Nicotine Increases Activation to Anticipatory Valence Cues in Anterior Insula and Striatum.

Introduction: Smoking is associated with significant morbidity and mortality. Understanding the neurobiology of the rewarding effects of nicotine promises to aid treatment development for nicotine dependence. Through its actions on mesolimbic dopaminergic systems, nicotine engenders enhanced responses to drug-related cues signaling rewards, a mechanism hypothesized to underlie the development and maintenance of nicotine addiction. Methods: We evaluated the effects of acute nicotine on neural responses to anticipatory cues signaling (nondrug) monetary reward or loss among 11 nonsmokers who had no prior history of tobacco smoking. In a double-blind, crossover design, participants completed study procedures while wearing nicotine or placebo patches at least 1 week apart. In each drug condition, participants underwent functional magnetic resonance imaging while performing the monetary incentive delay task and performed a probabilistic monetary reward task, probing reward responsiveness as measured by response bias toward a more frequently rewarded stimulus. Results: Nicotine administration was associated with enhanced activation, compared with placebo, of right fronto-anterior insular cortex and striatal regions in response to cues predicting possible rewards or losses and to dorsal anterior cingulate for rewards. Response bias toward rewarded stimuli correlated positively with insular activation to anticipatory cues. Conclusion: Nicotinic enhancement of monetary reward-related brain activation in the insula and striatum in nonsmokers dissociated acute effects of nicotine from effects on reward processing due to chronic smoking. Reward responsiveness predicted a greater nicotinic effect on insular activation to salient stimuli. Implications: Previous research demonstrates that nicotine enhances anticipatory responses to rewards in regions targeted by midbrain dopaminergic systems. The current study provides evidence that nicotine also enhances responses to rewards and losses in the anterior insula. A previous study found enhanced insular activation to rewards and losses in smokers and ex-smokers, a finding that could be due to nicotine sensitization or factors related to current or past smoking. Our finding of enhanced anterior insula response after acute administration of nicotine in nonsmokers provides support for nicotine-induced sensitization of insular response to rewards and losses.

Lower gray matter density and functional connectivity in the anterior insula in smokers compared with never smokers.

Although nicotine addiction is characterized by both structural and functional abnormalities in brain networks involved in salience and cognitive control, few studies have integrated these data to understand how these abnormalities may support addiction. This study aimed to (1) evaluate gray matter density and functional connectivity of the anterior insula in cigarette smokers and never smokers and (2) characterize how differences in these measures were related to smoking behavior. We compared structural magnetic resonance imaging (MRI) (gray matter density via voxel-based morphometry) and seed-based functional connectivity MRI data in 16 minimally deprived smokers and 16 matched never smokers. Compared with controls, smokers had lower gray matter density in left anterior insula extending into inferior frontal and temporal cortex. Gray matter density in this region was inversely correlated with cigarettes smoked per day. Smokers exhibited negative functional connectivity (anti-correlation) between the anterior insula and regions involved in cognitive control (left lPFC) and semantic processing/emotion regulation (lateral temporal cortex), whereas controls exhibited positive connectivity between these regions. There were differences in the anterior insula, a central region in the brain's salience network, when comparing both volumetric and functional connectivity data between cigarette smokers and never smokers. Volumetric data, but not the functional connectivity data, were also associated with an aspect of smoking behavior (daily cigarettes smoked).

From palm to practice: prescription digital therapeutics for mental and brain health at the National Institutes of Health.

Prescription Digital Therapeutics (PDTs) are emerging as promising tools for treating and managing mental and brain health conditions within the context of daily life. This commentary distinguishes PDTs from other Software as Medical Devices (SaMD) and explores their integration into mental and brain health treatments. We focus on research programs and support from the National Institutes of Health (NIH), discussing PDT research supported by the NIH's National Institute on Child Health and Development (NICHD), National Institute of Mental Health (NIMH), and National Institute on Aging (NIA). We present a hierarchical natural language processing topic analysis of NIH-funded digital therapeutics research projects. We delineate the PDT landscape across different mental and brain health disorders while highlighting opportunities and challenges. Additionally, we discuss the research foundation for PDTs, the unique therapeutic approaches they employ, and potential strategies to improve their validity, reliability, safety, and effectiveness. Finally, we address the research and collaborations necessary to propel the field forward, ultimately enhancing patient care through innovative digital health solutions.

National Institute on Aging's 50th Anniversary: Advancing Cognitive Aging Research and the Cognitive Health of Older Adults.

