Survey of healthcare professionals' experiences of care delivery in patients with chronic intestinal failure: ATLAS of Variance.

BACKGROUND AND AIM: Chronic intestinal failure (IF) is a rare but life-altering condition, care delivery of which is complex. The ATLAS Programme was initiated in 2016 to increase disease awareness and address inconsistencies in delivery of care across Europe. We describe the results of a non-interventional study that aimed to explore how adult patients with chronic IF are managed across Europe. MATERIALS AND METHODS: This mixed-methods, non-interventional, cross-sectional study comprised a desk-based landscape assessment (Phase 1), qualitative interviews (Phase 2), and an online quantitative survey (Phase 3) completed by healthcare professionals (HCPs) involved in the management of adult patients with chronic IF during the period November 2020 to January 2021. Data were collected from 12 European countries. Survey data were anonymised and pooled for analysis at European and country level. Responses were summarised as frequencies, ranks and percentage. RESULTS: The quantitative survey was carried out on 119 HCPs across an estimated 58 centres. Gastroenterology was the most frequent specialty of respondents (45%). Three-quarters of HCPs (N = 119) reported that their department/unit had a multidisciplinary team for the management of patients with chronic IF. HCPs reported improving quality of life (QoL) to be the most important goal of treatment (39%), followed by reducing mortality (25%), intestinal rehabilitation (20%) and reducing morbidity (9%). Similarly, 63% of HCPs responded that improved QoL was the most important treatment goal from the perspective of their patients. Overall, 87% of HCPs reported that patients with chronic IF routinely receive home parenteral nutrition (HPN) in their country, which was more common in Western versus Eastern Europe. Meeting treatment goals (53%) and achieving better levels of support with HPN (44%) were reported as the main challenges faced by HCPs in the management of patients with chronic IF. A general lack of disease awareness of chronic IF among HCPs (46%), and insufficient accredited patient referral centres (41%) were considered the most important areas for improvement. CONCLUSIONS: HCPs specialising in treating chronic IF considered that improvement in QoL is needed for their patients. They reported a low level of awareness of chronic IF among non-specialist HCPs.

Survival after acute episodes of immune-mediated thrombotic thrombocytopenic purpura (iTTP) - cognitive functioning and health-related quality of life impact: a descriptive cross-sectional survey of adults living with iTTP in the United Kingdom.

OBJECTIVES: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare life-threatening thrombotic microangiopathy affecting adults with unpredictable disease onset and acute presentation. This study aimed to describe the health-related quality of life (HRQoL), cognitive functioning and work productivity of survivors following acute episode(s) of iTTP in the United Kingdom (UK). METHODS: An online survey was developed in collaboration with the TTP Network. Descriptive statistics were calculated for the health questionnaire Short Form Survey-36 Version 2 (SF-36v2), the Hospital Anxiety and Depression Score (HADS), the PROMIS Cognitive Function Abilities Subset - Short Form 6a (PROMIS CFAS - SF6a), and the Work Productivity and Activity Index: Specific Health Problem (WPAI-SHP), along with several iTTP-specific bespoke questions. RESULTS: Fifty participants were recruited between July-November 2019. The mean (standard deviation [SD]) standardized SF-36v2 physical and mental component scores were 42.16 (9.59) and 33.61 (12.34), lower than population norms. The mean (SD) standardized PROMIS CFAS - SF6a score was 39.69 (7.86), lower than population norms. HADS mean (SD) scores of 12.18 (3.14) and 11.78 (2.36) indicated moderate levels of anxiety and depression, respectively. Of those employed (58%), approximately 42.73% of participants reported work productivity loss due to their iTTP. Participants also reported experiencing flashbacks, fatigue interference in family, social and intimate life, and fears of relapse. DISCUSSION AND CONCLUSION: Regardless of recency of the last acute episode, participant scores signified impairments in all domains. Remission from an acute episode of disease does not signify the conclusion of care, but rather the requirement for long-term healthcare particularly focused on psychological support.

Dimensional anhedonia and the adolescent brain: reward and aversion anticipation, effort and consummation.

