Search

Dietary restriction (DIET) and aerobic exercise (AEX) interventions may impact energy balance differently. Our aim was to describe the effects of weight loss interventions via DIET or AEX on measures of energy balance.Adults with overweight or obesity were randomized to 12 weeks of DIET or AEX with similar calorie deficit goals. A study day was conducted before and after the intervention to assess subjective and hormonal (ghrelin, peptide-YY, glucagon-like peptide-1) appetite responses to a control meal,Forty-four individuals were included (age: 37 ± 9 years, body mass index: 30.6 ± 3.1 kg/mAEX did not result in compensatory alterations in appetite

PURPOSE Up to half of the children undergoing epilepsy surgery will continue to have seizures (szs) despite a cortical resection or ablation. Functional connectivity has shown promise in better identifying the epileptogenic zone. We hypothesized that cortical areas showing high information outflow during interictal epileptiform discharges are part of the epileptogenic zone. METHODS We identified 22 children with focal epilepsy who had undergone stereo electroencephalography, surgical resection or ablation, and had ≥1 year of postsurgical follow-up. The mean phase slope index, a directed measure of functional connectivity, was calculated for each electrode contact during interictal epileptiform discharges. The positive predictive value and negative predictive value for a sz-free outcome were calculated based on whether high information outflow brain regions were resected. RESULTS Resection of high outflow (z-score ≥ 1) and very high outflow (z-score ≥ 2) electrode contacts was associated with higher sz freedom (high outflow: χ2 statistic = 59.1; P < 0.001; very high outflow: χ2 statistic = 31.3; P < 0.001). The positive predictive value and negative predictive value for sz freedom based on resection at the electrode level increased at higher z-score thresholds with a peak positive predictive value of 0.86 and a peak negative predictive value of 0.9. CONCLUSIONS Better identification of the epileptogenic zone has the potential to improve epilepsy surgery outcomes. If the surgical plan can be modified to include these very high outflow areas, more children might achieve sz freedom. Conversely, if deficits from resecting these areas are unacceptable, ineffective surgeries could be avoided and alternative therapies offered.

BACKGROUND: Conditioned food cues (e.g., smell, sight) can affect intake of foods associated with those cues, regardless of homeostatic need. As such, altering automatic associations with food cues could support weight loss or maintenance efforts by affecting the salience of those cues and the effort required to resist consumption. OBJECTIVES: This study investigated neuronal and behavioral effects of an implicit priming (IP) intervention, in which negatively valenced images were paired with high-calorie foods and positively valenced images with low-calorie foods. Priming images were presented immediately before food images, but below conscious perception (20 ms). We hypothesized that this evaluative conditioning approach could alter food cue responses by modifying affective associations. METHODS: The final sample included 41 adults with BMI ≥25 kg/m(2) (n = 22, active IP; n = 19, control IP). In control IP, food images were primed with neutral, scrambled images. Participants completed a visual food cue task during fMRI, both before and after IP. To determine the replicability of prior behavioral findings, food image ratings were completed before and after IP as a secondary outcome. RESULTS: In a whole-brain analysis, reduced dorsolateral prefrontal cortex (dlPFC) response to high-calorie foods was observed after active compared with control IP (t = 4.93, P = 0.033). With a region of interest analysis, reduced response to high-calorie foods in active compared with control IP was also observed in the striatum (t = 2.40, P = 0.009) and insula (t = 2.38, P = 0.010). Active compared with control IP was associated with reduced high-calorie food ratings (F = 4.70, P = 0.038). CONCLUSIONS: Reduced insula and striatum response to high-calorie foods after active compared with control IP suggests effectiveness of IP in altering food cue salience. Reduced dlPFC response to high-calorie foods after active compared with control IP may reflect fewer attentional resources being directed to those images and reduced engagement of inhibitory processes. This trial was registered at clinicaltrials.gov as NCT02347527.

Cognitive impairment is increasingly recognized as a characteristic feature of Parkinson's disease (PD), yet relatively little is known about its underlying neurobiology. Previous investigations suggest that dementia in PD is associated with subcortical atrophy, but similar studies in PD with mild cognitive impairment have been mixed. Variability in cognitive phenotypes and diversity of PD symptoms suggest that a common neuropathological origin results in a multitude of impacts within the brain. These direct and indirect impacts of disease pathology can be investigated using network analysis. Functional connectivity, for instance, may be more sensitive than atrophy to decline in specific cognitive domains in the PD population. 58 participants with PD underwent a neuropsychological test battery and scanning with structural and resting state functional MRI in a comprehensive whole-brain association analysis. To investigate atrophy as a potential marker of impairment, structural gray matter atrophy was associated with cognitive scores in each cognitive domain using voxel-based morphometry. To investigate connectivity, large-scale networks were correlated with voxel time series and associated with cognitive scores using distance covariance. Structural atrophy was not associated with any cognitive domain, with the exception of visuospatial measures in primary sensory and motor cortices. In contrast, functional connectivity was associated with attention, executive function, language, learning and memory, visuospatial, and global cognition in the bilateral hippocampus, left putamen, olfactory cortex and bilateral anterior temporal poles. These preliminary results suggest that cognitive domain-specific networks in PD are distinct from each other and could provide a network signature for different cognitive phenotypes.

