On the move:Towards understanding the neural basis of apathy

Apathie kan omschreven worden als een gedragskenmerk waarbij er sprake is van een verlies van motivatie en initiatief, en gevoelens van lusteloosheid. Het opstarten en volhouden van activiteiten is lastig voor mensen met apathie, waardoor minder activiteiten ondernomen worden, met name wanneer deze vanuit jezelf moeten komen. Ongetwijfeld voelt iedereen zich weleens ‘apathisch’, bijvoorbeeld bij een verkoudheid, slaapgebrek of na de griep. Soms kunnen deze apathische klachten echter ook langer voortduren, van maanden tot jaren, en kan het zelfs het ondernemen van eenvoudige alledaagse activiteiten ernstig bemoeilijken. Helaas komt apathie relatief vaak voor. In dit proefschrift is apathie onderzocht in de gezonde populatie, maar ook in patiëntgroepen met neurodegeneratieve stoornissen (zoals bij mensen met de ziekte van Alzheimer), bij mensen met niet-aangeboren hersenletsel (na een ongeluk of hersenbloeding bijvoorbeeld) en bij mensen met een psychische aandoening, namelijk schizofrenie. Het doel van dit proefschrift was om bij te dragen aan een beter begrip van apathie, met de nadruk op het in kaart brengen van mogelijk onderliggende neurale correlaten. De resultaten van dit proefschrift laten zien dat apathie samenhangt met een ander volume en ander activiteitsniveau in met name de frontale en striatale hersengebieden, maar ook in de pariëtale cortex. Daarnaast bleken de neurale correlaten van specifieke componenten van apathie, zoals zelfinitiatie en cognitieve controle respectievelijk niet en wel aangedaan in een gedeelte van de onderzochte populaties

Causal connectivity from right DLPFC to IPL in schizophrenia patients:a pilot study

Abnormal function and connectivity of the fronto-parietal network (FPN) have been documented in patients with schizophrenia, but studies are correlational. We applied repetitive transcranial magnetic stimulation (rTMS) to the dorso-lateral prefrontal cortex (DLPFC) and observed causal connectivity to the inferior parietal lobe (IPL). We hypothesized that patients with schizophrenia would have lower activation and slower reaction in the IPL following DLPFC stimulation. Thirteen patients with schizophrenia (SZ) and fourteen healthy controls subjects (HC) underwent rTMS at 10 Hz to the right DLPFC. Simultaneously, we measured brain activation in the IPL, represented as oxygenized hemoglobin (HbO) levels, using functional near-infrared spectroscopy (fNIRS). rTMS consisted of 20 trains of impulses at 10 Hz for 3 seconds, and 60 seconds waiting time. Using NIRSLab software, GLM was applied to estimate both hemodynamic response function (HRF) and its derivative. Following TMS to the DLPFC, SZ showed a smaller decrease in HbO levels in the bilateral IPL than HC (p = 0.05). Timecourse analysis revealed an immediate decrease in parietal HbO levels in HC, but not in SZ. This difference was significant (at a threshold level of p ≤ 0.05, with Bonferroni correction) for several time segments and channels in both rights and left IPL. Our findings suggest abnormal fronto-temporal connectivity in patients with schizophrenia, beyond a mere decrease or slowing of information processing. This is in line with the hypothesis of reduced fronto-parietal inhibition in schizophrenia

Making Connections:Social identification with New Treatment Groups for Lifestyle Management of Severe Obesity

Groups are regularly used to deliver healthcare services, including the management of obesity, and there is growing evidence that patients' experiences of such groups fundamentally shape treatment effects. This study investigated factors related to patients' shared social identity formed within the context of a treatment group for the management of severe obesity. A cross-sectional survey was administered to patients registered with a UK medical obesity service and enrolled on a group-based education and support programme. Patients (N=78; MBMI = 48 on entry to the service) completed measures of group demographics (e.g., group membership continuity) and psychosocial variables (e.g., past experiences of weight discrimination), and reported their social identification with the treatment group. The results showed that patients identified with the treatment group to the extent that there was continuity in membership across the programme and they perceived themselves more centrally in terms of their weight status. Weight centrality was negatively associated with external social support and positively associated with experiences of weight discrimination. Group continuity was positively correlated with session attendance frequency. Patients presenting to clinical treatment services with severe obesity often do so after sustained weight loss failure and exposure to negative societal experiences. This study highlights that providing a treatment environment wherein these experiences can be shared with other patients may provide common ground for development of a new, positive social identity that can structure programme engagement and progression

Neural basis of self-initiative in relation to apathy in a student sample

Human behaviour can be externally driven, e.g. catching a falling glass, or self-initiated and goaldirected, e.g. drinking a cup of coffee when one deems it is time for a break. Apathy refers to a reduction of self-initiated goal-directed or motivated behaviour, frequently present in neurological and psychiatric disorders. The amount of undertaken goal-directed behaviour varies considerably in clinical as well as healthy populations. In the present study, we investigated behavioural and neural correlates of self-initiated action in a student sample (N=39) with minimal to high levels of apathy. We replicated activation of fronto-parieto-striatal regions during self-initiation. The neural correlates of self-initiated action did not explain varying levels of apathy in our sample, neither when mass-univariate analysis was used, nor when multivariate patterns of brain activation were considered. Other hypotheses, e.g. regarding a putative role of deficits in reward anticipation, effort expenditure or executive difficulties, deserve investigation in future studies

