Title Promoter Affiliations Abstract "Shifting away from pain: Neurocognitive approach to explain and predict the response to the modern neuroscience approach for treating patients with whiplash associated disorders" "Mira Meeus" "Department of Rehabilitation Sciences" "Acute pain helps us to avoid danger. When pain becomes chronic, however, and there is no (longer) tissue damage, it can be very disabling. Chronic whiplash-associated disorder (WAD) is one type of chronic pain, typically characterized by neck pain. Many patients with WAD show poor treatment responses, presenting a challenge for rehabilitation. Recently, a new treatment was proposed: the modern pain neuroscience approach. This approach starts with pain neuroscience education. It explains, for instance, that pain can be present in the absence of tissue damage and that certain beliefs and fears regarding pain can amplify pain signaling via the brain. The second step is exercise treatment, emphasizing and challenging expectations, beliefs and fears regarding movements and pain. The proposed study will use neuroimaging to examine the neurocognitive effect of this new approach. For example, by studying how the brain processes pain, and whether treatment changes this. In addition, we examine the structure of the brain, such as whether communicatory neural pathways get stronger with treatment. We compare patients receiving the new treatment with patients receiving care as usual, and compare both groups with pain-free controls. With this study, we aim to unravel the working mechanisms of this promising treatment, and aim to explain and predict inter-individual differences in responses to treatment. The ultimate goal is to optimize and tailor the treatment to the individual." "A neurocognitive approach to the Self in Autism Spectrum Disorder" "Roeljan Wiersema" "Department of Experimental psychology, Department of Experimental clinical and health psychology" "Autism Spectrum Disorder (ASD) is a prevalent neurodevelopmental disorder, characterized by social difficulties. Research trying to explain these difficulties has focused mostly on problems with understanding others, but there are indications that the ‘sense of self’ is also altered in ASD. For example, infants who later get an ASD diagnosis respond less when hearing their own name. Adults with ASD, although they have learned to respond, still show a much smaller brain response. In addition, research suggests that the self-bias (the tendency to learn/remember things better when they are self-relevant) is smaller or absent in ASD. Still, findings are mixed: not all aspects of self-processing seem altered. To date it has not been clarified how self-processing in ASD differs, nor which neural processes are involved. I will investigate the hypothesis that self-related information is equally prioritised by individuals with ASD as by non-autistic individuals (‘neurotypicals’), but using different neural pathways. Whereas neurotypicals use pathways specific to social processing, autistic individuals may learn to emphasize self-related information in a non-social way. To investigate this, I will use advanced neuroimaging techniques to look at brain activity of autistic and non-autistic individuals of different ages, while they are processing information about themselves or others. This will lead to a better understanding of the social difficulties autistic individuals suffer from." "The role of neuro-cognitive research has related mood disorders" "Rudi De Raedt" "Department of Experimental clinical and health psychology" "Recent neuro-cognitive research has related mood disorders to a deficit within strategic attentional processes led by a frontocortical-subcortical network. The aim of this project is to explore these prefrontal attentional problems through rTMS and ERP brain researches while applying experimental attentional paradigms. These results prospect a functional relation between cognitive control and clinical indications." "Endophenotypes of autism spectrum disorders: neurocognition and brain imaging." "Ilse Noens" "Parenting and Special Education, Research Group Psychiatry, Translational MRI" "Autism Spectrum Disorders (ASD) are early onset neurodevelopmental disorders characterized by the co-occurrence of impairments in social reciprocity and communication, accompanied by a rigid and repetitive pattern of interests and activities. The disorder has a high heritability, but insight in the aetiology is still limited, mainly due to considerable heterogeneity between individuals with ASD. This large heterogeneity stimulates the search for 'endophenotypes' that allow us to delineate morehomogeneous subgroups. Endophenotypes are phenotypes that are more proximal to the biological aetiology of a clinical disorder than its signs and symptoms, and are influenced by one or more of the same genes that confer susceptibility to the condition. In other words, they are intermediate phenotypes that mediate the relationship between genotype and behavioural traits of the disorder. Additionally, endophenotypes are supposed to be biomarkers that are less genetically complex than the disorder