OBJECTIVES: The impact of in utero exposure to maternal overweight and obesity on offspring metabolic health is well documented. Neurodevelopmental outcomes among these children are, however, less well studied. To address this gap, the current study investigated brain function among 4 to 6-year-old children exposed to maternal overweight or obesity during gestation compared to that of children born to mothers with healthy body mass index in pregnancy. METHODS: Resting-state functional magnetic resonance imaging was used to study neuronal activity and connectivity during a passive viewing task (movie) among 101 typically developing children enrolled in the Healthy Start study, a longitudinal pre-birth cohort in Colorado. RESULTS: Forty-nine children (48%) were exposed to maternal overweight or obesity in utero (mean age = 5 years, SD = 0.9). Children born to mothers with overweight or obesity demonstrated hyperactivity in the left posterior cingulate cortex and hypoactivity in the dorsal anterior cingulate and the supplementary motor area (p

The neurobiology of autism spectrum disorder remains poorly understood. The present study addresses this knowledge gap by examining the relationship between functional brain connectivity and Autism Diagnostic Observation Schedule (ADOS) scores using publicly available data from the Autism Brain Imaging Data Exchange (ABIDE) database (N = 107). This relationship was tested across all brain voxels, without a priori assumptions, using a novel statistical approach. ADOS scores were primarily associated with decreased connectivity to right temporoparietal junction, right anterior insula, and left fusiform gyrus (p

OBJECTIVE: To evaluate the hypothesis that metabolic measures (fasting glucose, insulin and Homeostatic Model of Assessment for Insulin Resistance [HOMA-IR] levels) are inversely associated with performance on cognitive tasks using data from young (4- to 6-year-old), typically developing, healthy children. STUDY DESIGN: Data were obtained from children participating in the Healthy Start study, a pre-birth cohort in Colorado. HOMA-IR, glucose and insulin values were centered and scaled using the study sample means and standard deviations (SD). Thus, they are reported in number of SD units from the mean. Fully corrected T-scores for inhibitory control (Flanker task), cognitive flexibility (Dimensional Change Card Sort test), and receptive language (Picture Vocabulary test) were obtained via the NIH Toolbox cognition battery. RESULTS: Children included in this analysis (n = 137) were 4.6 years-old, on average. Per 1 SD unit, fasting glucose (B = - 2.02, 95% CI: −3.54, −0.49), insulin (B = −1.67, 95% CI: −2.96, - 0.38), and HOMA-IR values (B = −1.79, 95% CI: −3.09, −0.49) were each significantly and inversely associated with inhibitory control (P < .05 for all, respectively). Fasting glucose levels were also inversely associated with cognitive flexibility (B = −1.96, 95% CI: −3.71, −0.21, p = 0.03). CONCLUSION(S): Our data suggest that metabolic health may impact fluid cognitive function in healthy, young children.

Insula dysfunction contributes to nicotine use disorders. Yet, much remains unknown about how insular functions promote nicotine use. We review current models of brain networks in smoking and propose an extension to those models that emphasizes the role of the insula in craving. During acute withdrawal, the insula provides the sensation of craving to the cerebrum and is thought to negotiate craving sensations with cognitive control to guide behavior - either to smoke or abstain. Recent studies have shown that insula processing is saturable, such that different insular functions compete for limited resources. We propose that this saturability explains how craving during withdrawal can overload insular processing to the exclusion of other functions, such as saliency and network homeostasis. A novel signal flow model illustrates how limited insular capacity leads to breakdown of normal function. Finally, we discuss suitability of insula as a neuromodulation target to promote cessation. Given the limited efficacy of standard-of-care treatments for nicotine use disorder, insular neuromodulation offers an innovative, potentially therapeutic target for improving smoking cessation.

Objective Investigating intrinsic brain functional connectivity may help identify the neurobiology underlying cognitive patterns and biases contributing to obesity propensity. To address this, the current study used a novel whole-brain, data-driven approach to examine functional connectivity differences in large-scale network interactions between obesity-prone (OP) and obesity-resistant (OR) individuals. Methods OR (N = 24) and OP (N = 25) adults completed functional magnetic resonance imaging (fMRI) during rest. Large-scale brain networks were identified using independent component analysis (ICA). Voxel-specific between-network connectivity analysis assessed correlations between ICA component time series’ and individual voxel time series, identifying regions strongly connected to many networks, i.e., “hubs”. Results Significant group differences in between-network connectivity (OP vs. OR; FDR-corrected) were observed in bilateral basal ganglia (left: q = 0.009; right: q = 0.010) and right dorsolateral prefrontal cortex (dlPFC; q = 0.026), with OP>OR. Basal ganglia differences were largely driven by a more strongly negative correlation with a lateral sensorimotor network in OP, with dlPFC differences driven by a more strongly negative correlation with an inferior visual network in OP. Conclusions Greater between-network connectivity was observed in the basal ganglia and dlPFC in OP, driven by stronger associations with lateral sensorimotor and inferior visual networks, respectively. This may reflect a disrupted balance between goal-directed and habitual control systems and between internal/external monitoring processes.

BACKGROUND: Individual differences in cortical gray matter (GM) structure are associated with cognitive function and psychiatric disorders with developmental origins. Identifying when individual differences in cortical structure are established in childhood is critical for understanding the timing of abnormal cortical development associated with neuropsychiatric disorders. METHODS: We studied the development of cortical GM and white matter (WM) volume, cortical thickness (CT) and surface area (SA) using structural magnetic resonance imaging (MRI) in two unique cohorts of singleton (121 male/131 female) and twin (99 male/83 female) children imaged longitudinally from birth to 6 years. RESULTS: Cortical GM volume increases rapidly in the first year of life, with more gradual growth thereafter. Between ages 1 and 6 years, total SA expands 29%, while average CT decreases about 3.5%. In both cohorts, a large portion of individual variation in cortical GM volume (81-87%) and total SA (73-83%) at 6 years is present by age 1 year. Regional heterogeneity of CT observed at age 6 is largely in place at age 1. CONCLUSIONS: These findings indicate that individual differences in cortical GM structure are largely established by the end of the first year of life, following a period of rapid postnatal GM growth. This suggests that alterations in GM structure associated with psychiatric disorders with developmental origins may largely arise in the first year of life, and that interventions to normalize or mitigate abnormal GM development may need to be targeted to very early childhood.