BACKGROUND: Given the heterogeneity of depression the Research Domain Criteria Framework suggests a dimensional approach to understanding the nature of mental illness. Neural reward function has been suggested as underpinning the symptom of anhedonia in depression but how anhedonia is related to aversion processing is unclear. AIMS: To assess how the dimensional experience of anhedonia and depression severity relate to reward and aversion processing in the human brain. METHOD: We examined adolescents and emerging adults (n = 84) in the age range 13-21 years. Using a dimensional approach we examined how anhedonia and depression related to physical effort to gain reward or avoid aversion and neural activity during the anticipation, motivation/effort and consummation of reward and aversion. RESULTS: As anhedonia increased physical effort to gain reward decreased. As anhedonia increased neural activity decreased during effort to avoid in the precuneus and insula (trend) and increased in the caudate during aversive consummation. We found participants with depression symptoms invested less physical effort than controls and had blunted neural anticipation of reward and aversion in the precuneus, insula and prefrontal cortex and blunted neural activity during effort for reward in the putamen. CONCLUSIONS: We show for the first time that both physical effort and neural activity during effort correlate with anhedonia in adolescents and that amotivation might be a specific deficit of anhedonia irrespective of valence. Future work will assess if these neural mechanisms can be used to predict blunted approach and avoidance in adolescents at risk of depression.

Anhedonia and depression severity dissociated by dmPFC resting-state functional connectivity in adolescents.

INTRODUCTION: Given the heterogeneity within depression, in this study we aim to examine how resting-state functional connectivity (RSFC) in adolescents is related to anhedonia and depression severity on a continuum in line with the research domain criteria (RDoC) approach. METHODS: We examined how RSFC in the dorsal medial prefrontal cortex (dmPFC), nucleus accumbens (NAcc) and pregenual anterior cingulate cortex (pgACC) was related to anhedonia and depression severity in 86 adolescents (13-21 years). RESULTS: We found both anhedonia and depression severity related to decreased dmPFC RSFC with the precuneus, a part of the default mode network. However we also found that increased dmPFC connectivity with the ACC/paracingulate gyrus related to anhedonia whereas increased RSFC with the frontal pole related to depression severity. DISCUSSION: This work extends the view that the dmPFC is a potential therapeutic target for depression in two ways: 1. We report dmPFC connectivity in adolescents; and 2. We show different dmPFC RSFC specific to anhedonia and depression severity, providing neural targets for intervention in young people at risk of depression.

Bupropion Administration Increases Resting-State Functional Connectivity in Dorso-Medial Prefrontal Cortex.

Background: Patients on the selective serotonergic reuptake inhibitors like citalopram report emotional blunting. We showed previously that citalopram reduces resting-state functional connectivity in healthy volunteers in a number of brain regions, including the dorso-medial prefrontal cortex, which may be related to its clinical effects. Bupropion is a dopaminergic and noradrenergic reuptake inhibitor and is not reported to cause emotional blunting. However, how bupropion affects resting-state functional connectivity in healthy controls remains unknown. Methods: Using a within-subjects, repeated-measures, double-blind, crossover design, we examined 17 healthy volunteers (9 female, 8 male). Volunteers received 7 days of bupropion (150 mg/d) and 7 days of placebo treatment and underwent resting-state functional Magnetic Resonance Imaging. We selected seed regions in the salience network (amygdala and pregenual anterior cingulate cortex) and the central executive network (dorsal medial prefrontal cortex). Mood and anhedonia measures were also recorded and examined in relation to resting-state functional connectivity. Results: Relative to placebo, bupropion increased resting-state functional connectivity in healthy volunteers between the dorsal medial prefrontal cortex seed region and the posterior cingulate cortex and the precuneus cortex, key parts of the default mode network. Conclusions: These results are opposite to that which we found with 7 days treatment of citalopram in healthy volunteers. These results reflect a different mechanism of action of bupropion compared with selective serotonergic reuptake inhibitors. These results help explain the apparent lack of emotional blunting caused by bupropion in depressed patients.

Blunted neural response to anticipation, effort and consummation of reward and aversion in adolescents with depression symptomatology.

