Neural Correlates of Stress and Alcohol Cue-Induced Alcohol Craving and of Future Heavy Drinking: Evidence of Sex Differences.

OBJECTIVE: Stress and alcohol cue reactivity are associated with poor treatment outcomes in alcohol use disorder (AUD), but sex-specific neural correlates of stress and alcohol cue-induced craving compared with neutral cue-induced craving and of heavy drinking outcomes in AUD have not been examined. Thus, this study prospectively examined these associations and assessed sex differences. METHODS: Treatment-seeking adults with AUD (N=77; 46 men and 31 women) completed a functional MRI task involving stress, alcohol, and neutral cue exposure with repeated assessments of alcohol craving. Most of these participants (N=72; 43 men and 29 women) then participated in an 8-week standardized behavioral AUD treatment program, during which the percentage of heavy drinking days was assessed. RESULTS: Significant increases in both stress and alcohol cue-induced craving relative to neutral cue-induced craving were observed, with a greater alcohol-neutral contrast in craving relative to the stress-neutral contrast among men and equivalent stress-neutral and alcohol-neutral contrasts in craving among women. Whole-brain voxel-based regression analyses showed craving-associated hyperactivation in the neutral condition, but hypoactive prefrontal (ventromedial and lateral prefrontal, supplementary motor, and anterior cingulate regions) and striatal responses during exposure to stressful images (stress-neutral contrast) and alcohol cues (alcohol-neutral contrast), with significant sex differences. Additionally, a higher percentage of heavy drinking days was associated with hypoactivation of the subgenual anterior cingulate cortex and the bed nucleus of the stria terminalis in the stress-neutral contrast among women, hyperactivation of the hypothalamus in the stress-neutral contrast among men, and hyperactivation of the hippocampus in the alcohol-neutral contrast among men. CONCLUSIONS: Sex differences in stress- and alcohol cue-induced responses in the cortico-striatal-limbic network related to subjective alcohol craving and to heavy drinking indicated that distinct brain circuits underlie alcohol use outcomes in women and men. These findings underscore the need for sex-specific therapeutics to address this neural dysfunction effectively.

Advances in Nanomaterials for Sustainable Gas Separation and Storage: Focus on Clathrate Hydrates.

ConspectusClathrate hydrates, also known as gas hydrates, are a type of inclusion compound formed in highly developed nanoporous lattice spaces created by water molecules, where gas molecules such as CO2, H2, CH4, and other low-molecular-weight liquid molecules are trapped. The nanoporous cage formed by water molecules serves as the "host", while the trapped gas or low-molecular-weight liquid molecules such as tetrahydrofuran act as "guests". Early on, clathrate hydrates drew attention as a potential replacement for conventional natural gas due to their natural gas hydrate form, which contains natural gases as guests and exists in permafrost or sea floors. Recently, based on the unique physicochemical properties of clathrate hydrates, efforts are being made to utilize synthetic clathrate hydrates in various separation processes such as post- and pre-combustion CO2 capture, H2 storage, natural gas storage and transportation, wastewater desalination, and more. While it is undeniable that clathrate hydrates are based on principles that are beneficial for the separation and storage of gas molecules, there are several challenges that must be addressed for their practical application. These challenges include (i) the limitation of gas storage capacity due to the confined size of nanoporous cages, (ii) the relatively high-pressure and low-temperature thermodynamic storage conditions typically required for clathrate hydrate formation, and (iii) slow formation kinetics and low gas hydrate conversion, which are also essential issues that need to be resolved for the meaningful implementation of clathrate hydrates. In this Account, we aim to introduce recent noteworthy research findings, including those from our research team, focusing on addressing these challenges. We explored the untapped potential of clathrate hydrates by bridging the gap between macroscopic and microscopic properties. This has led to breakthroughs in sustainable gas separation and storage applications. By revealing the hidden nature of these hydrates, we have effectively mitigated their inherent limitations, setting the stage for more feasible and efficient H2 storage solutions through the introduction of hydrogen-natural gas blends to clathrate hydrates. Additionally, we have demonstrated the tuning effect on all naturally formed hydrate structures, offering new insights into their underlying properties and macroscopic behavior. Furthermore, our research has proposed a highly efficient hydrate-based pre-combustion CO2 capture approach that leverages porous media with appropriate wettability and considers the implications of microstructure properties. This emphasizes the crucial connection between nano-structure and macroscopic properties, underscoring the significance of understanding their interplay for economic feasibility. We believe that our efforts to unveil the hidden nature of gas hydrates provide strategies to address challenges and lay the groundwork for practical applications.

