Significant Decrease in Alcohol Use Disorder Symptoms Secondary to Semaglutide Therapy for Weight Loss: A Case Series.

Objective: Despite being a major cause of preventable death worldwide, alcohol use disorder (AUD) currently has only 3 FDA-approved pharmacotherapies. The glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide has shown promise in preclinical studies for reducing alcohol consumption, but there are currently no randomized clinical trials that associate a decline in AUD symptoms with semaglutide use. This case series presents 6 patients with positive AUD screenings who were treated with semaglutide for weight loss. All subsequently exhibited significant improvement in AUD symptoms.Methods: Retrospective chart review was utilized to identify patients treated with semaglutide for weight loss who also had positive screenings for AUD on the Alcohol Use Disorder Identification Test (AUDIT; score > 8 considered positive) prior to initiation of semaglutide therapy. Six patients were identified who met these criteria. A paired t test was utilized to compare initial AUDIT scores with AUDIT scores after initiation of semaglutide therapy.Results: All 6 identified patients (100%) had significant reduction in AUD symptomatology based on AUDIT score improvement following treatment with semaglutide (mean decrease of 9.5 points, P < .001).Conclusions: This case series is consistent with preclinical data and suggests that GLP-1RAs have strong potential in the treatment of AUD. Additional randomized, placebo-controlled clinical studies are needed to fully assess the efficacy of semaglutide in treating AUD.

Successful treatment of binge eating disorder with the GLP-1 agonist semaglutide: A retrospective cohort study.

Objective: Binge eating disorder (BED) is the most common eating disorder, and yet only one pharmacotherapy (lisdexamfetamine), which has known abuse-potential, is FDA-approved. Topiramate is also commonly prescribed off-label for binge eating but has many contraindications. In contrast, the glucagon-like peptide-1 (GLP1) analog semaglutide has profound effects on central satiety signaling leading to reduced food intake, and has been approved for the treatment of obesity based on its efficacy and safety profile. Semaglutide would thus seem to be a potential candidate for the treatment of BED. Methods: This open-label study examined the effects of semaglutide on Binge Eating Scale (BES) scores in individuals with BED. Patients were divided into three groups: those prescribed semaglutide, those prescribed either lisdexamphetamine or topiramate, and those prescribed a combination of semaglutide with lisdexamphetamine or topiramate. Results: Patients receiving semaglutide only exhibited greater reductions in BES scores compared to the other groups. Combined pharmacotherapy with both semaglutide and the other anti-obesity medications did not result in greater reductions in BES scores compared to the semaglutide-only group. Findings were similar in patients with moderate/severe BED, as well as the full sample. Conclusion: The therapeutic effects of semaglutide in binge eating disorder warrant further investigation.

Dietary fat restriction affects brain reward regions in a randomized crossover trial.

BACKGROUNDWeight-loss diets often target dietary fat or carbohydrates, macronutrients that are sensed via distinct gut-brain pathways and differentially affect peripheral hormones and metabolism. However, the effects of such diet changes on the human brain are unclear. METHODSWe investigated whether selective isocaloric reductions in dietary fat or carbohydrates altered dopamine D2/3 receptor binding potential (D2BP) and neural activity in brain-reward regions in response to visual food cues in 17 inpatient adults with obesity as compared with a eucaloric baseline diet using a randomized crossover design. RESULTSOn the fifth day of dietary fat restriction, but not carbohydrate restriction, both D2BP and neural activity to food cues were decreased in brain-reward regions. After the reduced-fat diet, ad libitum intake shifted toward foods high in both fat and carbohydrates. CONCLUSIONThese results suggest that dietary fat restriction increases tonic dopamine in brain-reward regions and affects food choice in ways that may hamper diet adherence. TRIAL REGISTRATIONClinicalTrials.gov NCT00846040 FUNDING. NIDDK 1ZIADK013037.

Aberrant gastric functioning in weight-restored but not acute restricting-type anorexia nervosa: An electrogastrography study.