Functional connectivity is providing new insights into the network nature of epilepsy with growing clinical applications. Our objective was to validate a novel magnetoencephalography-based method to non-invasively measure the epileptic network. We retrospectively identified pediatric and adult patients with refractory focal epilepsy who underwent pre-surgical magnetoencephalography with subsequent intracranial electrographic monitoring. Magnetoencephalography tracings were visually reviewed, and interictal epileptiform discharges ("spikes") were individually marked. We then evaluated differences in whole-brain connectivity during brief epochs preceding the spikes and during the spikes using the Network-Based Statistic to test differences at the network level. In six patients with statistically-significant network differences, we observed substantial overlap between the spike-associated networks and electrographically active areas identified during intracranial monitoring (the spike-associated network was 78% and 83% sensitive for intracranial electroencephalography-defined regions in the irritative and seizure onset zones, respectively). These findings support the neurobiological validity of the spike-associated network method. Assessment of spike-associated networks has the potential to improve surgical planning in epilepsy surgery patients by identifying components of the epileptic network prior to implantation.

Exercise is accepted as a method to improve weight loss maintenance; however, the mechanisms by which this occurs have yet to be elucidated. In this pilot study, 13 women with obesity underwent a structured weight loss program (goal 8%–10% weight loss) and were then randomized to either a 12-wk diet (n = 7) or an aerobic exercise training (n = 6) intervention aimed at maintaining weight loss. At baseline, post–weight loss, and following the weight loss maintenance interventions, measurements of appetite (hunger and satiety) and appetite-regulating hormones (leptin, ghrelin, peptide tyrosine tyrosine, and glucagon-like peptide 1) were obtained after an overnight fast and for 3 h after a standardized test meal. Ad libitum energy intake was measured at a lunch meal. During the weight loss phase, participants lost 9.1% ± 1.1% of baseline body weight. Participants in both groups maintained weight loss during the 12-wk weight loss maintenance intervention. No differences in fasting leptin (P = 0.68) or in ghrelin (P = 0.30), peptide tyrosine tyrosine (P = 0.93), and glucagon-like peptide 1 (P = 0.98) area under the curve were detected between groups. Similarly, ratings of hunger (P = 0.99) and satiety (P = 0.65) area under the curve after the standardized test meal also did not differ between the groups nor did ad libitum energy intake at lunch. In summary, the 12-wk diet and exercise interventions were equally effective at maintaining weight loss in women, and no differences in measures of appetite regulation and food intake were found.

While current treatments for schizophrenia often provide much relief for positive symptoms such as hallucinations, other symptoms, particularly cognitive deficits, persist and contribute to substantial suffering and reduced quality of life for patients. In searching for novel therapeutic avenues to treat cognitive deficits in schizophrenia, recent work is exploring nicotinic receptor neurobiology. Supported by a large body of evidence, with contributions from studies of smoking behaviors, genetics, receptor distribution and function, animal models and nicotinic effects on illness symptoms, the alpha7 nicotinic receptor has emerged as a potential therapeutic target. Despite promise in early clinical trials, however, no drug targeting nicotinic systems has succeeded in larger phase 3 trials. Following a brief review of nicotinic receptor biology and the evidence that has led to pursuit of alpha7 nicotinic agonism as a therapeutic strategy, this review will provide an update on the status of recent trials, discuss potential issues that may have contributed to negative outcomes, and point to new directions and promising advances in developing alpha7 nicotinic receptor-based treatment for cognitive symptoms in schizophrenia. IMPLICATIONS: By examining alpha7 nicotinic receptor biology and recent efforts to target the receptor in clinical trials, it is hoped that investigators will be motivated to explore novel, promising directions focusing on the receptor as a strategy to treat cognitive symptoms in schizophrenia.

OBJECTIVE The current study aimed to identify how sex influences neurobiological responses to food cues, particularly those related to hedonic eating, and how this relates to obesity propensity, using functional magnetic resonance imaging (fMRI). METHODS Adult men and women who were either obesity resistant (OR) or obesity prone (OP) underwent fMRI while viewing visual food cues (hedonic foods, neutral foods, and nonfood objects) in both fasted and fed states. RESULTS When fasted, a significant sex effect on the response to hedonic vs. neutral foods was observed, with greater responses in women than men in the nucleus accumbens (P = 0.0002) and insula (P = 0.010). Sex-based differences were not observed in the fed state. No significant group effects (OP vs. OR) or group-by-sex interactions were observed in fasted or fed states. CONCLUSIONS Greater fasted responses to hedonic food cues in reward-related brain regions were observed in women compared with men, suggesting that women may be more sensitive to the reward value of hedonic foods than men when fasted. This may indicate sex-dependent neurophysiology underlying eating behaviors.

The risk of becoming overweight among offspring exposed to gestational diabetes (GDM) in utero is two-fold higher than in the general population. The responsible mechanisms are likely multifactorial, with some evidence that GDM exposure alters brain satiety signaling, which may impact eating behavior. To better understand these effects, we investigated the relationship between GDM exposure, eating behavior, and total energy intake in 268 adolescents from the Exploring Perinatal Outcomes among Children cohort, who were exposed (n = 50) or not exposed (n = 217) to GDM in utero. Eating behavior was measured by the Eating in the Absence of Hunger in Children and Adolescents (EAH-C) questionnaire, which included subscale scores for Negative Affect, External Stimuli, and Fatigue/Boredom. Total energy intake (kcal/day) was derived from the Block Kid's Food Questionnaire. The associations between GDM exposure and the outcomes of total score and each EAH-C subscale were evaluated in separate multivariable models. In addition to the main predictor, GDM, the models included a GDM-by-sex interaction term and were adjusted for important covariates. The associations between EAH-C total and subscale scores and the outcome of total energy intake were also tested in separate multivariable models. Female offspring exposed to GDM in utero (vs unexposed males and females) were more likely to continue eating beyond satiation due to feelings of boredom and fatigue (β = 0.47, 95% CI: 0.11, 0.83), and in general (EAH-C total score; β = 4.20, 95% CI: 0.56, 7.86) compared to unexposed males. All EAH-C subscale and total scores were significantly, positively associated with higher energy intake (p

