Persistent transcriptional events in ventral tegmental area (VTA) and other reward relevant brain regions contribute to enduring behavioral adaptations that characterize substance use disorder. ...Recent data from our laboratory indicate that aberrant accumulation of the newly discovered histone post-translational modification (PTM), H3 dopaminylation at glutamine 5 (H3Q5dop), contributes significantly to cocaine-seeking behavior following prolonged periods of abstinence. It remained unclear, however, whether this modification is important for relapse vulnerability in the context of other drugs of abuse, such as opioids. Here, we showed that H3Q5dop plays a critical role in heroin-mediated transcriptional plasticity in midbrain regions, particularly the VTA. In rats undergoing abstinence from heroin self-administration (SA), we found acute and persistent accumulation of H3Q5dop in VTA. Attenuation of H3Q5dop during abstinence induced persistent changes in gene expression programs associated with neuronal signaling and dopaminergic function in heroin abstinence and led to reduced heroin-seeking behavior. Interestingly, the observed changes in molecular pathways after heroin SA showed significant yet reversed overlap with the same genes altered in cocaine SA. These findings establish an essential role for H3Q5dop, and its downstream transcriptional consequences, in heroin-induced functional plasticity in VTA.
•Caregiving for a child with an autism spectrum disorder (ASD) is a chronic stressor.•How caregivers integrate stressful experiences is correlated with mental and psychobiological health ...outcomes.•Caregivers with more integrated narratives had slower telomere shortening over 18 months.•Narrative integration, not affective themes, correlated with positive biological indicators.•Integrating what caregiving means for self-identity may be a source of stress resilience.
Chronic caregiving stress may accelerate biological aging; however, the ability to integrate the meaning of caregiving through self-awareness, adaptation, and growth can buffer the negative effects of stress. Narrative researchers have shown that people who coherently integrate difficult experiences into their life story tend to have better mental health, but no prior study has examined the prospective association between narrative identity and biological indicators, such as telomere length. We tested whether narrative identity might be prospectively associated with resilience to long-term parenting stress, depressive symptoms, and protection from telomere shortening, especially among caregivers.
We conducted a semi-structured interview about parenting and quantified narrative themes by applying well-validated, standardized coding systems with high inter-rater reliability among 88 mothers: 32 “caregivers” (mothers with a child diagnosed with an autism spectrum disorder), and 56 “controls” (mothers with a neurotypical child). To assess longitudinal changes, we measured mental health (parenting stress PS, depressive symptoms DS) and leukocyte telomere length LTL, a biomarker of aging, at baseline and again 18 months later. We examined whether narrative identity themes were related to these outcomes and whether associations differed across caregivers versus controls.
Caregivers exhibited significantly higher basal levels of PS and DS relative to controls (all p’s < .05), but no significant difference in LTL (p > .05). Caregivers rated higher in the narrative theme of integration showed healthier future 18-month trajectories in PS (B = −0.832, 99% CI: −1.315, −0.155, p < .01) and LTL (B = 1.193, 99% CI: 0.526, 2.130, p < .01), but no differences in depressive symptoms (p > .05), adjusting for age and antidepressant use. Analyses examining affective themes in caregiver narratives did not demonstrate significant associations. Narrative themes did not predict outcomes in controls.
The data suggest that narratives reflecting coherent integration, but not necessarily affect, prospectively relate to psychological and biological stress resilience. Maternal caregivers’ ability to tell an integrated story of their parenting experiences forecasts lower parenting stress and telomere shortening over time. This study suggests the possibility that helping individuals better integrate the meaning of stressful experiences, but not necessarily to affectively redeem them, may constitute a potential novel target for intervention among chronically stressed populations such as caregivers.