OBJECTIVE: Individuals with anorexia nervosa (AN) have high levels of gastrointestinal (GI) symptoms, functional GI disorders, and alterations in interoception. The primary aims of the current study were to determine (1) whether individuals with AN differed in gastric physiology as measured by electrogastrography (EGG) as compared to healthy individuals and (2) whether their EGG activity changed from pre- to post-weight restoration. METHOD: Adolescent and young adult females receiving inpatient treatment for restricting-type AN (n = 20) and healthy control females (n = 21) completed two EGG sessions, with measurements taken in fasting state and after administration of a water load. Participants with AN completed the first session while underweight and the second session following weight restoration. Healthy control participants also completed two sessions matched for length of time between sessions. RESULTS: Participants with AN exhibited decreased normogastria post-water load when they were weight restored compared to when they were underweight. Healthy control participants' EGG measures were stable across sessions. DISCUSSION: Findings provide evidence for aberrant gastric physiology in individuals with AN who have been weight restored, but not those in the acute phase of the illness. This supports the need for further research on GI functioning in AN. PUBLIC SIGNIFICANCE: Anorexia nervosa (AN) is a highly debilitating eating disorder that is difficult to treat. The causes of AN are largely unknown, but some theories suggest problems in gastrointestinal functioning may contribute to the disorder. This study found aberrant gastric functioning in individuals diagnosed with AN after weight restoration treatment. These findings contribute to our understanding of the causes and maintenance of AN and may ultimately lead to better treatments.

Effects of Parent Emotion Socialization on the Neurobiology Underlying Adolescent Emotion Processing: A Multimethod fMRI Study.

Parents' emotion socialization (ES) practices impact socioemotional development throughout adolescence. Little is known, however, regarding the neurobiology underlying these effects. This study used functional magnetic resonance imaging (fMRI) to examine how parent ES practices relate to adolescent brain function during emotion processing. Thirty-three adolescents (ages 14-16) reported on ES practices of a focal parent (primarily mothers) using the Emotions as a Child (EAC) Scale. Adolescents also completed a conflict discussion task with this parent, and parents' statements were coded for emotional valence. Adolescents performed two fMRI tasks: a standard emotion processing (EP) task (n = 32) and the Testing Emotional Attunement and Mutuality (TEAM) task (n = 27). The EP task consisted of viewing emotional pictures and either reacting naturally or using cognitive reappraisal to regulate emotional responses. The TEAM task was performed with the parent and included trials during which adolescents were shown that their parent made an error, costing the dyad $5. Parent negative verbalizations during the conflict discussion were associated with greater activity in the thalamus during the emotion reactivity condition of the EP task and in the thalamus, superior medial and superior frontal gyri, anterior insula, and dorsolateral prefrontal cortex during the costly error condition of the TEAM task. Unsupportive ES was associated with greater activity in the supplementary motor area and less activity in the paracentral gyrus and amygdala during the costly error condition of the TEAM task. This study supports the premise that ES influences adolescents' emotion-related neural processing, particularly when using ecologically valid tasks in social contexts.

The Role of Neurobiological Bases of Dyadic Emotion Regulation in the Development of Psychopathology: Cross-Brain Associations Between Parents and Children.

Daily interactions between parents and children play a large role in children's emotional development and mental health. Thus, it is important to investigate the neural mechanisms underlying this association within the context of these dyadic social interactions. We suggest that examining cross-brain associations, coordinated brain responses, among parents and children increases our understanding of patterns of social and emotion-related processes that occur during parent-child interactions, which may influence the development of child emotion regulation and psychopathology. Therefore, we extend the Parent-Child Emotion Regulation Dynamics Model (Morris et al., in: Cole and Hollenstein (eds) Dynamics of emotion regulation: A matter of time, Taylor & Francis, 2018) to include cross-brain associations involved in dyadic emotion regulation during parent-child social emotional interactions and discuss how this model can inform future research and its broader applications.

Into the Unknown: Examining Neural Representations of Parent-Adolescent Interactions.