In celebration of the National Institute on Aging's (NIA) 50th anniversary, this paper highlights the significant advances in cognitive aging research and the promotion of cognitive health among older adults. Since its inception in 1974, the NIA has played a pivotal role in understanding cognitive aging, including cognitive epidemiology, interventions, and methods, for measuring cognitive change. Key milestones include the shift toward understanding cognitive impairment and Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD), the development of large-scale longitudinal studies, and the incorporation of AD/ADRD-related biomarkers in cognitive aging cohorts. Additionally, NIA has championed diversifying the scientific workforce through initiatives, such as the Resource Centers for Minority Aging Research and the Butler-Williams Scholars Program. The next 50 years will continue to emphasize the importance of inclusion, innovation, and impactful research to enhance the cognitive health and well-being of older adults.

Lower hippocampal volume predicts decrements in lane control among drivers with amnestic mild cognitive impairment.

OBJECTIVES: There are few methods to discern driving risks in patients with early dementia and mild cognitive impairment (MCI). We aimed to determine whether structural magnetic resonance imaging (MRI) of the hippocampus-a biomarker of probable Alzheimer pathology and a measure of disease severity in those affected--is linked to objective ratings of on-road driving performance in older adults with and without amnestic MCI. METHODS: In all, 49 consensus-diagnosed participants from an Alzheimer's Disease Research Center (15 diagnosed with amnestic MCI and 34 demographically similar controls) underwent structural MRI and on-road driving assessments. RESULTS: Mild atrophy of the left hippocampus was associated with less-than-optimal ratings in lane control but not with other discrete driving skills. Decrements in left hippocampal volume conferred higher risk for less-than-optimal lane control ratings in the patients with MCI (B = -1.63, standard error [SE] = .74, Wald = 4.85, P = .028), but not in controls (B = 0.13, SE = .415, Wald = 0.10, P = .752). The odds ratio and 95% confidence interval for below-optimal lane control in the MCI group was 4.41 (1.18-16.36), which was attenuated to 3.46 (0.88-13.60) after accounting for the contribution of left hippocampal volume. CONCLUSION: These findings suggest that there may be a link between hippocampal atrophy and difficulties with lane control in persons with amnestic MCI. Further study appears warranted to better discern patterns of brain atrophy in MCI and Alzheimer disease and whether these could be early markers of clinically meaningful driving risk.

The NIH Science of Behavior Change Program: Looking Toward the Future.

The National Institutes of Health established the Science of Behavior Change (SOBC) program to promote basic research on the initiation, personalization, and maintenance of health behavior change. The SOBC Resource and Coordinating Center now leads and supports activities to maximize the creativity, productivity, scientific rigor, and dissemination of the experimental medicine approach and experimental design resources. Here, we highlight those resources, including the Checklist for Investigating Mechanisms in Behavior-change Research (CLIMBR) guidelines introduced in this special section. We describe the ways in which SOBC can be applied across a range of domains and contexts, and end by considering ways to extend SOBC's perspective and reach, so as to best promote behavior change linked with health, quality of life, and well-being.

fMRI reactivity on a delay discounting task predicts weight gain in obese women.

Obesity can be accompanied by abnormalities in executive function and related neural circuitry. A useful task for studying executive function is delay discounting (DD), in which an individual chooses between sooner and delayed, but greater, amounts of money or other commodities. We previously found that obese compared to normal-weight women made more immediate choices on a monetary DD task, or had greater delay discounting. In the present study, we performed functional magnetic resonance imaging (fMRI) of obese women during performance of a DD of money task. Confirming the results of previous studies, we found that more difficult compared to easy DD trials resulted in activation in putative executive function areas of the brain, the middle and inferior frontal gyri, and medial prefrontal cortex. Most interestingly, we also found that less activation in executive function areas such as the inferior, middle, and superior frontal gyri on difficult vs. easy DD trials predicted a greater rate of weight gain over the subsequent 1.3-2.9 years. These results suggest that suboptimal functioning of executive function areas such as prefrontal cortex contributes to the progression of obesity.

Momentary Influences on Self-Regulation in Two Populations With Health Risk Behaviors: Adults Who Smoke and Adults Who Are Overweight and Have Binge-Eating Disorder.