Binge drinking is associated with higher cortisol and lower hippocampal and prefrontal gray matter volume: Prospective association with future alcohol intake.

Background: Cortisol is a significant driver of the biological stress response that is potently activated by acute alcohol intake and increased with binge drinking. Binge drinking is associated with negative social and health consequences and risk of developing alcohol use disorder (AUD). Both cortisol levels and AUD are also associated with changes in hippocampal and prefrontal regions. However, no previous research has assessed structural gray matter volume (GMV) and cortisol concurrently to examine BD effects on hippocampal and prefrontal GMV and cortisol, and their prospective relationship to future alcohol intake. Methods: Individuals who reported binge drinking (BD: N = 55) and demographically matched non-binge moderate drinkers (MD: N = 58) were enrolled and scanned using high-resolution structural MRI. Whole brain voxel-based morphometry was used to quantify regional GMV. In a second phase, 65% of the sample volunteered to participate in prospective daily assessment of alcohol intake for 30 days post-scanning. Results: Relative to MD, BD showed significantly higher cortisol and smaller GMV in regions including hippocampus, dorsal lateral prefrontal cortex (dlPFC), prefrontal and supplementary motor, primary sensory and posterior parietal cortex (FWE, p < 0.05). GMV in bilateral dlPFC and motor cortices were negatively associated with cortisol levels, and smaller GMV in multiple PFC regions was associated with more subsequent drinking days in BD. Conclusion: These findings indicate neuroendocrine and structural dysregulation associated with BD relative to MD. Notably, BD-associated lower GMV regions were those involved in stress, memory and cognitive control, with lower GMV in cognitive control and motor regions also predicting higher levels of future alcohol intake in BD.

Biometabolites of Citrus unshiu Peel Enhance Intestinal Permeability and Alter Gut Commensal Bacteria.

Flavanones in Citrus unshiu peel (CUP) have been used as therapeutic agents to reduce intestinal inflammation; however, the anti-inflammatory effects of their biometabolites remain ambiguous. Here, we identified aglycone-type flavanones, such as hesperetin and naringenin, which were more abundant in the bioconversion of the CUP than in the ethanol extracts of the CUP. We found that the bioconversion of the CUP induced the canonical nuclear factor-κB pathway via degradation of IκB in Caco-2 cells. To check the immune suppressive capacity of the aglycones of the CUP in vivo, we orally administered the bioconversion of the CUP (500 mg/kg) to mice for two weeks prior to the 3% dextran sulfate sodium treatment. The CUP-pretreated group showed improved body weight loss, colon length shortage, and intestinal inflammation than the control mice. We also found a significant decrease in the population of lamina propria Th17 cells in the CUP-pretreated group following dextran sodium sulfate (DSS) treatment and an increase in mRNA levels of occludin in CUP-treated Caco-2 cells. Pyrosequencing analysis revealed a decreased abundance of Alistipes putredinis and an increased abundance of Muribaculum intestinale in the feces of the CUP-pretreated mice compared to those of the control mice. Overall, these findings suggest that the pre-administration of CUP biometabolites may inhibit the development of murine colitis by modulating intestinal permeability and the gut microbiome.

Neural correlates linking trauma and physical symptoms.