The parent-adolescent relationship is important for adolescents' emotion regulation (ER), yet little is known regarding the neural patterns of dyadic ER that occur during parent-adolescent interactions. A novel measure that can be used to examine such patterns is cross-brain connectivity (CBC)-concurrent and time-lagged connectivity between two individuals' brain regions. This study sought to provide evidence of CBC and explore associations between CBC, parenting, and adolescent internalizing symptoms. Thirty-five adolescents (mean age = 15 years, 69% female, 72% Non-Hispanic White, 17% Black, 11% Hispanic or Latino) and one biological parent (94% female) completed an fMRI hyperscanning conflict discussion task. Results revealed CBC between emotion-related brain regions. Exploratory analyses indicated CBC is associated with parenting and adolescent depressive symptoms.

Impact of ibuprofen and peroxisome proliferator-activated receptor gamma on emotion-related neural activation: A randomized, placebo-controlled trial.

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have shown initial promise in producing antidepressant effects. This is perhaps due to these drugs being peroxisome proliferator-activated receptor gamma (PPARγ) agonists, in addition to their inhibition of cyclooxygenase enzymes. Some, albeit mixed, evidence suggests that PPARγ agonists have antidepressant effects in humans and animals. This double-blind, placebo-controlled, pharmacologic functional magnetic resonance imaging (ph-fMRI) study aimed to elucidate the impact of ibuprofen on emotion-related neural activity and determine whether observed effects were due to changes in PPARγ gene expression. Twenty healthy volunteers completed an emotional face matching task during three fMRI sessions, conducted one week apart. Placebo, 200 mg, or 600 mg ibuprofen was administered 1 h prior to each scan in a pseudo-randomized order. Peripheral blood mononuclear cells were collected at each session to isolate RNA for PPARγ gene expression. At the doses used, ibuprofen did not significantly change PPARγ gene expression. Ibuprofen dose was associated with decreased blood oxygen level-dependent (BOLD) activation in the dorsolateral prefrontal cortex and fusiform gyrus during emotional face processing (faces-shapes). Additionally, PPARγ gene expression was associated with increased BOLD activation in the insula and transverse and superior temporal gyri (faces-shapes). No interaction effects between ibuprofen dose and PPARγ gene expression on BOLD activation were observed. Thus, results suggest that ibuprofen and PPARγ may have independent effects on emotional neurocircuitry. Future studies are needed to further delineate the roles of ibuprofen and PPARγ in exerting antidepressant effects in healthy as well as clinical populations.

Childhood Adversity and Perceived Distress from the COVID-19 Pandemic.

Childhood exposure to adversity may increase an individual's reactivity to subsequent stressors. In this paper, we examine how adverse childhood experiences (ACEs) are associated with experiencing greater perceived distress during the pandemic. In this volunteer clinical cohort study, 177 pregnant women (ages 16-38) were recruited from two university-affiliated perinatal clinics located in a small metropolitan city between October 2017 and May 2018. Longitudinal data collection is ongoing. The current study includes the 101 women who participated through the eighth and most recent survey conducted in mid-April 2020. OLS regression analyses were used to examine the association between childhood adversity and pandemic-related distress. We found that ACE scores were associated with higher levels of distress (b = .08; se = .03; p < .01) when controlling for demographic characteristics. The addition of loneliness to the model fully mediates the association between ACEs score and distress. Findings suggest that adverse childhood experiences influence COVID-19-related distress due to greater social isolation. Those who had greater adversity during childhood may be less likely to have the social connectedness needed to reduce distress due to the pandemic.

Associated Changes in E-cigarette Puff Duration and Cigarettes Smoked per Day.