Weight of evidence evaluation of the metabolism disrupting effects of triphenyl phosphate using an expert knowledge elicitation approach

All partners acknowledge the contribution of their institutes for additional financial support. We would also like to acknowledge the scientific contributions from François Pouzaud, Sakina Mhaouty-Kodja and René Habert for the development of the EKE methodology within the frame of the Anses ED Expert group. Contributions from additional members of the GOLIATH consortium: Pierre-Etienne Toulemonde and Romane Multon from Anses are also acknowledged.Peer reviewe

The goliath project: Towards an internationally harmonised approach for testing metabolism disrupting compounds

Copyright © 2020 by the authors. The purpose of this project report is to introduce the European “GOLIATH” project, a new research project which addresses one of the most urgent regulatory needs in the testing of endocrine-disrupting chemicals (EDCs), namely the lack of methods for testing EDCs that disrupt metabolism and metabolic functions. These chemicals collectively referred to as “metabolism disrupting compounds” (MDCs) are natural and anthropogenic chemicals that can promote metabolic changes that can ultimately result in obesity, diabetes, and/or fatty liver in humans. This project report introduces the main approaches of the project and provides a focused review of the evidence of metabolic disruption for selected EDCs. GOLIATH will generate the world’s first integrated approach to testing and assessment (IATA) specifically tailored to MDCs. GOLIATH will focus on the main cellular targets of metabolic disruption—hepatocytes, pancreatic endocrine cells, myocytes and adipocytes—and using an adverse outcome pathway (AOP) framework will provide key information on MDC-related mode of action by incorporating multi-omic analyses and translating results from in silico, in vitro, and in vivo models and assays to adverse metabolic health outcomes in humans at real-life exposures. Given the importance of international acceptance of the developed test methods for regulatory use, GOLIATH will link with ongoing initiatives of the Organisation for Economic Development (OECD) for test method (pre-)validation, IATA, and AOP development

Cancer data quality and harmonization in Europe: the experience of the BENCHISTA Project – international benchmarking of childhood cancer survival by stage

IntroductionVariation in stage at diagnosis of childhood cancers (CC) may explain differences in survival rates observed across geographical regions. The BENCHISTA project aims to understand these differences and to encourage the application of the Toronto Staging Guidelines (TG) by Population-Based Cancer Registries (PBCRs) to the most common solid paediatric cancers.MethodsPBCRs within and outside Europe were invited to participate and identify all cases of Neuroblastoma, Wilms Tumour, Medulloblastoma, Ewing Sarcoma, Rhabdomyosarcoma and Osteosarcoma diagnosed in a consecutive three-year period (2014-2017) and apply TG at diagnosis. Other non-stage prognostic factors, treatment, progression/recurrence, and cause of death information were collected as optional variables. A minimum of three-year follow-up was required. To standardise TG application by PBCRs, on-line workshops led by six tumour-specific clinical experts were held. To understand the role of data availability and quality, a survey focused on data collection/sharing processes and a quality assurance exercise were generated. To support data harmonization and query resolution a dedicated email and a question-and-answers bank were created.Results67 PBCRs from 28 countries participated and provided a maximally de-personalized, patient-level dataset. For 26 PBCRs, data format and ethical approval obtained by the two sponsoring institutions (UCL and INT) was sufficient for data sharing. 41 participating PBCRs required a Data Transfer Agreement (DTA) to comply with data protection regulations. Due to heterogeneity found in legal aspects, 18 months were spent on finalizing the DTA. The data collection survey was answered by 68 respondents from 63 PBCRs; 44% of them confirmed the ability to re-consult a clinician in cases where stage ascertainment was difficult/uncertain. Of the total participating PBCRs, 75% completed the staging quality assurance exercise, with a median correct answer proportion of 92% [range: 70% (rhabdomyosarcoma) to 100% (Wilms tumour)].ConclusionDifferences in interpretation and processes required to harmonize general data protection regulations across countries were encountered causing delays in data transfer. Despite challenges, the BENCHISTA Project has established a large collaboration between PBCRs and clinicians to collect detailed and standardised TG at a population-level enhancing the understanding of the reasons for variation in overall survival rates for CC, stimulate research and improve national/regional child health plans

Apathy Is Related to Reduced Activation in Cognitive Control Regions During Set-Shifting

Apathy is a prominent and influential symptom in several neurological and psychiatric disorders, but it also occurs in the healthy population. It has considerable impact on daily life functioning, in clinical as well as healthy samples. Even though cognitive control is thought to be disrupted in people with apathy, the exact neural underpinnings of apathy remain unclear. Because flexible shifting between behaviors (set-shifting) is crucial for goal-directed behavior, disruptions in set-shifting may underlie apathy. In this study, the neural correlates of apathy during set-shifting were studied in 34 healthy participants with varying levels of apathy, measured by the Apathy Evaluation Scale. During functional MRI scanning participants performed a set-shifting task, distinguishing between behavioral switches (a change in response to different stimuli), cognitive switches (a change in response rule), and salience decoupling (detecting a change in relevant stimuli). Regression analysis was used to assess the relationship between apathy and brain activation. Results showed that higher apathy scores were related to reduced activation in the medial superior frontal gyrus and cerebellum (Crus I/II) during cognitive set-shifting, but not behavioral shifting and salience decoupling. No relationship between apathy and accuracy or response time was found. These results support the idea that alterations in the neural basis of cognitive control, especially cognitive set-shifting, may contribute to apathy. (C) 2017 Wiley Periodicals, Inc