Trauma and chronic pain frequently co-occur, but the underlying neurological mechanisms are poorly understood. The current study investigated the neural correlates of stress and physical symptoms in trauma patients using functional magnetic resonance imaging (fMRI) and follow-up smartphone surveys. Participants were 10 patients diagnosed with Trauma- and Stressor-Related Disorders and 18 demographically-matched healthy controls who completed a fMRI stress provocation task in which they viewed stressful and neutral-relaxing images. Subsequently, participants completed daily smartphone surveys which prospectively monitored their stress and physical symptoms for 30 days. The trauma group experienced a significantly higher frequency of physical symptoms than controls during the follow-up period. During stress, trauma patients exhibited increased activity in the hippocampus, insula, and sensorimotor areas, but decreased activity in the ventromedial prefrontal cortex (vmPFC), lateral prefrontal cortex (LPFC), and dorsal striatum relative to controls. In all participants, higher physical symptom frequency was significantly associated with a hyperactive left hippocampal response to stress. The current study reports that trauma is characterized by greater physical symptoms and decreased prefrontal but increased limbic responses to stress. Our findings suggest that trauma may increase physical health symptoms by compromising hippocampal function, which could also increase vulnerability to stress- and pain-related disorders.

Daily stress predicts later drinking initiation via craving in heavier social drinkers: A prospective in-field daily diary study.

Stress has been linked to increased alcohol use but how stress may increase drinking in social drinkers is not well understood. Negative reinforcement processes may explain this link but the role of specific motivational processes, such as craving, and how these motivational processes are altered by drinking have not been studied. The current study assessed social drinkers (n = 81) for recent quantity and frequency of alcohol intake (quantity and frequency index, QFI) upon study enrollment, who then completed 30 days of electronic daily records of stress, craving, and alcohol intake. Multilevel structural equation models tested if person-averaged (between-person) and daily (within-person) craving mediated the link between stress and later drinking each evening and if recent quantity-frequency of drinking (QFI) moderated these associations. At the between-person level, both greater subjective stress, Est = .38, 95% confidence interval (CI) [.19, .57], and higher QFI predicted higher levels of craving, Est = .34, 95% CI [.20, .49]. Higher craving predicted more frequent drinking throughout the study, Est = .34, 95% CI [.01, .29]. At the within-person level, higher subjective stress predicted higher within-person craving; and the link between craving and later drinking was significant among those who had a higher QFI, Est = .84, 95% CI [.58, 1.12]. The subjective stress-drinking relationship was mediated by a greater alcohol craving response in social drinkers, and higher the QFI, greater the alcohol craving response. These results indicate that both higher levels of stress and greater recent alcohol intake patterns sensitize the craving response that in turn facilitates later alcohol intake. The findings suggest that higher recent alcohol use predict greater stress-potentiated initiation of drinking via higher craving responses. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Stress-level glucocorticoids increase fasting hunger and decrease cerebral blood flow in regions regulating eating.

CONTEXT: The neural regulation of appetite and energy homeostasis significantly overlaps with the neurobiology of stress. Frequent exposure to repeated acute stressors may cause increased allostatic load and subsequent dysregulation of the cortico-limbic striatal system leading to inefficient integration of postprandial homeostatic and hedonic signals. It is therefore important to understand the neural mechanisms by which stress generates alterations in appetite that may drive weight gain. OBJECTIVE: To determine glucocorticoid effects on metabolic, neural and behavioral factors that may underlie the association between glucocorticoids, appetite and obesity risk. METHODS: A randomized double-blind cross-over design of overnight infusion of hydrocortisone or saline followed by a fasting morning perfusion magnetic resonance imaging to assess regional cerebral blood flow (CBF) was completed. Visual Analog Scale (VAS) hunger, cortisol and metabolic hormones were also measured. RESULTS: Hydrocortisone relative to saline significantly decreased whole brain voxel based CBF responses in the hypothalamus and related cortico-striatal-limbic regions. Hydrocortisone significantly increased hunger VAS pre-scan, insulin, glucose and leptin, but not other metabolic hormones versus saline CBF groups. Hydrocortisone related increases in hunger were predicted by less reduction of CBF (hydrocortisone minus saline) in the medial OFC, medial brainstem and thalamus, left primary sensory cortex and right superior and medial temporal gyrus. Hunger ratings were also positively associated with plasma insulin on hydrocortisone but not saline day. CONCLUSIONS: Increased glucocorticoids at levels akin to those experienced during psychological stress, result in increased fasting hunger and decreased regional cerebral blood flow in a distinct brain network of prefrontal, emotional, reward, motivation, sensory and homeostatic regions that underlie control of food intake.