they underlie. Therefore, endophenotypes may be particularly useful for understanding the aetiology of complex disorders, such as ASD and to unravel biological pathways from genes to behavioural characteristics of thedisorder.Neurocognitive characteristics are potentially interestingASD endophenotypes, since they provide a crucial interface between brain and behaviour. This project focusses on two dominant neurocognitive accounts for ASD: 1) the Executive Functioning (EF) theory and 2) the WeakCentral Coherence account of alterations in local-global processing in individuals with ASD. The general aim of this dissertation is to assess which aspects of EF and local-global visual processing provide good endophenotype candidates for ASD. Inview of the problematic validity of existing EF and local-global processing measures, we first developed a neurocognitive battery aimed to increase the validity of these measures. In this battery a distinction was made between five EF domains (inhibition, cognitive flexibility, generativity, working memory and planning), and between local versus global visual processing abilities and visual processing style. Good ASD endophenotypes have to meet several criteria, of which two are addressed here, namely: they should co-occur with ASD and they are expressed at a higher rate in unaffected first degree relatives of probands with ASD than in the general population. To evaluate these criteria, the neurocognitive battery was administered to children and adolescents with ASD, their first degree relatives and Typically Developing (TD) controls (N = 306). When comparing individuals with ASD and TD individuals, we found that individuals with ASD showed impairments in all EF domains, but deficits were more pronounced in (and sometimes even restricted to) open-ended compared to highly structured settings. Furthermore, they displayed a more locally oriented processing style, intact local processing abilities and selective global processing impairments on tasks with high integrative demands. The first degree relatives of these probands with ASD shared EF difficulties in response inhibition, cognitive flexibility and generativity measured with EF tasks, and they showed EF impairments in daily life. For local-global visual processing, ASD relatives did show more attention to detail in daily life compared to TD individuals, but no group differences were found on any of the more controlled tasks. These findings suggest thatmainly impairments in response inhibition, cognitive flexibility and generativity are valuable endophenotype candidates for ASD. However, further research is needed to replicate these findings and to evaluate the additional endophenotype criteria. Finally, we address some remaining issues regarding phenotypic and cognitive heterogeneity and provide suggestions for clinical practice." "High-Functioning ASD. Really? Socio-Demographic, behavioral and neurocognitive predictors of adaptive functioning, quality of life and internalizing-externalizing problems." "Ilse Noens" "Parenting and Special Education" "Autism Spectrum Disorders (ASD) are characterized by impairments in social interaction and social communication, combined with restricted, repetitive behavior patterns and interests. Underlying these behavioral problems, neurocognitive theories of ASD have focused on 1) local and global processing, 2) social cognition, and 3) executive functioning. The spectrum is characterized by a considerable amount of intra- and inter-individual variability at the level of behavioral and neurocognitive symptoms, but also the outcome (adaptive functioning, QoL and internalizingexternalizing problems) is highly diverse. Furthermore, the discrepancy between intelligence and adaptive functioning can be puzzling. In three work packages, we will investigate the relationship between an individual’s characteristics (socio-demographic, behavioral and neurocognitive variables) and outcome. Insight in this association will help us to understand and explain apparently inconsistent findings. In addition, individual developmental trajectories will be better understood, and maybe even predictable, which is of high clinical relevance, both at the level of assessment and at the level of intervention (shifting the focus of interventions towards training of neurocognitive functions)." "The neurocognitive development of preschoolers at risk for dyslexia and ADHD" "Pol Ghesquière" "Parenting and Special Education" " Up until now, research on the cognitive precursors of dyslexia has merely focused on children with a family or cognitive risk for dyslexia. However, a substantially large group of these children also have a behavioral risk for ADHD. To date, far too little studies paid attention to this double risk group, as most dyslexia studies excluded children with an additional risk for ADHD. This doctoral project firstly aims to close the gap by investigating the neurocognitive profile of preschoolers with a double risk for dyslexia and ADHD, compared to preschoolers with a single risk for dyslexia or ADHD (3rd kindergarten). The second goal is to follow these children for three consecutive