Neural reward function has been proposed as a possible biomarker for depression. However, how the neural response to reward and aversion might differ in young adolescents with current symptoms of depression is as yet unclear. Thirty-three adolescents were recruited, 17 scoring low on the Mood and Feelings Questionnaire (low risk group) and 16 scoring high (high risk group). Our functional magnetic resonance imaging task measured; anticipation (pleasant/unpleasant cue), effort (achieve a pleasant taste or avoid an unpleasant taste) and consummation (pleasant/unpleasant tastes) in regions of interest; ventral medial prefrontal cortex, pregenual cingulate cortex, the insula and ventral striatum. We also examined whole brain group differences. In the regions of interest analysis we found reduced activity in the high risk group in the pregenual cingulate cortex during anticipation and reduced pregenual cingulate cortex and ventral medial prefrontal cortex during effort and consummation. In the whole brain analysis we also found reduced activity in the high risk group in the prefrontal cortex and the precuneus during anticipation. We found reduced activity in the hippocampus during the effort phase and in the anterior cingulate/frontal pole during consummation in the high risk group. Increased anhedonia measures correlated with decreased pregenual cingulate cortex activity during consummation in the high risk group only. Our results are the first to show that adolescents with depression symptoms have blunted neural responses during the anticipation, effort and consummation of rewarding and aversive stimuli. This study suggests that interventions in young people at risk of depression, that can reverse blunted responses, might be beneficial as preventative strategies.

Decreased anticipated pleasure correlates with increased salience network resting state functional connectivity in adolescents with depressive symptomatology.

Previous studies have found dysfunctional resting state functional connectivity (RSFC) in depressed patients. Examining RSFC might aid biomarker discovery for depression. However RSFC in young people at risk of depression has yet to be examined. 35 healthy adolescents (13-18 yrs old.) were recruited. 17 scoring high on the Mood and Feelings Questionnaire (MFQ > 27 (High Risk: HR), and 18 scoring low on the MFQ < 15 (Low Risk: LR) matched on age and gender. We selected seed regions in the salience network (SN: amygdala and pregenual anterior cingulate cortex (pgACC)) and the central executive network (CEN: dorsal medial prefrontal cortex (dmPFC)). Mood and anhedonia measures were correlated with brain connectivity. We found decreased RSFC in the HR group between the amygdala and the pgACC and hippocampus and precuneus. We also found decreased RSFC in the HR group between the pgACC and the putamen and between the dmPFC and the precuneus. The pgACC RSFC with the insula/orbitofrontal cortex correlated inversely with the anticipation of pleasure in all subjects. Increased RSFC was observed between the pgACC and the prefrontal cortex and the amygdala and the temporal pole in the HR group compared to the LR group. Our findings are the first to show that adolescents with depression symptoms have dysfunctional RSFC between seeds in the SN and CEN with nodes in the Default Mode Network. As increased connectivity between the pgACC and the insula correlated with decreased ability to anticipate pleasure, we suggest this might be mechanism underlying the risk of experiencing anhedonia, a suggested biomarker for depression.

The CB1 Neutral Antagonist Tetrahydrocannabivarin Reduces Default Mode Network and Increases Executive Control Network Resting State Functional Connectivity in Healthy Volunteers.

BACKGROUND: The cannabinoid cannabinoid type 1 (CB1) neutral antagonist tetrahydrocannabivarin (THCv) has been suggested as a possible treatment for obesity, but without the depressogenic side-effects of inverse antagonists such as Rimonabant. However, how THCv might affect the resting state functional connectivity of the human brain is as yet unknown. METHOD: We examined the effects of a single 10mg oral dose of THCv and placebo in 20 healthy volunteers in a randomized, within-subject, double-blind design. Using resting state functional magnetic resonance imaging and seed-based connectivity analyses, we selected the amygdala, insula, orbitofrontal cortex, and dorsal medial prefrontal cortex (dmPFC) as regions of interest. Mood and subjective experience were also measured before and after drug administration using self-report scales. RESULTS: Our results revealed, as expected, no significant differences in the subjective experience with a single dose of THCv. However, we found reduced resting state functional connectivity between the amygdala seed region and the default mode network and increased resting state functional connectivity between the amygdala seed region and the dorsal anterior cingulate cortex and between the dmPFC seed region and the inferior frontal gyrus/medial frontal gyrus. We also found a positive correlation under placebo for the amygdala-precuneus connectivity with the body mass index, although this correlation was not apparent under THCv. CONCLUSION: Our findings are the first to show that treatment with the CB1 neutral antagonist THCv decreases resting state functional connectivity in the default mode network and increases connectivity in the cognitive control network and dorsal visual stream network. This effect profile suggests possible therapeutic activity of THCv for obesity, where functional connectivity has been found to be altered in these regions.