to switch between two dimensions (where the target on the attended dimension served both as a signal for a response and as an indicator to shift attention to the other dimension), or to switch attention between two dimensions but make an overt response only to targets on one of the dimensions. Using functional imaging, we identify areas of lateral cerebellar cortex that are recruited when subjects must reassign motor responses to different stimuli. Furthermore, we demonstrate that switching of attention between dimensions without a motor response does not produce stronger activation within the cerebellum compared with conditions involving response and attention to a single dimension. These results suggest the cerebellum is involved in response reassignment.

BACKGROUND: Hunger enhances sensitivity to reward, yet individuals with anorexia nervosa (AN) are not motivated to eat when starved. This study investigated brain response to rewards during hunger and satiated states to examine whether diminished response to reward could underlie food restriction in AN. METHODS: Using a delay discounting monetary decision task known to discriminate brain regions contributing to processing of immediate rewards and cognitive control important for decision making regarding future rewards, we compared 23 women remitted from AN (RAN group; to reduce the confounding effects of starvation) with 17 healthy comparison women (CW group). Monetary rewards were used because the rewarding value of food may be confounded by anxiety in AN. RESULTS: Interactions of Group (RAN, CW) 3 Visit (hunger, satiety) revealed that, for the CW group, hunger significantly increased activation in reward salience circuitry (ventral striatum, dorsal caudate, anterior cingulate cortex) during processing of immediate reward, whereas satiety increased activation in cognitive control circuitry (ventrolateral prefrontal cortex, insula) during decision making. In contrast, brain response in reward and cognitive neurocircuitry did not differ during hunger and satiety in the RAN group. A main effect of group revealed elevated response in the middle frontal gyrus for the RAN group compared with the CW group. CONCLUSIONS: Women remitted from AN failed to increase activation of reward valuation circuitry when hungry and showed elevated response in cognitive control circuitry independent of metabolic state. Decreased sensitivity to the motivational drive of hunger may explain the ability of individuals with AN to restrict food when emaciated. Difficulties in valuating emotional salience may contribute to inabilities to appreciate the risks inherent in this disorder.

Objective There is evidence of altered neural taste response in female adolescents who are obese, and in adolescents who are at risk for obesity. To further understand risk factors for the development of overeating and obesity, we investigated response to tastes of sucrose and water in 23 obese and healthy weight children. Methods and design Thirteen healthy weight (HW) and 10 obese (OB) 8–12 year old children underwent functional magnetic resonance imaging while tasting sucrose and water. Additionally, children completed an eating in the absence of hunger paradigm and a sucrose liking task. Results A region of interest analysis revealed an elevated BOLD response to taste (sucrose and water) within the bilateral insula and amygdala in OB children relative to HW children. Whole brain analyses revealed a group by condition interaction within the paracingulate, medial frontal, middle frontal gyri, and right amygdala: post hoc analyses suggested an increased response to sucrose for OB relative to HW children, whereas HW children responded more strongly to water relative to sucrose. In addition, OB children, relative to HW, tended to recruit the right putamen as well as medial and lateral frontal and temporal regions bilaterally. Conclusion This study showed increased reactivity in the amygdala and insula in the OB compared to HW children, but no functional differentiation in the striatum, despite differences in the striatum previously seen in older samples. These findings support the concept of the association between increased neural processing of food reward in the development of obesity, and raise the possibility that emotional and interoceptive sensitivity could be an early vulnerability in obesity.

To examine set shifting in a group of women previously diagnosed with anorexia nervosa (AN) who are now weight-restored (AN-WR) and a control group and then apply a biologically-based computational model (Competition between Verbal and Implicit Systems; COVIS) to simulate the pattern of category learning and set shifting performances observed in the AN-CW group. Method: Nineteen AN-WR women and 35 control women (CW) were administered an explicit category learning task that required the initial acquisition of a rule, and after a certain number of trials, a set shift following a rule change. COVIS was first fit to the behavioral results of the controls and then parameters of the model theoretically relevant to AN were altered to mimic the behavioral results. Results: Relative to CW, the AN-WR group displayed steeper learning curves (i.e., hyper learning) prior to the rule shift, but greater difficulty in learning the new categories after the rule shift (i.e., a deficit in set shifting). Hyper learning and set shifting deficits in the AN-CW group were not associated and demonstrated a different pattern of correlations with clinical measures. Hyper learning in the AN-WR group was simulated by increasing the model parameter that represents sensitivity to negative feedback ( parameter), whereas the deficit in set shifting was simulated by altering the parameters that represent changes in rule selection and flexibility ( and parameters, respectively), processes dependent on dopamine levels. Conclusions: These simulations suggest that multiple factors can impact category learning and set shifting in AN-WR individuals (e.g., alterations in sensitivity to negative feedback, rule selection deficits, and inflexibility) and provide an important starting point to further investigate this pervasive deficit in adult AN.