Introduction: Self-regulation has been implicated in health risk behaviors and is a target of many health behavior interventions. Despite most prior research focusing on self-regulation as an individual-level trait, we hypothesize that self-regulation is a time-varying mechanism of health and risk behavior that may be influenced by momentary contexts to a substantial degree. Because most health behaviors (e.g., eating, drinking, smoking) occur in the context of everyday activities, digital technologies may help us better understand and influence these behaviors in real time. Using a momentary self-regulation measure, the current study (which was part of a larger multi-year research project on the science of behavior change) used ecological momentary assessment (EMA) to assess if self-regulation can be engaged and manipulated on a momentary basis in naturalistic, non-laboratory settings. Methods: This one-arm, open-label exploratory study prospectively collected momentary data for 14 days from 104 participants who smoked regularly and 81 participants who were overweight and had binge-eating disorder. Four times per day, participants were queried about momentary self-regulation, emotional state, and social and environmental context; recent smoking and exposure to smoking cues (smoking sample only); and recent eating, binge eating, and exposure to binge-eating cues (binge-eating sample only). This study used a novel, momentary self-regulation measure comprised of four subscales: momentary perseverance, momentary sensation seeking, momentary self-judgment, and momentary mindfulness. Participants were also instructed to engage with Laddr, a mobile application that provides evidence-based health behavior change tools via an integrated platform. The association between momentary context and momentary self-regulation was explored via mixed-effects models. Exploratory assessments of whether recent Laddr use (defined as use within 12 h of momentary responses) modified the association between momentary context and momentary self-regulation were performed via mixed-effects models. Results: Participants (mean age 35.2; 78% female) in the smoking and binge-eating samples contributed a total of 3,233 and 3,481 momentary questionnaires, respectively. Momentary self-regulation subscales were associated with several momentary contexts, in the combined as well as smoking and binge-eating samples. For example, in the combined sample momentary perseverance was associated with location, positively associated with positive affect, and negatively associated with negative affect, stress, and tiredness. In the smoking sample, momentary perseverance was positively associated with momentary difficulty in accessing cigarettes, caffeine intake, and momentary restraint in smoking, and negatively associated with temptation and urge to smoke. In the binge-eating sample, momentary perseverance was positively associated with difficulty in accessing food and restraint in eating, and negatively associated with urge to binge eat. While recent Laddr use was not associated directly with momentary self-regulation subscales, it did modify several of the contextual associations, including challenging contexts. Conclusions: Overall, this study provides preliminary evidence that momentary self-regulation may vary in response to differing momentary contexts in samples from two exemplar populations with risk behaviors. In addition, the Laddr application may modify some of these relationships. These findings demonstrate the possibility of measuring momentary self-regulation in a trans-diagnostic way and assessing the effects of momentary, mobile interventions in context. Health behavior change interventions may consider measuring and targeting momentary self-regulation in addition to trait-level self-regulation to better understand and improve health risk behaviors. This work will be used to inform a later stage of research focused on assessing the transdiagnostic mediating effect of momentary self-regulation on medical regimen adherence and health outcomes. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT03352713.

Cognitive function among older adults with diabetes and prediabetes, NHANES 2011-2014.

AIMS: To determine the association between diabetes status, glycemia, and cognitive function among a national U.S. sample of older adults in the 2011-2014 National Health and Nutrition Examinations Surveys. METHODS: Among 1,552 adults age ≥ 60 years, linear and multivariable logistic regressions were used to determine the association between diabetes status (diabetes, prediabetes, normoglycemia) and cognitive function [Consortium to Establish a Registry for Alzheimer's Disease-Word Learning (CERAD W-L), Animal Fluency test, Digit Symbol Substitution Test (DSST)]. RESULTS: Overall, diabetes was associated with mild cognitive dysfunction. In age-adjusted models, adults with diabetes had significantly poorer performance on the delayed and total word recalls (CERAD W-L) compared to those with normoglycemia (5.8 vs. 6.8 words; p = 0.002 and 24.5 vs. 27.6 words; p < 0.001, respectively); the association was non-significant after adjusting for cardiovascular disease. Among all adults, cognitive function scores decreased with increasing HbA1c for all assessments, but remained significant in the fully adjusted model for the Animal Fluency and DSST [beta coefficient = -0.44;-1.11, p < 0.05, respectively]. As measured by the DSST, the proportion with cognitive impairment was significantly higher for older adults with HbA1c ≥ 8.0% (≥64 mmol/mol) vs. HbA1c < 7.0% (<53 mmol/mol) (14.6% vs. 6.3%, p = 0.04). CONCLUSIONS: Dysglycemia, as measured by HbA1c, was associated with poorer executive function and processing speed.

Core Neuropsychological Measures for Obesity and Diabetes Trials: Initial Report.