Although functional abnormalities of the salience network are associated with schizophrenia, the acute effects of nicotine on its function and network dynamics during the resting state in patients are poorly understood. In this study, the effects of a 7 mg nicotine patch (vs. placebo) on salience network connectivity were examined in 17 patients with schizophrenia and 19 healthy subjects. We hypothesized abnormal connectivity between the salience network and other major networks (e.g. executive network) in patients under placebo administration and amelioration of this difference after nicotine. We also examined effects of nicotine on betweenness centrality (a measure of the influence of a region on information transfer throughout the brain) and local efficiency (a measure of local information transfer) of the network. A hybrid independent component analysis (ICA) / seed-based connectivity approach was implemented in which the salience network was extracted by ICA and cortical network peaks (anterior cingulate cortex (ACC), left and right insula) were used as seeds for whole-brain seed-to-voxel connectivity analysis. Significant drug X diagnosis interactions were observed between the ACC seed and superior parietal lobule and ventrolateral prefrontal cortex. A significant interaction effect was also observed between the left insula seed and middle cingulate cortex. During placebo conditions, abnormal connectivity predicted negative symptom severity and lower global functioning in patients. A significant drug X diagnosis interaction was also observed for betweenness centrality of the ACC. These results suggest that nicotine may target abnormalities in functional connectivity between salience and executive network areas in schizophrenia as well as affect the ability of the salience network to act as an integrator of global signaling in the disorder.

Patients with schizophrenia self-administer nicotine at rates higher than is self-administered for any other psychiatric illness. Although the reasons are unclear, one hypothesis suggests that nicotine is a form of ‘self-medication’ in order to restore normal levels of nicotinic signaling and target abnormalities in neuronal function associated with cognitive processes. This brief review discusses evidence from neurophysiological and neuroimaging studies in schizophrenia patients that nicotinic agonists may effectively target dysfunctional neuronal circuits in the illness. Evidence suggests that nicotine significantly modulates a number of these circuits, although relatively few studies have used modern neuroimaging techniques (e.g. functional magnetic resonance imaging (fMRI)) to examine the effects of nicotinic drugs on disease-related neurobiology. The neuronal effects of nicotine and other nicotinic agonists in schizophrenia remain a priority for psychiatry research.

Working memory impairments represent a core cognitive deficit in schizophrenia, predictive of patients’ daily functioning, and one that is unaffected by current treatments. To address this, working memory is included in the MATRICS Consensus Cognitive Battery (MCCB), a standardized cognitive battery designed to facilitate drug development targeting cognitive symptoms. The neurobiology underlying these deficits in MCCB working memory is currently unknown, however, mirroring the poor understanding of working memory deficits in general in schizophrenia. To investigate this neurobiology, 28 subjects with schizophrenia were administered working memory tests from the MATRICS Consensus Cognitive Battery (MCCB) and examined with resting state fMRI. Intrinsic Connectivity Networks were estimated with Independent Components Analysis. Every voxel’s time series was correlated with each network time series, creating a feature vector for voxel-level connectivity analysis. This feature vector was associated with working memory using the Distance Covariance statistic. Results demonstrated that the neurobiology of MCCB working memory tests largely follows the multi-component model of working memory, but revealed unexpected differences. The dorsolateral prefrontal cortex was not associated with working memory. The Central Executive system was instead associated with delocalized Right and Left Executive Control Networks. The Phonologic Loop within the multicomponent model, a subsystem involved in storing linguistic information, was associated with connectivity to the left temporoparietal junction and inferior frontal gyrus. However, connections to the Language Network did not predict working memory test performance. These results provide supporting evidence for the multi-component model of working memory in terms of the biology underlying the MCCB.

Neuroimaging studies using functional magnetic resonance imaging (fMRI), which measures brain activity by detecting the changes in blood oxygenation levels, are advancing our understanding of the pathophysiology of dystonia. Neurobiological disturbances in dystonia, however, may affect neurovascular coupling and impact the interpretability of fMRI studies. We evaluated here whether the hemodynamic response patterns during a behaviorally matched motor task are altered in isolated cervical dystonia (CD). Twenty-five CD patients and 25 healthy controls (HCs) underwent fMRI scanning during a paced finger tapping task (nondystonic task in patients). Imaging data were analyzed using a constrained principal component analysis-a statistical method that combines regression analysis and principal component analysis and enables the extraction of task-related functional networks and determination of the spatial and temporal hemodynamic response patterns associated with the task performance. Data from three patients and two controls were removed due to excessive movement. No significant differences in demographics or motor performance were observed. Three task-associated functional brain networks were identified. During task performance, reduced hemodynamic responses were seen in a sensorimotor network and in a network that included key nodes of the default mode, executive control and visual networks. During rest, reductions in hemodynamic responses were seen in the cognitive/visual network. Lower hemodynamic responses within the primary sensorimotor network in patients were correlated with the increased dystonia severity. Pathophysiological disturbances in isolated CD, such as alterations in inhibitory signaling and dopaminergic neurotransmission, may impact neurovascular coupling. Not accounting for hemodynamic response differences in fMRI studies of dystonia could lead to inaccurate results and interpretations.