Dietary treatment is important in management of type 2 diabetes or prediabetes, but uncertainty exists about the optimal diet. We randomized adults (n = 34) with glycated hemoglobin (HbA1c) > 6.0% ...and elevated body weight (BMI > 25) to a very low-carbohydrate ketogenic (LCK) diet (n = 16) or a moderate-carbohydrate, calorie-restricted, low-fat (MCCR) diet (n = 18). All participants were encouraged to be physically active, get sufficient sleep, and practice behavioral adherence strategies based on positive affect and mindful eating. At 12 months, participants in the LCK group had greater reductions in HbA1c levels (estimated marginal mean (EMM) at baseline = 6.6%, at 12 mos = 6.1%) than participants in MCCR group (EMM at baseline = 6.9%, at 12 mos = 6.7%), p = .007. Participants in the LCK group lost more weight (EMM at baseline = 99.9 kg, at 12 mos = 92.0 kg) than participants in the MCCR group (EMM at baseline = 97.5 kg, at 12 mos = 95.8 kg), p < .001. The LCK participants experienced larger reductions in diabetes-related medication use; of participants who took sulfonylureas or dipeptidyl peptidase-4 inhibitors at baseline, 6/10 in the LCK group discontinued these medications compared with 0/6 in the MCCR group (p = .005). In a 12-month trial, adults with elevated HbA1c and body weight assigned to an LCK diet had greater reductions in HbA1c, lost more weight, and reduced more medications than those instructed to follow an MCCR diet.
To examine the feasibility of an integrated mind-body MDD treatment combining cognitive behavioral therapy (CBT) and whole-body hyperthermia (WBH).
In this single-arm trial, 16 adults with MDD ...initially received 8 weekly CBT sessions and 8 weekly WBH sessions. Outcomes included WBH sessions completed (primary), self-report depression assessments completed (secondary), and pre-post intervention changes in depression symptoms (secondary). We also explored changes in mood and cognitive processes and assessed changes in mood as predictors of overall treatment response.
Thirteen participants (81.3%) completed
4 WBH sessions (primary outcome); midway through the trial, we reduced from 8 weekly to 4 bi-weekly WBH sessions to increase feasibility. The
= 12 participants who attended the final assessment visit completed 100% of administered self-report depression assessments; all enrolled participants (
= 16) completed 89% of these assessments. Among the
= 12 who attended the final assessment visit, the average pre-post-intervention BDI-II reduction was 15.8 points (95% CI: -22.0, -9.70),
0.0001, with 11 no longer meeting MDD criteria (secondary outcomes). Pre-post intervention improvements in negative automatic thinking, but not cognitive flexibility, achieved statistical significance. Improved mood from pre-post the initial WBH session predicted pre-post treatment BDI-II change (36.2%;
= 0.60,
= 0.038); mood changes pre-post the first CBT session did not.
Small sample size and single-arm design limit generalizability.
An integrated mind-body intervention comprising weekly CBT sessions and bi-weekly WBH sessions was feasible. Results warrant future larger controlled clinical trials.
NCT05708976.
Objective
The aim of this study was to examine whether baseline chronic stress and impulsive risk‐taking synergistically predict changes in visceral fat among healthy mothers in an observational, ...longitudinal, 18‐month study.
Methods
A prospective cohort of 113 adult women (age, mean ± SD: 42.83 ± 4.70; BMI, mean ± SD: 24.86 ± 4.32; 74%, n = 84 white) completed assessments at baseline and 18‐month follow‐up. Chronically stressed mothers caring for a child with an autism spectrum disorder (“caregivers”; n = 72 participants) were compared with lower stress mothers caring for a neurotypical child (“controls”; n = 41). This study objectively assessed impulsive risk‐taking by using the Behavioral Analog Risk Task at baseline and assessed visceral fat at baseline and 18‐month follow‐up by using bioelectrical impedance (ViScan; Tanita Corporation, Tokyo, Japan).
Results
The interaction of baseline chronic caregiving stress and impulsive risk‐taking predicted an 18‐month change in visceral fat, such that greater impulsive risk‐taking was associated with greater 18‐month increases in visceral fat among caregivers (ß = 0.423; P = 0.005) but not among controls (ß = −0.030; P = 0.802), both in unadjusted models and after accounting for covariates. Neither chronic stress nor impulsive risk‐taking independently predicted 18‐month changes in visceral fat.
Conclusions
The combination of high chronic stress and high impulsive risk‐taking may increase risk for visceral fat gain over time and therefore may be an important intervention target in obesity prevention.
