Body dissatisfaction is an important precipitating and maintenance factor in anorexia nervosa (AN) and behavioral studies suggest that a cognitive–affective component and a perceptual component ...(perceptual disturbance of one's own body) are both important in this pathophysiology. However, the functional neuroanatomy of body dissatisfaction in AN is largely unknown. This study has investigated self-other body-shape comparison to establish neural correlates of body dissatisfaction in patients with AN. 17 women with AN and 18 age and sex-matched healthy control (HC) subjects were scanned using functional magnetic resonance imaging while comparing themselves with images of slim idealized female bodies (active condition) or viewing images of interior home designs (control condition). Participants were asked to compare their body shape or room design with those presented.
Patients with AN (in comparison to the HC group) showed greater anxiety to the self-other body-shape comparison, and they were less satisfied with their current body shape. In the patient group (in comparison to the HC group) the self-other body-shape comparison induced more activation of the right sensorimotor brain regions (insula, premotor cortex) and less activation of the rostral anterior cingulate cortex (ACC). Insula hyperactivation along with ACC hypoactivation may be critical for altered interoceptive awareness to body self-comparison and/or for altered implicit motivation to thin-idealized body images in AN patients.
To maintain nutritional homeostasis, external food-related stimuli have to be evaluated in relation to the internal states of hunger or satiety. To examine the neural circuitry responsible for ...integration of internal and external determinants of human eating behaviour, brain responses to visual and complex gustatory food-related stimuli were measured using functional magnetic resonance imaging in 18 healthy non-smokers (10 women, 8 men). Each individual was studied on two occasions, the order of which was counterbalanced; after eating as usual and after 24
h fasting. Raised plasma free fatty acids and lower insulin and leptin concentrations confirmed that participants fasted as requested. When fasted, participants reported more hunger, nervousness and worse mood and rated the visual (but not gustatory) food-related stimuli as more pleasant. The effect of fasting on hunger was stronger in women than in men. No circuitry was identified as differentially responsive in fasting compared to satiety to both visual and gustatory food-related stimuli. The left insula response to the gustatory stimuli was stronger during fasting. The inferior occipito-temporal response to visual food-related stimuli also tended to be stronger during fasting. The responses in the occipito-temporal cortex to visual and in the insula to gustatory stimuli were stronger in women than in men. There was no interaction between gender and fasting. In conclusion, food reactivity in modality-specific sensory cortical areas is modulated by internal motivational states. The stronger reactivity to external food-related stimuli in women may be explored as a marker of gender-related susceptibility to eating disorders.
Abstract
Monitoring sleep and activity through wearable devices such as wrist-worn actigraphs has the potential for long-term measurement in the individual’s own environment. Long periods of data ...collection require a complex approach, including standardized pre-processing and data trimming, and robust algorithms to address non-wear and missing data. In this study, we used a data-driven approach to quality control, pre-processing and analysis of longitudinal actigraphy data collected over the course of 1 year in a sample of 95 participants. We implemented a data processing pipeline using open-source packages for longitudinal data thereby providing a framework for treating missing data patterns, non-wear scoring, sleep/wake scoring, and conducted a sensitivity analysis to demonstrate the impact of non-wear and missing data on the relationship between sleep variables and depressive symptoms. Compliance with actigraph wear decreased over time, with missing data proportion increasing from a mean of 4.8% in the first week to 23.6% at the end of the 12 months of data collection. Sensitivity analyses demonstrated the importance of defining a pre-processing threshold, as it substantially impacts the predictive value of variables on sleep-related outcomes. We developed a novel non-wear algorithm which outperformed several other algorithms and a capacitive wear sensor in quality control. These findings provide essential insight informing study design in digital health research.
Abstract
Identifying biomarkers of antidepressant response may advance personalized treatment of major depressive disorder (MDD). We aimed to identify longitudinal changes in gene expression ...associated with response to antidepressants in a sample of MDD patients treated with escitalopram. Patients (
N
= 153) from the CAN-BIND-1 cohort were treated for 8 weeks, and depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale at 0, 2, 4, 6, and 8 weeks. We identified three groups of patients according to response status: early responders (22.9%), later responders (32.0%), and nonresponders (45.1%). RNA sequencing was performed in blood obtained at weeks 0, 2, and 8. RNA expression was modeled using growth models, and differences in the longitudinal changes in expression according to response were investigated using multiple regression models. The expression of RNAs related to response was investigated in the brains of depressed individuals, as well as in neuronal cells in vitro. We identified four RNAs (
CERCAM, DARS-AS1, FAM228B, HBEGF
) whose change over time was independently associated with a response status. For all except
HBEGF
, responders showed higher expression over time, compared to nonresponders. While the change in all RNAs differentiated early responders from nonresponders, changes in
DARS-AS1
and
HBEGF
also differentiated later responders from nonresponders. Additionally,
HBEGF
was downregulated in the brains of depressed individuals, and increased in response to escitalopram treatment in vitro. In conclusion, using longitudinal assessments of gene expression, we provide insights into biological processes involved in the intermediate stages of escitalopram response, highlighting several genes with potential utility as biomarkers of antidepressant response.
Traditional diagnoses of major depressive disorder (MDD) suggested that the presence or absence of stress prior to onset results in either 'reactive' or 'endogenous' subtypes of the disorder, ...respectively. Several lines of research suggest that the biological underpinnings of 'reactive' or 'endogenous' subtypes may also differ, resulting in differential response to treatment. We investigated this hypothesis by comparing the gene-expression profiles of three animal models of 'reactive' and 'endogenous' depression. We then translated these findings to clinical samples using a human post-mortem mRNA study.