Obesity and diabetes are known to be related to cognitive abilities. The Core Neuropsychological Measures for Obesity and Diabetes Trials Project aimed to identify the key cognitive and perceptual domains in which performance can influence treatment outcomes, including predicting, mediating, and moderating treatment outcome and to generate neuropsychological batteries comprised of well-validated, easy-to-administer tests that best measure these key domains. The ultimate goal is to facilitate inclusion of neuropsychological measures in clinical studies and trials so that we can gather more information on potential mediators of obesity and diabetes treatment outcomes. We will present the rationale for the project and three options for the neuropsychological batteries to satisfy varying time and other administration constraints. Future directions are discussed. Preprint version of the document is available at https://osf.io/preprints/nutrixiv/7jygx/.

Corrigendum: Core Neuropsychological Measures for Obesity and Diabetes Trials: Initial Report.

[This corrects the article DOI: 10.3389/fpsyg.2020.554127.].

Resting-State Brain Connectivity Predicts Weight Loss and Cognitive Control of Eating Behavior After Vertical Sleeve Gastrectomy.

OBJECTIVE: The effects of sleeve gastrectomy (SG) on functional connectivity (FC) and associations with weight loss and eating-related cognitive control were investigated. METHODS: In a longitudinal study, 14 SG patients (13 female; 42.1 presurgery BMI) completed study visits 1 month pre surgery and 12 months post surgery. Patients completed the Dutch Eating Behavior Questionnaire and resting-state functional magnetic resonance imaging scanning to measure FC. Data were analyzed using a seed-to-voxel approach in the CONN Toolbox to investigate pre-/postsurgery changes (n = 12) and to conduct predictive analysis (n = 14). RESULTS: Seed-to-voxel analysis revealed changes in magnitude (decreases) and directionality (positively correlated to anticorrelated) of FC pre to post surgery within and between default mode network, salience network, and frontoparietal network nodes [Family-Wise Error (FWE) corrected at P < 0.05]. Baseline FC of the nucleus accumbens (with insula) and hypothalamus (with precentral gyrus) predicted 12-month post-SG % total weight loss (FWE-P < 0.05). Baseline FC of the hippocampus, frontoparietal network, and default mode network nodes predicted improvement in cognitive control of eating behavior 12 months after SG (FWE-P < 0.05). CONCLUSIONS: Our findings demonstrate changes in FC magnitude and directionality post versus pre surgery within and between resting-state networks and frontal, paralimbic, and visual areas in SG patients. Baseline FC predicted weight loss and changes in cognitive control of food intake behavior at 12 months. These could serve as predictive biomarkers for bariatric surgery.

Peptide YY levels are associated with appetite suppression in response to long-chain fatty acids.

Release of peptide YY(3-36) (PYY(3-36)) has been proposed to contribute to postprandial satiety. Using a randomized, double-blind design, we examined the effects of a 417 kcal beverage with 95% of the calories from long-chain fatty acids compared to a 21 kcal lipid-free control beverage on the temporal profiles of total plasma PYY levels and appetite ratings in 12 normal-weight human subjects. Ratings were taken before ingestion of the beverage and 15, 30, 60, 120, and 180 min later. Blood samples were taken from the subjects when ratings were made. The lipid beverage increased plasma PYY relative to the control beverage at 60-180 min after ingestion. Subjects were divided into High and Low PYY groups (N=6 in each group) on the basis of a median split. In the High PYY group, the lipid beverage was more effective in suppressing hunger and enhancing satiety than in the Low PYY group, in which the lipid beverage had no effects on appetite. Within the High PYY group, changes in mean relative hunger suppression (changes in hunger specifically attributable to the lipid load) across the 3-h test closely paralleled changes in plasma PYY after ingestion of the lipid beverage relative to the control beverage. The close temporal correspondence between these variables supports the proposed role of this peptide in the intermediate-term control of intake, possibly acting to regulate appetite during the intermeal interval.

Nicotine-induced activation of caudate and anterior cingulate cortex in response to errors in schizophrenia.