High-Risk Drinkers Engage Distinct Stress-Predictive Brain Networks.

BACKGROUND: Excessive alcohol intake is a major public health problem and can be triggered by stress. Heavy drinking in patients with alcohol use disorder also alters neural, physiological, and emotional stress responses. However, it is unclear whether adaptations in stress-predictive brain networks can be an early marker of risky drinking behavior. METHODS: Risky social drinkers (regular bingers; n = 53) and light drinker control subjects (n = 51) aged 18 to 53 years completed a functional magnetic resonance imaging-based sustained stress protocol with repeated measures of subjective stress state, during which whole-brain functional connectivity was computed. This was followed by prospective daily ecological momentary assessment for 30 days. We used brain computational predictive modeling with cross-validation to identify unique brain connectivity predictors of stress in risky drinkers and determine the prospective utility of stress-brain networks for subsequent loss of control over drinking. RESULTS: Risky drinkers had anatomically and functionally distinct stress-predictive brain networks (showing stronger predictions from visual and motor networks) compared with light drinkers (default mode and frontoparietal networks). Stress-predictive brain networks defined for risky drinkers selectively predicted future real-world stress levels for risky drinkers and successfully predicted prospective future real-world loss of control over drinking across all participants. CONCLUSIONS: These results indicate adaptations in computationally derived stress-related brain circuitry among high-risk drinkers, suggesting potential targets for early preventive intervention and revealing the malleability of the neural processes that govern stress responses.

A methodological checklist for fMRI drug cue reactivity studies: development and expert consensus.

Cue reactivity is one of the most frequently used paradigms in functional magnetic resonance imaging (fMRI) studies of substance use disorders (SUDs). Although there have been promising results elucidating the neurocognitive mechanisms of SUDs and SUD treatments, the interpretability and reproducibility of these studies is limited by incomplete reporting of participants' characteristics, task design, craving assessment, scanning preparation and analysis decisions in fMRI drug cue reactivity (FDCR) experiments. This hampers clinical translation, not least because systematic review and meta-analysis of published work are difficult. This consensus paper and Delphi study aims to outline the important methodological aspects of FDCR research, present structured recommendations for more comprehensive methods reporting and review the FDCR literature to assess the reporting of items that are deemed important. Forty-five FDCR scientists from around the world participated in this study. First, an initial checklist of items deemed important in FDCR studies was developed by several members of the Enhanced NeuroImaging Genetics through Meta-Analyses (ENIGMA) Addiction working group on the basis of a systematic review. Using a modified Delphi consensus method, all experts were asked to comment on, revise or add items to the initial checklist, and then to rate the importance of each item in subsequent rounds. The reporting status of the items in the final checklist was investigated in 108 recently published FDCR studies identified through a systematic review. By the final round, 38 items reached the consensus threshold and were classified under seven major categories: 'Participants' Characteristics', 'General fMRI Information', 'General Task Information', 'Cue Information', 'Craving Assessment Inside Scanner', 'Craving Assessment Outside Scanner' and 'Pre- and Post-Scanning Considerations'. The review of the 108 FDCR papers revealed significant gaps in the reporting of the items considered important by the experts. For instance, whereas items in the 'General fMRI Information' category were reported in 90.5% of the reviewed papers, items in the 'Pre- and Post-Scanning Considerations' category were reported by only 44.7% of reviewed FDCR studies. Considering the notable and sometimes unexpected gaps in the reporting of items deemed to be important by experts in any FDCR study, the protocols could benefit from the adoption of reporting standards. This checklist, a living document to be updated as the field and its methods advance, can help improve experimental design, reporting and the widespread understanding of the FDCR protocols. This checklist can also provide a sample for developing consensus statements for protocols in other areas of task-based fMRI.

Social Support Effects on Neural Stress and Alcohol Reward Responses.