INTRODUCTION: To examine whether changes in select measures of e-cigarette puffing topography are associated with changes in smoking behavior. METHODS: Sixteen current cigarette smokers were instructed to completely switch from smoking combustible cigarettes to using e-cigarettes over a 2-week period. The study was completed in the Southern Midwestern region of the United States. Measures included demographics, smoking history, and cigarette dependence, as well as baseline and 2-week follow-up self-reported cigarettes per day, cigarette craving and urges, exhaled carbon monoxide readings, and e-cigarette usage data (puff number, puffing time, and average puff duration) collected via the e-cigarette built-in puff counter. RESULTS: Over the 2-week switching period, participants significantly reduced their cigarettes per day (~80% reduction, p < .0001). Although the number of e-cigarette puffs/day remained relatively stable (p > .05), the average total e-cigarette daily puffing time increased significantly (p = .001). Users' average puff duration increased by 91 ms/puff/d (p < .001). The percentage decrease in cigarettes smoked per day was significantly and directly related to the slope of subjects' average puff duration over time (r(13) = .62, p = .01), such that as cigarettes per day decreased, puff duration increased. Self-reported smoking urges remained relatively stable from baseline to the end of the 2-week period (p > .05). CONCLUSIONS: Among smokers switching to an e-cigarette, greater increases in e-cigarette puff duration was associated with greater reductions in cigarette smoking. IMPLICATIONS: The current study is one of the first to examine changes in smokers' e-cigarette puffing behavior and associated changes in cigarette consumption as they attempt to completely switch to e-cigarettes. During a 2-week switching period, participants reduced their cigarettes per day. Moreover, although e-cigarette puffs per day remained relatively stable, users' average puff duration increased significantly. Greater increases in e-cigarette puff duration were associated with greater reductions in cigarette smoking. Understanding how to effectively use an e-cigarette to best reduce and eventually quit smoking will be necessary as smokers increasingly turn to these products to facilitate possible cessation.

The effects of inhibition of fatty acid amide hydrolase (FAAH) by JNJ-42165279 in social anxiety disorder: a double-blind, randomized, placebo-controlled proof-of-concept study.

JNJ-42165279 is a selective inhibitor of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of fatty acid amides (FAA) including anandamide (AEA), palmitoylethanolamide (PEA), and N-oleoylethanolamide (OEA). We assessed the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of treatment with JNJ-42165279 in subjects with social anxiety disorder (SAD). This was a multicenter, double-blind, placebo-controlled study randomizing subjects to 12 weeks of treatment with either JNJ-42165279 (25 mg daily) or placebo (PBO). The primary endpoint was the change in the Liebowitz Social Anxiety Scale (LSAS) total score from baseline to end of study. Secondary endpoints included the Hamilton Anxiety Scale (HAM-A), Hamilton Depression Rating Scale (HDRS17), and the Clinical Global Impression-Improvement (CGI-I). Samples were collected for plasma concentration of AEA, PEA, OEA, and JNJ-42165279. A total of 149 subjects were enrolled with a mean baseline LSAS total score of 102.6 (SD 16.84). The mean change from baseline (SD) in LSAS total score at week 12 was numerically greater for JNJ-42165279: -29.4 (27.47) compared to PBO: -22.4 (23.57) but not significant. The percentage of subjects with ≥30% improvement from baseline in the LSAS total score was significantly higher for JNJ-42165279 (42.4%) compared to PBO (23.6%) (p value = 0.04). The percentage of subjects with a CGI-I score of much or very much improved was also significantly higher for JNJ-42165279 (44.1%) than for PBO (23.6%) (p value = 0.02). The drug was well tolerated. JNJ-42165279 appears to elicit an anxiolytic effect in subjects with SAD although trough concentrations with 25 mg once daily appeared to be insufficient to completely inhibit FAAH activity which may have led to suboptimal efficacy. ClinicalTrials.gov Identifier: NCT02432703.

Beyond synchrony: the capacity of fMRI hyperscanning for the study of human social interaction.

Hyperscanning-simultaneous brain scanning of two or more individuals-holds great promise in elucidating the neurobiological underpinnings of social cognitive functions. This article focuses on functional magnetic resonance imaging (fMRI) hyperscanning and identifies promising targets for studying the neuroscience of social interaction with fMRI hyperscanning. Specifically, we present applications of fMRI hyperscanning in the study of social interaction along with promising analysis approaches for fMRI hyperscanning, with its high spatial and low temporal resolution. We first review fMRI hyperscanning studies in social neuroscience and evaluate the premise of using this costly neuroimaging paradigm. Many second-person social neuroscience studies are possible without fMRI hyperscanning. However, certain fundamental aspects of social cognition in real-life social interactions, including different roles of interactors, shared intention emerging through interaction and history of interaction, can be addressed only with hyperscanning. We argue that these fundamental aspects have not often been investigated in fMRI hyperscanning studies. We then discuss the implication of the signal coupling found in fMRI hyperscanning and consider analysis approaches that make fair use of it. With fMRI hyperscanning, we can explore not only synchronous brain activations but whole-brain asymmetric activation patterns with a lagged association between interacting individuals.