Author(s): Connolly, Colm G; Bischoff-Grethe, Amanda; Jordan, Stephan J; Woods, Steven Paul; Ellis, Ronald J; Paulus, Martin P; Grant, Igor; Translational Methamphetamine AIDS Research Center (TMARC) Group | Abstract: BackgroundRisky decision-making is commonly observed in persons at risk for and infected with HIV and is associated with executive dysfunction. Yet it is currently unknown whether HIV alters brain processing of risk-taking decision-making.MethodsThis study examined the neural substrate of a risky decision-making task in 21 HIV seropositive (HIV+) and 19 seronegative (HIV-) comparison participants. Functional magnetic resonance imaging was conducted while participants performed the risky-gains task, which involves choosing among safe (20 cents) and risky (40/80 cent win or loss) choices. Linear mixed effects analyses examining group and decision type were conducted. Robust regressions were performed to examine the relationship between nadir CD4 count and Kalichman sexual compulsivity and brain activation in the HIV+ group. The overlap between the task effects and robust regressions was explored.ResultsAlthough there were no serostatus effects in behavioral performance on the risky-gains task, HIV+ individuals exhibited greater activation for risky choices in the basal ganglia, i.e. the caudate nucleus, but also in the anterior cingulate, dorsolateral prefrontal cortex, and insula relative to the HIV- group. The HIV+ group also demonstrated reduced functional responses to safe choices in the anterior cingulate and dorsolateral prefrontal cortex relative to the HIV- group. HIV+ individuals with higher nadir CD4 count and greater sexual compulsivity displayed lower differential responses to safe versus risky choices in many of these regions.ConclusionsThis study demonstrated fronto-striatal loop dysfunction associated with HIV infection during risky decision-making. Combined with similar between-group task behavior, this suggests an adaptive functional response in regions critical to reward and behavioral control in the HIV+ group. HIV-infected individuals with higher CD4 nadirs demonstrated activation patterns more similar to seronegative individuals. This suggests that the severity of past immunosuppression (CD4 nadir) may exert a legacy effect on processing of risky choices in the HIV-infected brain.

Implicit motor learning tasks typically involve comparisons of subject responses during a sequence versus a random condition. In neuroimaging, brain regions that are correlated with a sequence are described, but the temporal relationship of sequence versus nonsequence conditions is often not explored. We present a functional magnetic resonance imaging (fMRI) study describing activation related to sequential predictability in an implicit sensorimotor learning task and the history (context) dependence of these effects. Participants regarded four squares displayed horizontally across a screen and pressed a button when any one of the four targets was illuminated in a particular color. A repeating spatial sequence with varying levels of predictability was embedded within a random color presentation. Both the right dorsolateral prefrontal cortex (R DLPFC) and right caudate displayed a positive correlation to increasing predictability, whereas the left posterior parietal cortex (L PPC) displayed a negative correlation. However, the activation changes within the caudate were significant when transitioning from high predictability to low predictability but not for the reverse case, suggesting a sensitivity not only to predictability but to order effects as well. These results support the hypothesized relationship between basal ganglia and visuomotor sequential learning, but demonstrate the importance of context upon sequence learning.

The association of nonverbal predictability and brain activation was examined using functional magnetic resonance imaging in humans. Participants regarded four squares displayed horizontally across a screen and counted the incidence of a particular color. A repeating spatial sequence with varying levels of predictability was embedded within a random color presentation. Both Wernicke's area and its right homolog displayed a negative correlation with temporal predictability, and this effect was independent of individuals' conscious awareness of the sequence. When individuals were made aware of the underlying sequential predictability, a widespread network of cortical regions displayed activity that correlated with the predictability. Conscious processing of predictability resulted in a positive correlation to activity in right prefrontal cortex but a negative correlation in posterior parietal cortex. These results suggest that conscious processing of predictability invokes a large-scale cortical network, but independently of awareness, Wernicke's area processes predictive events in time and may not be exclusively associated with language.

Individuals with anorexia nervosa (AN) engage in relentless restrictive eating and often become severely emaciated. Because there are no proven treatments, AN has high rates of relapse, chronicity, and death. Those with AN tend to have childhood temperament and personality traits, such as anxiety, obsessions, and perfectionism, which may reflect neurobiological risk factors for developing AN. Restricted eating may be a means of reducing negative mood caused by skewed interactions between serotonin aversive or inhibitory and dopamine reward systems. Brain imaging studies suggest that altered eating is a consequence of dysregulated reward and/or awareness of homeostatic needs, perhaps related to enhanced executive ability to inhibit incentive motivational drives. An understanding of the neurobiology of this disorder is likely to be important for developing more effective treatments.(Reprinted with permission from the Trends in Neurosciences 2013; 36:110–120)

Arrowsmith is a unique computer-assisted strategy designed to assist investigators in detecting biologically-relevant connections between two disparate sets of articles in Medline. This paper describes how an inter-institutional consortium of neuroscientists used the UIC Arrowsmith web interface http://arrowsmith.psych.uic.edu in their daily work and guided the development, refinement and expansion of the system into a suite of tools intended for use by the wider scientific community.