Background: There is evidence that the regulation of energy intake (EI) changes with aging. The “anorexia of aging” is defined as the reduction of hunger and EI in late life. Yet, despite decreased EI and weight loss, obesity has also increased among the geriatric population. With few studies in older adults with obesity, we aimed to address this paradox by evaluating age-related differences in appetite regulation. Hypotheses: We hypothesized that there is decreased ad libitum EI in older adults with obesity (OOb) as compared to younger adults with obesity (YOb), related to decreased subjective appetite and eating-related behaviors, and differences in appetite-related peptides. Methods: We performed a cross-sectional pilot study in OOb aged 65-85 years as compared to YOb aged 21-45 years, all with BMI 30-40 kg/m2. Appetite-related ratings and peptides, eating-related behaviors and ad libitum EI in OOb were compared to YOb. Exclusions included comorbidities and medications that affect appetite and weight, tobacco or marijuana use, body weight >300 lbs, or weight loss in the past 6 months. Appetite (Visual Analogue Scales for hunger and satiety) and hormones (ghrelin, peptide YY [PYY] and glucagon-like peptide-1 [GLP-1]) were measured in the fasted state and every 30 minutes for 3 hours following a test breakfast meal. Eating behaviors and ad libitum EI at a lunch meal were also measured. Results: Data from 6 OOb and 15 YOb were analyzed (age 71±3 vs. 35±8 yrs, p

BACKGROUND: Patients diagnosed with schizophrenia (SZs) show atypical activation of the brain’s prefrontal cortex—particularly the dorsolateral prefrontal cortex (DLPFC)—during challenging cognitive tasks. Compared to healthy comparison subjects (HCs), SZs appear to activate a more topographically diffuse region. To better understand the nature of this activation, we modeled functional connectivity between the posterior and anterior regions of the DLPFC, as modulated by cognitive load, while HCs and SZs completed a working memory task. METHODS: Participants were 25 HCs and 27 SZs matched on age and gender. Participants performed a working memory task (N-back) with 5 load conditions (1- through 5-back) while undergoing functional magnetic resonance imaging (fMRI) scans that were sensitive to the blood-oxygen-level dependent (BOLD) signal. Data were analyzed using structural equation modeling. RESULTS: HCs and SZs both showed significantly positive activation of the posterior DLPFC (HC B0 = 0.22, p < .001; SZ B0 = 0.17, p < .001) at 1-back versus baseline. Only SZs showed significantly positive activation of the anterior DLPFC (HC B0 = 0.07, p = .313; SZ B0 = 0.149, p = .025). Within each region, both groups showed significantly positive constant effects of load combined with significantly negative proportional (or autoregressive) effects. However, whereas HCs showed significantly negative proportional effects over load between ROIs (anterior on posterior B1 = -0.83, p < .001; posterior on anterior B1 = -0.66, p = .012), SZs did not (anterior on posterior B1 = 0.01, p = .937; posterior on anterior B1 = -0.47, p = .270). DISCUSSION: Our results indicate that while SZs activate a more topographically diffuse region of the DLPFC—comprising both the posterior and anterior portions—activation in these regions is not functionally connected. The results suggest that diffuse activation of the DLPFC by SZs during challenging cognitive tasks reflects functionally independent processes. Future studies are needed to determine the functional correlates of this atypical activation, as it does not appear to subserve or direct core cognitive control processes that are typically involved in working memory.

Applications of quantitative network analysis to functional brain connectivity have become popular in the last decade due to their ability to describe the general topological principles of brain networks. However, many issues arise when standard statistical analysis techniques are applied to functional magnetic resonance imaging (fMRI) connectivity maps. Frequently, summary measures of these maps, such as global efficiency and clustering coefficients, collapse the changing structures of graph topology from many scales to one. This can result in a loss of whole-brain spatio-temporal pattern information that may be significant in association and prediction analyses. Drawing from the electrical engineering field, the resistance perturbation distance is a quantification of similarity between graphs on the same vertex set that has been shown to identify changes in dynamic graphs, such as those from fMRI, while not being computationally expensive or result in a loss of information. This work proposes a novel kernel-based regression scheme that incorporates the resistance perturbation distance to better understand the association with biological phenotypes from fMRI using both simulated and real datasets.

Bariatric surgery is associated with significant and sustained weight loss and improved metabolic outcomes. It is unclear if weight loss alone is the main mechanism of improved metabolic health. The purpose of this trial was to compare indices of appetite regulation, insulin sensitivity and energy intake (EI) between participants achieving 10 kg of weight loss via Roux‐en‐Y Gastric Bypass (RYGB) or dietary restriction (DIET); intake of a very low calorie liquid diet (800 kcal/d; 40% protein, 40% fat, 20% carbohydrate that matched the post‐RYGB dietary protocol). Adults qualifying for bariatric surgery were studied before and after 10 kg of weight loss (RYGB [n = 6]) or DIET [n = 17]). Appetite (hunger, satiety, and prospective food consumption [PFC]), appetite–related hormones, and metabolites (ghrelin, PYY, GLP‐1, insulin, glucose, free fatty acids [FFA], and triglycerides [TG]) were measured in the fasting state and every 30 min for 180 min following breakfast. Participants were provided lunch to evaluate acute ad libitum EI, which was similarly reduced in both groups from pre to post weight loss. Fasting ghrelin was reduced to a greater extent following RYGB compared to DIET (P = 0.04). Area under the curve (AUC) for ghrelin (P = 0.01), hunger (P

Our objective was to summarize and evaluate the rapidly-expanding body of literature studying functional connectivity in childhood epilepsy. In the self-limited childhood epilepsies, awareness of cognitive comorbidities has been steadily increasing, and recent advances in our understanding of the network effects of these disorders promise insights into the underlying neurobiology. We reviewed publications addressing functional connectivity in children with epilepsy with an emphasis on studies of children with self-limited childhood epilepsies. The majority of studies have been published in the last ten years and predominantly examine childhood epilepsy with centrotemporal spikes and childhood absence epilepsy. Cognitive network alterations are commonly observed across the childhood epilepsies. Some of these effects appear to be nonspecific or epilepsy syndrome or even to category of neurological disorder. Other patterns, such as changes in the connectivity of cortical language areas in childhood epilepsy with centrotemporal spikes, provide clues to the underlying cognitive deficits seen in affected children. The literature to date is dominated by general observations of connectivity patterns without a priori hypotheses. These data-driven studies build an important foundation for hypothesis generation and are already providing useful insights into the neuropathology of the childhood epilepsies. Future work should emphasize hypothesis-driven approaches and rigorous clinical correlations to better understand how the knowledge of network alterations can be applied to guidance and treatment for the children in our clinics.