TEAMwork: Testing Emotional Attunement and Mutuality During Parent-Adolescent fMRI.

The parent-child relationship and family context influence the development of emotion regulation (ER) brain circuitry and related skills in children and adolescents. Although both parents' and children's ER neurocircuitry simultaneously affect how they interact with one another, neuroimaging studies of parent-child relationships typically include only one member of the dyad in brain imaging procedures. The current study examined brain activation related to parenting and ER in parent-adolescent dyads during concurrent fMRI scanning with a novel task - the Testing Emotional Attunement and Mutuality (TEAM) task. The TEAM task includes feedback trials indicating the other dyad member made an error, resulting in a monetary loss for both participants. Results indicate that positive parenting practices as reported by the adolescent were positively correlated with parents' hemodynamic activation of the ventromedial prefrontal cortex, a region related to empathy, during these error trials. Additionally, during feedback conditions both parents and adolescents exhibited fMRI activation in ER-related regions, including the dorsolateral prefrontal cortex, anterior insula, fusiform gyrus, thalamus, caudate, precuneus, and superior parietal lobule. Adolescents had higher left amygdala activation than parents during the feedback condition. These findings demonstrate the utility of dyadic fMRI scanning for investigating relational processes, particularly in the parent-child relationship.

Learning situated emotions.

From the perspective of constructivist theories, emotion results from learning assemblies of relevant perceptual, cognitive, interoceptive, and motor processes in specific situations. Across emotional experiences over time, learned assemblies of processes accumulate in memory that later underlie emotional experiences in similar situations. A neuroimaging experiment guided participants to experience (and thus learn) situated forms of emotion, and then assessed whether participants tended to experience situated forms of the emotion later. During the initial learning phase, some participants immersed themselves in vividly imagined fear and anger experiences involving physical harm, whereas other participants immersed themselves in vividly imagined fear and anger experiences involving negative social evaluation. In the subsequent testing phase, both learning groups experienced fear and anger while their neural activity was assessed with functional magnetic resonance imaging (fMRI). A variety of results indicated that the physical and social learning groups incidentally learned different situated forms of a given emotion. Consistent with constructivist theories, these findings suggest that learning plays a central role in emotion, with emotion adapted to the situations in which it is experienced.

Appetite changes reveal depression subgroups with distinct endocrine, metabolic, and immune states.

There exists little human neuroscience research to explain why some individuals lose their appetite when they become depressed, while others eat more. Answering this question may reveal much about the various pathophysiologies underlying depression. The present study combined neuroimaging, salivary cortisol, and blood markers of inflammation and metabolism collected prior to scanning. We compared the relationships between peripheral endocrine, metabolic, and immune signaling and brain activity to food cues between depressed participants experiencing increased (N = 23) or decreased (N = 31) appetite and weight in their current depressive episode and healthy control participants (N = 42). The two depression subgroups were unmedicated and did not differ in depression severity, anxiety, anhedonia, or body mass index. Depressed participants experiencing decreased appetite had higher cortisol levels than subjects in the other two groups, and their cortisol values correlated inversely with the ventral striatal response to food cues. In contrast, depressed participants experiencing increased appetite exhibited marked immunometabolic dysregulation, with higher insulin, insulin resistance, leptin, CRP, IL-1RA, and IL-6, and lower ghrelin than subjects in other groups, and the magnitude of their insulin resistance correlated positively with the insula response to food cues. These findings provide novel evidence linking aberrations in homeostatic signaling pathways within depression subtypes to the activity of neural systems that respond to food cues and select when, what, and how much to eat. In conjunction with prior work, the present findings strongly support the existence of pathophysiologically distinct depression subtypes for which the direction of appetite change may be an easily measured behavioral marker.