Optimal carbohydrate intake is an important and controversial area in the nutritional management of type 2 diabetes. Some evidence indicates that reducing overall carbohydrate intake with a low- or ...very low-carbohydrate eating plan can improve glycemic control compared to following eating plans that involve greater carbohydrate intake. However, critical knowledge gaps currently prevent clear recommendations about carbohydrate intake levels.
The LEGEND (Lifestyle Education about Nutrition for Diabetes) Trial aims to compare a very low-carbohydrate diet to a moderate-carbohydrate plate-method diet for glycemic control in adults with type 2 diabetes. This two-site trial plans to recruit 180 adults with type 2 diabetes. We will randomize participants to either a 20-session group-based diet and lifestyle intervention that teaches either a very low-carbohydrate diet or a moderate-carbohydrate plate-method diet. We will assess participants at study entry and 4 and 12 months later. The primary outcome is HbA1c, and secondary outcomes include inflammation (high sensitivity C-reactive protein), body weight, changes in diabetes medications, lipids (small particle LDL, HDL, triglycerides), skeletal metabolism (bone mineral density from dual-energy x-ray absorptiometry and bone turnover markers serum procollagen type I N propeptide and serum C-terminal telopeptide of type I collagen), and body composition (percent body fat, percent lean body mass).
The LEGEND trial is a randomized controlled trial to assess optimal carbohydrate intake in type 2 diabetes by evaluating the effects of a very low-carbohydrate diet vs. a moderate-carbohydrate plate-method diet over a year-long period. The research addresses important gaps in the evidence base for the nutritional management of type 2 diabetes by providing data on potential benefits and adverse effects of different levels of carbohydrate intake.
ClinicalTrials.gov NCT05237128. Registered on February 11, 2022.
•This study examines an immune mechanism that contributes to the antidepressant effects of whole-body hyperthermia.•Whole-body hyperthermia led to an acute, time-limited increase in the ratio of ...interleukin-6 (IL-6):soluble IL-6 receptor.•Increased ratio of IL-6:soluble IL-6 receptor was associated with the anti-depressant effect of whole-body hyperthermia.
There is urgent need for novel antidepressant treatments that confer therapeutic benefits via engagement with identified mechanistic targets. The objective of the study was to determine whether activation of the classical anti-inflammatory interleukin-6 signaling pathways is associated with the antidepressant effects of whole-body hyperthermia. A 6-week, randomized, double-blind study compared whole-body hyperthermia with a sham condition in a university-based medical center. Medically healthy participants aged 18–65 years who met criteria for major depressive disorder, were free of psychotropic medication use, and had a baseline 17-item Hamilton Depression Rating Scale score ≥ 16 were randomized with 1-to-1 allocation in blocks of 6 to receive whole-body hyperthermia or sham. Of 338 individuals screened, 34 were randomized, 30 received interventions and 26 had ≥ 2 blood draws and depressive symptom assessments. Secondary data analysis examined change in the ratio of IL-6:soluble IL-6 receptor pre-intervention, post-intervention, and at weeks 1 and 4. Hierarchical linear modeling tested whether increased IL-6:soluble IL-6 receptor ratio post-intervention was associated with decreased depressive symptom at weeks 1, 2, 4 and 6 for those randomized to whole-body hyperthermia. Twenty-six individuals were randomized to whole-body hyperthermia n = 12; 75 % female; age = 37.9 years (SD = 15.3) or sham n = 14; 57.1 % female; age = 41.1 years (SD = 12.5). When compared to the sham condition, active whole-body hyperthermia only increased the IL-6:soluble IL-6 receptor ratio post-treatment F(3,72) = 11.73,p < .001, but not pre-intervention or at weeks 1 and 4. Using hierarchical linear modeling, increased IL-6:sIL-6R ratio following whole-body hyperthermia moderated depressive symptoms at weeks 1, 2, 4 and 6, such that increases in the IL-6:soluble IL-6 receptor ratio were associated with decreased depressive symptoms at weeks 1, 2, 4 and 6 for those receiving the active whole-body hyperthermia compared to sham treatment (B = –229.44, t = -3.82,p < .001). Acute activation of classical intereukin-6 signaling might emerge as a heretofore unrecognized novel mechanism that could be harnessed to expand the antidepressant armamentarium.
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