BACKGROUND: Recent work has implicated disinhibited eating behaviors (DEB) as a potential pathway toward obesity development in children. However, the underlying neurobiology of disinhibited eating behaviors in young, healthy weight children, prior to obesity development, remains unknown. OBJECTIVES: This study tested the relationship between DEB and intrinsic neuronal activity and connectivity in young children without obesity. METHODS: Brain networks implicated in overeating including reward, salience and executive control networks, and the default mode network were investigated. DEB was measured by the Eating in the Absence of Hunger (EAH) paradigm with post-lunch kilocalories consumed from highly palatable foods (EAH kcal) used as the predictor. Intrinsic neuronal activity within and connectivity between specified networks was measured via resting state functional magnetic resonance imaging. Eighteen typically developing children (mean age = 5.8 years) were included. Results: EAH kcal was positively associated with activity of the nucleus accumbens, a major reward network hub (p < 0.05, corrected). EAH kcal was negatively associated with intrinsic prefrontal cortex connectivity to the striatum (p < 0.01, corrected). CONCLUSIONS: These results suggest that neural aspects of DEB are detectable in young children without obesity, providing a potential tool to better understand the development of obesity in this population.

Background PD is associated with disrupted connectivity to a large number of distributed brain regions. How the disease alters the functional topological organization of the brain, however, remains poorly understood. Furthermore, how levodopa modulates network topology in PD is largely unknown. The objective of this study was to use resting-state functional MRI and graph theory to determine how small-world architecture is altered in PD and affected by levodopa administration. Methods Twenty-one PD patients and 20 controls underwent functional MRI scanning. PD patients were scanned off medication and 1 hour after 200 mg levodopa. Imaging data were analyzed using 226 nodes comprising 10 intrinsic brain networks. Correlation matrices were generated for each subject and converted into cost-thresholded, binarized adjacency matrices. Cost-integrated whole-brain global and local efficiencies were compared across groups and tested for relationships with disease duration and severity. Results Data from 2 patients and 4 controls were excluded because of excess motion. Patients off medication showed no significant changes in global efficiency and overall local efficiency, but in a subnetwork analysis did show increased local efficiency in executive (P = 0.006) and salience (P = 0.018) networks. Levodopa significantly decreased local efficiency (P = 0.039) in patients except within the subcortical network, in which it significantly increased local efficiency (P = 0.007). Conclusions Levodopa modulates global and local efficiency measures of small-world topology in PD, suggesting that degeneration of nigrostriatal neurons in PD may be associated with a large-scale network reorganization and that levodopa tends to normalize the disrupted network topology in PD. © 2016 International Parkinson and Movement Disorder Society

Understanding how exercise affects communication across the brain in overweight/obese individuals may provide insight into mechanisms of weight loss and maintenance. In the current study, we examined the effects of a 6-month exercise program in 11 overweight/obese individuals (mean BMI: 33.6±1.4 mg/kg2; mean age: 38.2±3.2 years) on integrative brain “hubs,” which are areas with high levels of connectivity to multiple large-scale networks thought to play an important role in multimodal integration among brain regions. These integrative hubs were identified with a recently developed between-network connectivity (BNC) metric, using functional magnetic resonance imaging (fMRI). BNC utilizes a multiple regression analysis approach to assess relationships between the time series of large-scale functionally-connected brain networks (identified using independent components analysis) and the time series of each individual voxel in the brain. This approach identifies brain regions with high between-network interaction, i.e., areas with high levels of connectivity to many large-scale networks. Changes in BNC following exercise were determined using paired t-tests, with results considered significant at a whole-brain level if they exceeded a voxel-wise threshold of p < 0.01 and cluster-level family-wise error (FWE) correction for multiple comparisons of p < 0.05. Following the intervention, BNC in the posterior cingulate cortex (PCC) was significantly reduced (p < 0.001). The changes driving the observed effects were explored using Granger causality, finding significant reductions in both outgoing causal flow from the PCC to a number of networks (p < 0.05; language network, visual network, sensorimotor network, left executive control network, basal ganglia network, posterior default mode network), in addition to reductions in ingoing causal flow to the PCC from a number of networks (p < 0.05; ventral default mode network, language network, sensorimotor network, basal ganglia network). Change in BNC was related to changes in aerobic fitness level (VO2 max; p = 0.008) and perceived hunger (Three Factor Eating Questionnaire; p = 0.040). Overall, the impact of exercise on communication between large-scale networks may contribute to individual responsivity to exercise.

Although the ketogenic diet has shown promise in a pilot study and case report in schizophrenia, its effects in animal models of hypothesized disease mechanisms are unknown. This study examined effects of treatment with the ketogenic diet on hippocampal P20/N40 gating in DBA/2 mice, a translational endophenotype that mirrors inhibitory deficits in P50 sensory gating in schizophrenia patients. As expected, the diet increased blood ketone levels. Animals with the highest ketone levels showed the lowest P20/N40 gating ratios. These preliminary results suggest that the ketogenic diet may effectively target sensory gating deficits and is a promising area for additional research in schizophrenia.

A substantial body of literature has implicated metabolic health as a significant contributor to cognitive functioning in adults. However, this has not been investigated among young children whose cognitive functions are still developing. Using data from 4 to 6-year-old healthy children participating in the Healthy Start study, an ongoing pre-birth cohort, we tested the hypothesis that current metabolic parameters (fasting glucose, insulin and Homeostatic Model of Assessment for Insulin Resistance [HOMA-IR] levels) are inversely associated with performance on cognitive tasks, measured via the NIH Toolbox cognition battery. Fully corrected T-scores for inhibitory control (Flanker task), cognitive flexibility (Dimensional Change Card Sort test), and language (Picture Vocabulary test) were obtained. General linear models were used to test the associations between child metabolic markers and cognitive test scores. All models were stratified by race/ethnicity (n = 53 non-Hispanic white [NHW]; n = 45 others) and adjusted for APGAR scores at birth. Among NHW children, fasting glucose, insulin, and HOMA-IR were inversely associated with scores for inhibitory control (β = -3.16, β = -4.46; β = -3.90; p Disclosure A.L.B. Shapiro: None. G. Wilkening: None. J.R. Tregellas: None. J. Aalborg: None. B. Ringham: None. A.V. Stamatoiu: None. A. Banning: None. D. Dabelea: None.