Social support (SS), or having people to depend on during times of stress, may offer an emotional and neurological buffer to problem drinking. Specifically, SS may modulate reward and stress-related brain responses to mitigate perceptions of alcohol reward and stress. There is limited evidence, however, on this topic and specifically on brain networks that may modulate SS effects on stress and alcohol reward. Here we present a review of the current literature on this topic as well as data from a large community sample of 115 social drinkers. Findings from a novel fMRI task viewing alcohol cue, stress, and neutral images, in separate blocks, while providing ratings on subjective feelings of alcohol craving, stress, and arousal are included. Lower SS significantly predicted greater alcohol craving during alcohol cue and stress conditions, higher baseline levels of stress, and greater arousal in the alcohol cue, relative to neutral condition. Remarkably, individuals with low SS showed greater reward activation (ventral medial prefrontal cortex (VmPFC) and ventral striatum) during alcohol cue exposure, while those with high SS showed no such activation (p < 0.001, family wise error corrected at 0.05). Furthermore, individuals with lower SS showed greater stress circuit (VmPFC, dorsal striatum, and periaqueductal gray) activation not observed in the high SS groups. Both groups showed increased amygdala activation under stress condition. The findings support the notion that SS is a powerful modulator of stress response and reward motivation. High SS buffers neural and subjective stress responses, while low SS potentiates greater reward seeking with higher alcohol craving and greater brain activation during alcohol cue exposure. Previous research and current results suggest the need to further explore the role of SS in those at risk of developing alcohol use disorder and assess novel prevention strategies to boost SS in at-risk drinkers.

Irregular Autonomic Modulation Predicts Risky Drinking and Altered Ventromedial Prefrontal Cortex Response to Stress in Alcohol Use Disorder.

AIMS: Autonomic dysfunction has been associated with risky drinking and alcohol use disorder (AUD). Although autonomic nervous system (ANS) activity has been attributed to the ventromedial prefrontal cortex (VmPFC)-limbic-striatal regions, the specific role of ANS disruption in AUD and its association with these regions remain unclear. Using functional magnetic resonance imaging (fMRI) and concurrent electrocardiogram (ECG), the current study examined neural correlates of ANS activity in AUD and its role in AUD pathology. METHODS: Demographically matched 20 AUD patients and 20 social drinkers (SD) completed an fMRI task involving repeated exposure to stress, alcohol-cue and neutral-relaxing images in a block design. Based on the known VmPFC-limbic-striatal functions involved in emotions, reward and the ANS, we performed a regions of interest (ROI) analysis to examine the associations between ANS activity and neural responses in the VmPFC, amygdala, and ventral striatum. RESULTS: Across conditions, AUD patients showed significantly higher levels of overall heart rate (HR) and approximate entropy (ApEn) compared to SD (Ps < 0.05). In all participants, increased HR was associated with greater drinking volume (P < 0.05). In addition, higher ApEn levels were associated with greater drinking volume (P < 0.05) and decreased right VmPFC response to stress (P < 0.05). DISCUSSION: Our findings demonstrate ANS disruption in AUD indexed by high overall HR and ApEn. The association between ApEn and rVmPFC response suggests that ApEn may play a role in modulating drinking via interactions with neural regions of emotion regulation. These findings provide insight into patterns of ANS disruption and their relevance to AUD pathology.

Alcohol withdrawal symptoms predict corticostriatal dysfunction that is reversed by prazosin treatment in alcohol use disorder.

Chronic alcohol use increases risk of alcohol withdrawal symptoms (AW) and disrupts stress biology and resilient coping, thereby promoting excessive alcohol intake. Chronic alcohol intake and multiple alcohol detoxifications are known to impair brain medial prefrontal cortex (mPFC) and striatal functioning, regions involved in regulating stress, craving and alcohol intake. In two related studies, we examined whether AW predicts this functional brain pathology and whether Prazosin versus Placebo treatment may reverse these effects. In Study 1, patients with Alcohol Use Disorder (AUD) (N = 45) with varying AW levels at treatment entry were assessed to examine AW effects on corticostriatal responses to stress, alcohol cue and neutral visual images with functional magnetic resonance imaging (fMRI). In Study 2, 23 AUD patients entering a 12-week randomised controlled trial (RCT) of Prazosin, an alpha1 adrenergic antagonist that decreased withdrawal-related alcohol intake in laboratory animals, participated in two fMRI sessions at pretreatment and also at week 9-10 of chronic treatment (Placebo: N = 13; Prazosin: N = 10) to assess Prazosin treatment effects on alcohol-related cortico-striatal dysfunction. Study 1 results indicated that higher AW predicted greater disruption in brain mPFC and striatal response to stress and alcohol cues (p < 0.001, family-wise error [FWE] correction) and also subsequently greater heavy drinking days (HDD) in early treatment (p < 0.01). In Study 2, Prazosin versus Placebo treatment reversed mPFC-striatal dysfunction (p < 0.001, FWE), which in turn predicted fewer drinking days (p < 0.01) during the 12-week treatment period. These results indicate that AW is a significant predictor of alcohol-related prefrontal-striatal dysfunction, and Prazosin treatment reversed these effects that in turn contributed to improved alcohol treatment outcomes.