Appetite change profiles in depression exhibit differential relationships between systemic inflammation and activity in reward and interoceptive neurocircuitry.

Appetite change is a defining feature of major depressive disorder (MDD), yet little neuroscientific evidence exists to explain why some individuals experience increased appetite when they become depressed while others experience decreased appetite. Previous research suggests depression-related appetite changes can be indicative of underlying neural and inflammatory differences among MDD subtypes. The present study explores the relationship between systemic inflammation and brain circuitry supporting food hedonics for individuals with MDD. Sixty-four participants (31 current, unmedicated MDD and 33 healthy controls [HC]) provided blood samples for analysis of an inflammatory marker, C-reactive protein (CRP), and completed a functional magnetic resonance imaging (fMRI) scan in which they rated the perceived pleasantness of various food stimuli. Random-effects multivariate modeling was used to explore group differences in the relationship between CRP and the coupling between brain activity and inferred food pleasantness (i.e., strength of the relationship between activity and pleasantness ratings). Results revealed that for MDD with increased appetite, higher CRP in blood related to greater coupling between orbitofrontal cortex and anterior insula activity and inferred food pleasantness. Compared to HC, all MDD exhibited a stronger positive association between CRP and coupling between activity in striatum and inferred food pleasantness. These findings suggest that for individuals with MDD, systemic low-grade inflammation is associated with differences in reward and interoceptive-related neural circuitry when making hedonic inferences about food stimuli. In sum, altered immunologic states may affect appetite and inferences about food reward in individuals with MDD and provide evidence for physiological subtypes of MDD.

Always on my mind: Cross-brain associations of mental health symptoms during simultaneous parent-child scanning.

How parents manifest symptoms of anxiety or depression may affect how children learn to modulate their own distress, thereby influencing the children's risk for developing an anxiety or mood disorder. Conversely, children's mental health symptoms may impact parents' experiences of negative emotions. Therefore, mental health symptoms can have bidirectional effects in parent-child relationships, particularly during moments of distress or frustration (e.g., when a parent or child makes a costly mistake). The present study used simultaneous functional magnetic resonance imaging (fMRI) of parent-adolescent dyads to examine how brain activity when responding to each other's costly errors (i.e., dyadic error processing) may be associated with symptoms of anxiety and depression. While undergoing simultaneous fMRI scans, healthy dyads completed a task involving feigned errors that indicated their family member made a costly mistake. Inter-brain, random-effects multivariate modeling revealed that parents who exhibited decreased medial prefrontal cortex and posterior cingulate cortex activation when viewing their child's costly error response had children with more symptoms of depression and anxiety. Adolescents with increased anterior insula activation when viewing a costly error made by their parent had more anxious parents. These results reveal cross-brain associations between mental health symptomatology and brain activity during parent-child dyadic error processing.

Image processing and analysis methods for the Adolescent Brain Cognitive Development Study.

The Adolescent Brain Cognitive Development (ABCD) Study is an ongoing, nationwide study of the effects of environmental influences on behavioral and brain development in adolescents. The main objective of the study is to recruit and assess over eleven thousand 9-10-year-olds and follow them over the course of 10 years to characterize normative brain and cognitive development, the many factors that influence brain development, and the effects of those factors on mental health and other outcomes. The study employs state-of-the-art multimodal brain imaging, cognitive and clinical assessments, bioassays, and careful assessment of substance use, environment, psychopathological symptoms, and social functioning. The data is a resource of unprecedented scale and depth for studying typical and atypical development. The aim of this manuscript is to describe the baseline neuroimaging processing and subject-level analysis methods used by ABCD. Processing and analyses include modality-specific corrections for distortions and motion, brain segmentation and cortical surface reconstruction derived from structural magnetic resonance imaging (sMRI), analysis of brain microstructure using diffusion MRI (dMRI), task-related analysis of functional MRI (fMRI), and functional connectivity analysis of resting-state fMRI. This manuscript serves as a methodological reference for users of publicly shared neuroimaging data from the ABCD Study.