The prevalence of obesity among children in the United States is alarming, with recent work implicating disinhibited eating behaviors (DEBs) as a potential pathway toward obesity development. DEBs have been documented among young children, and are associated with longitudinal weight gain. However, the underlying neurobiology of DEBs in young, healthy weight children, prior to obesity development, remains unknown. This study investigated the relationship between DEBs and intrinsic neuronal connectivity in young children. We tested the hypothesis that greater DEBs would be positively associated with higher neuronal connectivity in the default mode network (DMN) and the salience network, and lower connectivity in the executive control network. The Eating in the Absence of Hunger paradigm was implemented to measure DEBs, with post-lunch calories consumed from highly palatable foods used as our main predictor. Resting state functional magnetic resonance imaging was used to examine neuronal connectivity within the networks of interest. Eighteen typically developing, healthy weight children (mean age = 5.8 years; BMI z-score = -0.6) were included in this analytic sample. Independent component analysis was used to isolate brain networks of interest. Associations between calories consumed and the three networks of interest were examined with second-level general linear models. A significant positive association was observed between calories consumed and functional connectivity in anterior cingulate cortex, a major anterior DMN hub (ACC; x=-6, y=14, z=41; t=5.23; p < 0.01, corrected). No other associations were significant. While preliminary, our results are consistent with previous studies in adults relating both DEBs and obesity status to altered neuronal response in the ACC. Our data suggest that aspects of the neurobiology of DEB are detectable in young, healthy weight children, providing a potential tool to better understand the development of obesity in this population. Disclosure A.L.B. Shapiro: None. S.L. Johnson: None. B. Mohl: None. G. Wilkening: None. K.T. Legget: None. D. Dabelea: None. J.R. Tregellas: None.

Although nicotine has been shown to improve attention deficits in schizophrenia, the neurobiological mechanisms underlying this effect are poorly understood. We hypothesized that nicotine would modulate attention-associated neuronal response in schizophrenia patients in the ventral parietal cortex (VPC), hippocampus, and anterior cingulate based on previous findings in control subjects. To test this hypothesis, the present study examined response in these regions in a cohort of nonsmoking patients and healthy control subjects using an auditory selective attention task with environmental noise distractors during placebo and nicotine administration. In agreement with our hypothesis, significant diagnosis (Control vs. Patient) X drug (Placebo vs. Nicotine) interactions were observed in the VPC and hippocampus. The interaction was driven by task-associated hyperactivity in patients (relative to healthy controls) during placebo administration, and decreased hyperactivity in patients after nicotine administration (relative to placebo). No significant interaction was observed in the anterior cingulate. Task-associated hyperactivity of the VPC predicted poor task performance in patients during placebo. Poor task performance also predicted symptoms in patients as measured by the Brief Psychiatric Rating Scale. These results are the first to suggest that nicotine may modulate brain activity in a selective attention-dependent manner in schizophrenia.

Developing translational biomarkers is a priority for psychiatry research. Task-independent functional brain imaging is a relatively novel technique that allows examination of the brain’s intrinsic networks, defined as functionally and (often) structurally connected populations of neurons whose properties reflect fundamental neurobiological organizational principles of the central nervous system. The ability to study the activity and organization of these networks has opened a promising new avenue for translational investigation, because they can be analogously examined across species and disease states. Interestingly, imaging studies have revealed shared spatial and functional characteristics of the intrinsic network architecture of the brain across species, including mice, rats, non-human primates, and humans. Using schizophrenia as an example, we show how intrinsic networks may show similar abnormalities in human diseases and animal models of these diseases, supporting their use as biomarkers in drug development.

Compared with healthy individuals, patients with schizophrenia had greater resting state hippocampal activity that was inversely related to schizophrenia symptoms and cognitive deficits, indicating a possible brain biomarker for developing cognitive therapies in schizophrenia.

Despite high rates of marijuana abuse in schizophrenia, the physiological interactions between tetrahydrocannabinol (THC) and antipsychotic medications are poorly understood. A well-characterized feature of schizophrenia is poor gating of the P50 auditory-evoked potential. This feature has been translationally modeled by the DBA/2 mouse, which exhibits poor suppression of the P20-N40 AEP, the rodent analog of the human P50. Previous work has demonstrated that this deficit is reversed by the antipsychotic clozapine. It is unknown, however, if this effect is altered by THC administration. Using a conditioning-testing paradigm with paired auditory stimuli, the effects of clozapine and dronabinol (a pharmaceutical THC formulation) on inhibitory P20-N40 AEP processing were assessed from in vivo hippocampal CA3 recordings in anesthetized DBA/2 mice. The effects of clozapine (0.33 mg/kg) and dronabinol (10 mg/kg) were assessed alone and in combination (0.33, 1 or 1.83 mg/kg clozapine with 10mg/kg dronabinol). Improved P20-N40 AEP gating was observed after acute administration of 0.33 mg/kg clozapine. Co-injection of 0.33 mg/kg clozapine and 10 mg/kg THC, however, did not improve gating relative to baseline. This effect was overcome by higher doses of clozapine (1 and 1.83 mg/kg), as these doses improved gating relative to baseline in the presence of 10 mg/kg THC. 10 mg/kg THC alone did not affect gating. In conclusion, THC does not prevent improvement of P20-N40 gating by clozapine.