Differential effects of recent versus past traumas on mood, social support, binge drinking, emotional eating and BMI, and on neural responses to acute stress.

Traumatic stress is associated with risk of psychiatric and physical illnesses. However, the differential and separable effects of past versus recent traumas on maladaptive coping and neural responses are not known. We conducted two studies to assess separate and combined effects of cumulative recent and past trauma on health outcomes (study 1) and on neural responses to acute stress exposure in a subsample of individuals (study 2). Study 1 assessed a large cohort of 677 community adults cross-sectionally, and findings indicated that both high recent (within the last 12 months) and past trauma (prior to the last twelve months) were associated with more physical and psychological symptoms, including increased depression (all p's < .05). However, recent trauma alone was associated with higher problematic alcohol use, a greater maximum number of alcohol drinks consumed, greater emotional eating scores, higher state and trait anxiety scores, and poorer lifestyle habits (all p's < .05). Past trauma alone was associated with higher BMI, decreased social support, and a lower average cortisol relative to ACTH ratio (all p's < .02). Study 2 involving a functional brain scan on a subsample (N = 75) indicated greater recent trauma was associated with a hyperactive response in the ventromedial prefrontal cortex (VmPFC) to neutral-relaxed exposure, but blunted VmPFC response to acute stress exposure (p < .05: whole brain corrected-WBC). By contrast, high past trauma was associated with a hyper-sensitized neural response to stress in the cortico-limbic-striatal regions (p < .05, WBC) critical for reward and emotion processing. Together, these findings suggest differential neurobehavioral and health effects of cumulative past versus recent trauma exposure.

Association of Prefrontal-Striatal Functional Pathology With Alcohol Abstinence Days at Treatment Initiation and Heavy Drinking After Treatment Initiation.

OBJECTIVE: Alcohol use disorder (AUD) is associated with neuroadaptations in brain stress and reward circuits. It is not known whether such neuroadaptations are affected by number of days of alcohol abstinence and whether they influence heavy drinking during the early treatment phase. The authors used a novel functional MRI (fMRI) approach to assess brain responses during sustained exposure to standardized visual stimuli of stressful, alcohol cue, and neutral control images combined with prospective assessment of drinking outcomes during early outpatient treatment, in two related studies. METHODS: In study 1, 44 treatment-entering patients with AUD and 43 demographically matched healthy control subjects participated in the fMRI experiment to identify dysfunctional responses associated with chronic alcohol abuse. In study 2, 69 treatment-entering patients with AUD were assessed for whether fMRI responses at treatment initiation were influenced by alcohol abstinence and were prospectively predictive of early heavy drinking outcomes. RESULTS: Relative to control subjects, patients with AUD showed significant hyperreactivity in the ventromedial prefrontal cortex (vmPFC) in response to neutral images, but significant hypoactivation in the vmPFC and ventral striatum in response to stress images and to alcohol cues relative to response to neutral images. In study 2, this specific prefrontal-ventral striatal dysfunction was associated with fewer days of alcohol abstinence and also predicted greater number heavy drinking days during the subsequent 2 weeks of treatment engagement. CONCLUSIONS: Number of days of alcohol abstinence at treatment initiation significantly affected functional disruption of the prefrontal-striatal responses to stress images and to alcohol cues in patients with AUD, and the severity of this disruption in turn predicted greater heavy drinking during early treatment. Treatments that target this functional prefrontal-striatal pathology could improve early treatment outcomes in AUD.