BACKGROUND: Nicotine improves attention and processing speed in individuals with schizophrenia. Few studies have investigated the effects of nicotine on cognitive control. Prior functional magnetic resonance imaging (fMRI) research demonstrates blunted activation of dorsal anterior cingulate cortex (dACC) and rostral anterior cingulate cortex (rACC) in response to error and decreased post-error slowing in schizophrenia. METHODS: Participants with schizophrenia (n = 13) and healthy controls (n = 12) participated in a randomized, placebo-controlled, crossover study of the effects of transdermal nicotine on cognitive control. For each drug condition, participants underwent fMRI while performing the stop signal task where participants attempt to inhibit prepotent responses to "go (motor activation)" signals when an occasional "stop (motor inhibition)" signal appears. Error processing was evaluated by comparing "stop error" trials (failed response inhibition) to "go" trials. Resting-state fMRI data were collected prior to the task. RESULTS: Participants with schizophrenia had increased nicotine-induced activation of right caudate in response to errors compared to controls (DRUG × GROUP effect: p corrected < 0.05). Both groups had significant nicotine-induced activation of dACC and rACC in response to errors. Using right caudate activation to errors as a seed for resting-state functional connectivity analysis, relative to controls, participants with schizophrenia had significantly decreased connectivity between the right caudate and dACC/bilateral dorsolateral prefrontal cortices. CONCLUSIONS: In sum, we replicated prior findings of decreased post-error slowing in schizophrenia and found that nicotine was associated with more adaptive (i.e., increased) post-error reaction time (RT). This proof-of-concept pilot study suggests a role for nicotinic agents in targeting cognitive control deficits in schizophrenia.

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums.

Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs. Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia. In addition, we define the concept of 'brain insulin resistance' and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance. Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs. By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike.

Applying novel technologies and methods to inform the ontology of self-regulation.

Self-regulation is a broad construct representing the general ability to recruit cognitive, motivational and emotional resources to achieve long-term goals. This construct has been implicated in a host of health-risk behaviors, and is a promising target for fostering beneficial behavior change. Despite its clear importance, the behavioral, psychological and neural components of self-regulation remain poorly understood, which contributes to theoretical inconsistencies and hinders maximally effective intervention development. We outline a research program that seeks to define a neuropsychological ontology of self-regulation, articulating the cognitive components that compose self-regulation, their relationships, and their associated measurements. The ontology will be informed by two large-scale approaches to assessing individual differences: first purely behaviorally using data collected via Amazon's Mechanical Turk, then coupled with neuroimaging data collected from a separate population. To validate the ontology and demonstrate its utility, we will then use it to contextualize health risk behaviors in two exemplar behavioral groups: overweight/obese adults who binge eat and smokers. After identifying ontological targets that precipitate maladaptive behavior, we will craft interventions that engage these targets. If successful, this work will provide a structured, holistic account of self-regulation in the form of an explicit ontology, which will better clarify the pattern of deficits related to maladaptive health behavior, and provide direction for more effective behavior change interventions.

Psychological and neural contributions to appetite self-regulation.

OBJECTIVE: This paper reviews the state of the science on psychological and neural contributions to appetite self-regulation in the context of obesity. METHODS: Three content areas (neural systems and cognitive functions; parenting and early childhood development; and goal setting and goal striving) served to illustrate different perspectives on the psychological and neural factors that contribute to appetite dysregulation in the context of obesity. Talks were initially delivered at an NIH workshop consisting of experts in these three content areas, and then content areas were further developed through a review of the literature. RESULTS: Self-regulation of appetite involves a complex interaction between multiple domains, including cognitive, neural, social, and goal-directed behaviors and decision-making. Self-regulation failures can arise from any of these factors, and the resulting implications for obesity should be considered in light of each domain. In some cases, self-regulation is amenable to intervention; however, this does not appear to be universally true, which has implications for both prevention and intervention efforts. CONCLUSIONS: Appetite regulation is a complex, multifactorial construct. When considering its role in the obesity epidemic, it is advisable to consider its various dimensions together to best inform prevention and treatment efforts.

Complex mechanisms linking neurocognitive dysfunction to insulin resistance and other metabolic dysfunction.

Scientific evidence has established several links between metabolic and neurocognitive dysfunction, and epidemiologic evidence has revealed an increased risk of Alzheimer's disease and vascular dementia in patients with diabetes. In July 2015, the National Institute of Diabetes, Digestive, and Kidney Diseases gathered experts from multiple clinical and scientific disciplines, in a workshop entitled "The Intersection of Metabolic and Neurocognitive Dysfunction", to clarify the state-of-the-science on the mechanisms linking metabolic dysfunction, and insulin resistance and diabetes in particular, to neurocognitive impairment and dementia. This perspective is intended to serve as a summary of the opinions expressed at this meeting, which focused on identifying gaps and opportunities to advance research in this emerging area with important public health relevance.