Affymetrix mouse whole-genome oligonucleotide arrays were used to measure gene expression from hippocampal tissues of 144 mice from the Genome-based Therapeutic Drugs for Depression (GENDEP) project. The study used four inbred mouse strains and two depressogenic 'stress' protocols (maternal separation and Unpredictable Chronic Mild Stress) to model 'reactive' depression. Stress-related mRNA differences in mouse were compared with a parallel mRNA study using Flinders Sensitive and Resistant rat lines as a model of 'endogenous' depression. Convergent genes differentially expressed across the animal studies were used to inform candidate gene selection in a human mRNA post-mortem case control study from the Stanley Brain Consortium.
In the mouse 'reactive' model, the expression of 350 genes changed in response to early stresses and 370 in response to late stresses. A minimal genetic overlap (less than 8.8%) was detected in response to both stress protocols, but 30% of these genes (21) were also differentially regulated in the 'endogenous' rat study. This overlap is significantly greater than expected by chance. The VAMP-2 gene, differentially expressed across the rodent studies, was also significantly altered in the human study after correcting for multiple testing.
Our results suggest that 'endogenous' and 'reactive' subtypes of depression are associated with largely distinct changes in gene-expression. However, they also suggest that the molecular signature of 'reactive' depression caused by early stressors differs considerably from that of 'reactive' depression caused by late stressors. A small set of genes was consistently dysregulated across each paradigm and in post-mortem brain tissue of depressed patients suggesting a final common pathway to the disorder. These genes included the VAMP-2 gene, which has previously been associated with Axis-I disorders including MDD, bipolar depression, schizophrenia and with antidepressant treatment response. We also discuss the implications of our findings for disease classification, personalized medicine and case-control studies of MDD.
Affective lability, defined as the propensity to experience excessive and unpredictable changes in mood, has been proposed as a potential transdiagnostic predictor of major mood and psychotic ...disorders. A parental diagnosis of bipolar disorder has been associated with increased affective lability in offspring. However, the association between affective lability and family history of other mood and psychotic disorders has not been examined. We measured affective lability using the self- and parent-reported Children’s Affective Lability Scale in a cohort of 320 youth aged 6–17 years, including 137 offspring of a parent with major depressive disorder, 68 offspring of a parent with bipolar disorder, 24 offspring of a parent with schizophrenia, and 91 offspring of control parents. We tested differences in affective lability between groups using mixed-effects linear regression. Offspring of a parent with major depressive disorder (
β
= 0.46, 95% CI 0.17–0.76,
p
= 0.002) or bipolar disorder (
β
= 0.47, 95% CI 0.12–0.81,
p
= 0.008) had significantly higher affective lability scores than control offspring. Affective lability did not differ significantly between offspring of a parent with schizophrenia and offspring of control parents. Our results suggest that elevated affective lability during childhood is a marker of familial risk for mood disorders.
Abstract Background Bipolar affective disorder (BPAD) is characterised by a lifelong vulnerability to develop episodes of depressed or elevated mood in response to stressful life events involving ...achievement or failure. We hypothesised that this latent vulnerability can manifest as reactivity of affect and self-esteem to experimentally induced experiences of success and failure and is shaped by history of childhood adversity. Methods Twenty-four people with remitted BPAD and twenty-four healthy controls underwent anagram-solving tasks designed to generate experiences of success and failure in two separate sessions. Positive and negative affect and implicit and explicit self-esteem were measured before and after each task. Early adversity was measured by Childhood Trauma Questionnaire. Results People with BPAD showed larger reactivity of affect and explicit self-esteem in response to experimental success and failure than did healthy controls. There were no significant differences in reactivity of implicit self-esteem. History of childhood trauma predicted increased affective reactivity to failure but not to success. Limitations We used a convenience sample. Conclusions The present experimental paradigm reveals reactivity of affect and self-esteem as features of BPAD, which are present even during good remission and thus are accessible as targets of interventions aiming at relapse prevention. Differential associations with childhood adversity indicate aetiological heterogeneity, with reactivity to failure influenced by early trauma and reactivity to success driven by other mechanisms.
Abstract
Cytochrome P450 drug-metabolizing enzymes may contribute to interindividual differences in antidepressant outcomes. We investigated the effects of
CYP2C19
and
CYP2D6
gene variants on ...response, tolerability, and serum concentrations. Patients (
N
= 178) were treated with escitalopram (ESC) from weeks 0–8 (Phase I), and at week 8, either continued ESC if they were responders or were augmented with aripiprazole (ARI) if they were non-responders (<50% reduction in Montgomery–Åsberg Depression Rating Scale from baseline) for weeks 8–16 (Phase II). Our results showed that amongst patients on ESC-Only,
CYP2C19
intermediate and poor metabolizers (IM + PMs), with reduced or null enzyme function, trended towards significantly lower symptom improvement during Phase II compared to normal metabolizers (NMs), which was not observed in ESC + ARI. We further showed that
CYP2D6
NMs and IM + PMs had a higher likelihood of reporting a treatment-related central nervous system side effect in ESC-Only and ESC + ARI, respectively. The differences in the findings between ESC-Only and ESC + ARI may be due to the altered pharmacokinetics of ESC by ARI coadministration in ESC + ARI. We provided evidence for this postulation when we showed that in ESC-Only,
CYP2C19
and
CYP2D6
IM + PMs demonstrated significantly higher ESC concentrations at Weeks 10 and 16 compared to NMs. In contrast, ESC + ARI showed an association with
CYP2C19
but not with
CYP2D6
metabolizer group. Instead, ESC + ARI showed an association between
CYP2D6
metabolizer group and ARI metabolite-to-drug ratio suggesting potential competition between ESC and ARI for CYP2D6. Our findings suggest that dosing based on
CYP2C19
and
CYP2D6
genotyping could improve safety and outcome in patients on ESC monotherapy.
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