a b s t r a c t Background: Adolescents with conduct disorder (CD) and substance use disorders (SUD) experience dif- ficulty evaluating and regulating their behavior in anticipation of future consequences. Given the role of the brain's default mode network (DMN) in self-reflection and future thought, this study investigates whether DMN is altered in adolescents with CD and SUD, relative to controls. Methods: Twenty adolescent males with CD and SUD and 20 male controls of similar ages underwent functional magnetic resonance imaging as they completed a risk-taking decision task. We used indepen- dent component analysis as a data-driven approach to identify the DMN spatial component in individual subjects. DMN activity was then compared between groups. Results: Compared to controls, patients showed reduced activity in superior, medial and middle frontal gyrus (Brodmann area (BA) 10), retrosplenial cortex (BA 30) and lingual gyrus (BA 18), and bilateral middle temporal gryus (BA 21/22) - DMN regions thought to support self-referential evaluation, memory, foresight, and perspective taking. Furthermore, this pattern of reduced activity in patients remained robust after adjusting for the effects of depression and attention-deficit hyperactivity disorder (ADHD). Conversely, when not adjusting for effects of depression and ADHD, patients demonstrated greater DMN activity than controls solely in the cuneus (BA 19). Conclusions: Collectively, these results suggest that comorbid CD and SUD in adolescents is characterized by atypical activity in brain regions thought to play an important role in introspective processing. These functional imbalances in brain networks may provide further insight into the neural underpinnings of conduct and substance use disorders.

Thorough analysis of translational endophenotypes is needed to improve therapeutic development in schizophrenia. Abnormal sensory gating, one such endophenotype, is associated with reduced expression of the α7 nicotinic receptor. However, typical gating measures such as the P50 evoked response are often low-pass filtered, and it is unclear how α7 expression affects gating at higher frequencies. Therefore, this study used time-frequency analysis to compare sensory gating at the beta and gamma frequencies between human patients and healthy controls as well as between α7 heterozygote mutant mice and wild-type. Gating of total beta (15–26 Hz) and gamma (30–50 Hz) power during paired clicks was assessed from mouse in vivo hippocampal CA3 recordings. Gating was also assessed in schizophrenia patients and healthy controls using electroencephalography. Relative to wild-type, α7 heterozygote mice showed impaired gating of total beta and gamma power. Similarly, relative to controls, patients showed impaired gating of total beta and gamma power. Poor beta gating was associated with negative symptoms. These results demonstrate that schizophrenia patients and α7 heterozygote mice show similar deficits in gating high frequency power. Time-frequency analysis of beta and gamma gating may thus be a translational method of assessing the genetic basis of gating deficits in schizophrenia.

Despite the common use of exercise as a weight loss strategy, little is known about its neuronal effects, and how these may be related to cognitive changes that impact food intake. The current study assessed the effects of a 6-month exercise intervention on intrinsic activity in the default mode network (DMN), a functionally connected network of brain regions including posterior cingulate cortex, cuneus/precuneus, medial prefrontal cortex, medial temporal lobe, and inferior parietal cortices, and salience network, which includes the anterior cingulate cortex and insula. Resting-state functional magnetic resonance imaging (fMRI) data were acquired in 12 overweight/obese individuals. The intervention was associated with a reduction in DMN activity in the precuneus (p=0.003, FWE-corrected), which was associated with greater fat mass loss (p=0.013) as well as reduced perceived hunger (Three Factor Eating Questionnaire, p=0.024) and hunger ratings in response to a meal (p=0.013). No changes were observed in the salience network in response to the exercise intervention. The association between DMN change and both fat mass loss and reduction of hunger ratings suggests that DMN function may be involved in the regulation of food intake behaviors. Given previous reports of DMN overactivity in overweight/obese individuals, the present findings may indicate an exercise-related “normalization” of network function.

While the majority of Americans are now overweight, some individuals maintain their weight with minimal effort. This study investigated behavioral differences between 58 individuals recruited as either obese-resistant (OR) or obese-prone (OP) based on self-identification, BMI, and personal/family weight history. Subjects were studied during Eucaloric (EU), Overfed (OF), and Underfed (UF) phases which included a run-in diet, 1 day intervention diet, and a study day. At baseline, subjects completed the Three Factor Eating Questionnaire (TFEQ) and Power of Food Scale (PFS). On the study day, ratings of appetite, food appeal and desire, and food cravings were performed in response to a breakfast shake. OF resulted in reduced hunger and food desire while UF resulted in increased hunger and food appeal and desire. While hunger did not differ between groups, OP had higher scores for TFEQ measures (hunger, restraint and disinhibition), higher "hedonic hunger" as measured by the PFS, and greater food cravings and ratings of food appeal and desire. These results suggest that subjective hunger and desire for food change significantly after only one day of over- or underfeeding. Additionally, we found several behavioral differences between groups that are likely to promote weight gain over time in the OP.

Patients with schizophrenia frequently report difficulties paying attention during important tasks, because they are distracted by noise in the environment. The neurobiological mechanism underlying this problem is, however, poorly understood. The goal of this study was to determine if early sensory processing deficits contribute to sensitivity to distracting noise in schizophrenia. To that end, we examined the effect of environmentally relevant distracting noise on performance of an attention task in 19 patients with schizophrenia and 22 age and gender-matched healthy comparison subjects. Using electroencephalography, P50 auditory gating ratios also were measured in the same subjects and were examined for their relationship to noise-induced changes in performance on the attention task. Positive symptoms also were evaluated in patients. Distracting noise caused a greater increase in reaction time in patients, relative to comparison subjects, on the attention task. Higher P50 auditory gating ratios also were observed in patients. P50 gating ratio significantly correlated with the magnitude of noise-induced increase in reaction time. Noise-induced increase in reaction time was associated with delusional thoughts in patients. P50 ratios were associated with delusional thoughts and hallucinations in patients. In conclusion, the observation of noise effects on attention in patients is consistent with subjective reports from patients. The observed relationship between noise effects on reaction time and P50 auditory gating supports the hypothesis that early inhibitory processing deficits may contribute to susceptibility to distraction in the illness.