Hippocampal seed connectome-based modeling predicts the feeling of stress.

Although the feeling of stress is ubiquitous, the neural mechanisms underlying this affective experience remain unclear. Here, we investigate functional hippocampal connectivity throughout the brain during an acute stressor and use machine learning to demonstrate that these networks can specifically predict the subjective feeling of stress. During a stressor, hippocampal connectivity with a network including the hypothalamus (known to regulate physiological stress) predicts feeling more stressed, whereas connectivity with regions such as dorsolateral prefrontal cortex (associated with emotion regulation) predicts less stress. These networks do not predict a subjective state unrelated to stress, and a nonhippocampal network does not predict subjective stress. Hippocampal networks are consistent, specific to the construct of subjective stress, and broadly informative across measures of subjective stress. This approach provides opportunities for relating hypothesis-driven functional connectivity networks to clinically meaningful subjective states. Together, these results identify hippocampal networks that modulate the feeling of stress.

Differential Resting State Connectivity Responses to Glycemic State in Type 1 Diabetes.

CONTEXT: Individuals with type 1 diabetes mellitus (T1DM) have alterations in brain activity that have been postulated to contribute to the adverse neurocognitive consequences of T1DM; however, the impact of T1DM and hypoglycemic unawareness on the brain's resting state activity remains unclear. OBJECTIVE: To determine whether individuals with T1DM and hypoglycemia unawareness (T1DM-Unaware) had changes in the brain resting state functional connectivity compared to healthy controls (HC) and those with T1DM and hypoglycemia awareness (T1DM-Aware). DESIGN: Observational study. SETTING: Academic medical center. PARTICIPANTS: 27 individuals with T1DM and 12 HC volunteers participated in the study. INTERVENTION: All participants underwent blood oxygenation level dependent (BOLD) resting state functional magnetic brain imaging during a 2-step hyperinsulinemic euglycemic (90 mg/dL)-hypoglycemic (60 mg/dL) clamp. OUTCOME: Changes in resting state functional connectivity. RESULTS: Using 2 separate methods of functional connectivity analysis, we identified distinct differences in the resting state brain responses to mild hypoglycemia between HC, T1DM-Aware, and T1DM-Unaware participants, particularly in the angular gyrus, an integral component of the default mode network (DMN). Furthermore, changes in angular gyrus connectivity also correlated with greater symptoms of hypoglycemia (r = 0.461, P = 0.003) as well as higher scores of perceived stress (r = 0.531, P = 0.016). CONCLUSION: These findings provide evidence that individuals with T1DM have changes in the brain's resting state connectivity patterns, which may be further associated with differences in awareness to hypoglycemia. These changes in connectivity may be associated with alterations in functional outcomes among individuals with T1DM.

Sex differences in neural stress responses and correlation with subjective stress and stress regulation.

Emotional stress responses, encompassing both stress reactivity and regulation, have been shown to differ between men and women, but the neural networks supporting these processes remain unclear. The current study used functional neuroimaging (fMRI) to investigate sex differences in neural responses during stress and the sex-specific relationships between these responses and emotional stress responses for men and women. A significant sex by condition interaction revealed that men showed greater stress responses in prefrontal cortex (PFC) regions, whereas women had stronger responses in limbic/striatal regions. Although men and women did not significantly differ in emotional stress reactivity or subjective reports of stress regulation, these responses were associated with distinct neural networks. Higher dorsomedial PFC responses were associated with lower stress reactivity in men, but higher stress reactivity in women. In contrast, while higher ventromedial PFC stress responses were associated with worse stress regulation in men (but better regulation in women), dynamic increases in vmPFC responses during stress were associated with lower stress reactivity in men. Finally, stress-induced hippocampal responses were more adaptive for women: for men, high and dynamically increasing responses in left hippocampus were associated with high stress reactivity, and dynamic increases in the left (but not right) hippocampus were associated with worse stress regulation. Together, these results reveal that men and women engage distinct neural networks during stress, and sex-specific neural stress responses facilitate optimal emotional stress responses.

Limbic response to stress linking life trauma and hypothalamus-pituitary-adrenal axis function.

Trauma alters neuroendocrine responses to stress and increases vulnerability to stress-related disorders. Yet, relationships among trauma, stress-induced neural changes and hypothalamic-pituitary-adrenal (HPA) axis activity have not been determined. The present study used functional magnetic resonance imaging to investigate the impact of life trauma on basal cortisol levels and neural responses to acute stress in 73 healthy individuals during brief stress and neutral-relaxing imagery using a well-established, individualized imagery method. We hypothesized that trauma experience would have a negative impact on brain function, resulting in altered basal cortisol levels via dysregulated neural control over the HPA axis system. Results showed that higher life trauma exposure was significantly associated with lower basal cortisol levels. Neuroimaging results indicated that both higher life trauma and low morning cortisol levels were associated with increased response to acute stress in limbic-medial temporal lobe (MTL) regions including the amygdala and hippocampus. A mediation analysis showed that increased limbic-MTL response to stress mediated the relationship between life trauma and low cortisol levels. Findings revealed a significant impact of lifetime trauma on neural responses to acute stress and HPA axis activity. Life trauma may sensitize limbic-MTL regions and its related peripheral systems, which could compromise stress regulation and HPA axis function, and increase risk for negative stress-related health outcomes.

Food Cues and Obesity: Overpowering Hormones and Energy Balance Regulation.

PURPOSE OF REVIEW: In the modern obesogenic environment, food cues play a crucial role in the development of obesity by disrupting hormone and energy balance mechanisms. Thus, it is critical to understand the neurobiology of feeding behaviors and obesity in the context of ubiquitous food cues. The current paper reviews the physiology of feeding, hormonal regulation of energy balance, and food cue responses and discusses their contributions to obesity. RECENT FINDINGS: Food cues have strong impact on human physiology. Obese individuals have altered food cue-elicited responses in the brain and periphery, overpowering hormone and energy balance regulation. Disrupted homeostasis during food cue exposure leads to continued food intake, unsuccessful weight management, and poor treatment outcomes, which further contributes to obesity epidemic. Findings from the review emphasize the crucial role of food cues in obesity epidemic, which necessitates multidimensional approaches to the prevention and treatment of obesity, including psychosocial interventions to reduce food cue reactivity, along with conventional treatment.

Hypoglycemia unawareness in type 1 diabetes suppresses brain responses to hypoglycemia.

BACKGROUND: Among nondiabetic individuals, mild glucose decrements alter brain activity in regions linked to reward, motivation, and executive control. Whether these effects differ in type 1 diabetes mellitus (T1DM) patients with and without hypoglycemia awareness remains unclear. METHODS: Forty-two individuals (13 healthy control [HC] subjects, 16 T1DM individuals with hypoglycemia awareness [T1DM-Aware], and 13 T1DM individuals with hypoglycemia unawareness [T1DM-Unaware]) underwent blood oxygen level-dependent functional MRI brain imaging during a 2-step hyperinsulinemic euglycemic (90 mg/dl)-hypoglycemic (60 mg/dl) clamp for assessment of neural responses to mild hypoglycemia. RESULTS: Mild hypoglycemia in HC subjects altered activity in the caudate, insula, prefrontal cortex, and angular gyrus, whereas T1DM-Aware subjects showed no caudate and insula changes, but showed altered activation patterns in the prefrontal cortex and angular gyrus. Most strikingly, in direct contrast to HC and T1DM-Aware subjects, T1DM-Unaware subjects failed to show any hypoglycemia-induced changes in brain activity. These findings were also associated with blunted hormonal counterregulatory responses and hypoglycemia symptom scores during mild hypoglycemia. CONCLUSION: In T1DM, and in particular T1DM-Unaware patients, there is a progressive blunting of brain responses in cortico-striatal and fronto-parietal neurocircuits in response to mild-moderate hypoglycemia. These findings have implications for understanding why individuals with impaired hypoglycemia awareness fail to respond appropriately to falling blood glucose levels. FUNDING: This study was supported in part by NIH grants R01DK020495, P30 DK045735, K23DK109284, K08AA023545. The Yale Center for Clinical Investigation is supported by an NIH Clinical Translational Science Award (UL1 RR024139).