years to assess the development of different cognitive factors (i.e., phonological skills, executive functioning, processing speed and academic functioning). As a last objective, groups will be retrospectively analyzed based on possible clinical diagnosis (2nd grade). This last objective does not only allow us to attribute specific cognitive impairments and strengths to a specific disorder, but also permits us to unravel risk and protective factors for each profile. Furthermore, this study will result in deeper knowledge about the cognitive development of preschoolers only at risk for dyslexia OR ADHD versus those at risk for dyslexia AND ADHD" "Improving the prediction of language recovery in stroke patients by including risk and protective neurocognitive factors." "Maaike Vandermosten" "Research Group Experimental Oto-rhino-laryngology" "Aphasia is a language disorder most commonly caused by a cerebrovascular accident, or stroke, in the left hemisphere. Approximately 15-45% of patients in acute stroke settings have aphasia, which impairs their communication and dramatically affects their quality of life. In the first months after stroke, there is often spontaneous and intervention-induced recovery, but for 26-43% a chronic language deficit remains. To date, individual language recovery in patients with aphasia remains hard to predict. Yet, the identification of early predictors of aphasia recovery could not only manage patients’ expectations, but also maximize the recovery potential through well-targeted individualized interventions. While it is established that neuroplasticity is an important driver of language recovery, it is unknown which neural reorganization processes are effective and which are maladaptive for good language outcomes. Improved knowledge on how the brain reorganizes after stroke, especially during the first months, will be helpful to inform neuroimaging-based prediction of long-term language outcomes.The present dissertation had two overarching aims. The first aim was to identify early markers that improve the prediction of language recovery in stroke patients. Several predictors of language recovery after stroke have been identified, yet there is a lack of predictors that can be measured immediately after stroke - i.e., in the clinically relevant acute phase. Moreover, previous research has mainly focused on the influence of brain damage and language deficits on language outcomes. What has largely been missing is the focus on possible protective factors as potential predictors of recovery, including intact gray and white matter, intact general cognitive abilities and their corresponding neural substrates. Our hypothesis was that statistical learning, a mechanism upon which we rely heavily in daily life to learn the structure inherent to our complex linguistic environment, and the hippocampus, as one of the potential neural substrates of statistical learning, could support language (re)learning in aphasia. The second aim was to gain insight in neuroplastic changes during recovery and their associations with language. Past research has been mostly restricted to the study of neuroplasticity in cortical regions years after the stroke has occurred, while there is a lack of knowledge on how the brain reorganizes in the first months after stroke. Moreover, language is not organized in isolated brain regions, but rather in a complex structural network of interconnected cortical regions. We therefore explored early plasticity in long-ranging white matter connections involved in language processing, i.e., the dorsal arcuate fasciculus (AF) and the ventral inferior fronto-occipital fasciculus (IFOF). These two overarching aims were addressed in four different studies.In the first study (Chapter 4), we conducted a thorough review of the literature to obtain a complete picture of what is known on neuroplasticity patterns in the post stroke aphasia population. We found that stroke-induced neuroplasticity related to language interventions was not limited to language structures in the left hemisphere, but involved a bilateral network of structures that support language from a broader cognitive perspective. In our second study (Chapter 5), we showed that it is possible to construct tasks that can capture non-linguistic statistical learning in healthy elderly and that are at the same time feasible in difficult-to-test populations, such as patients with aphasia. Our third and fourth study entailed a longitudinal follow-up of patients with post stroke aphasia. In our third study (Chapter 6), we showed that we were indeed able to measure non-linguistic statistical learning in patients with aphasia in the subacute phase, which was intact compared to a healthy older control group. According to our expectations, the subacute behavioral statistical learning results were associated with acute hippocampal measures. Moreover, the acute volume of the left hippocampus significantly contributed to the prediction of long-term language outcomes over and above traditional predictors. In our last study (Chapter 7), we established that the acute connection strength of the AF and IFOF was associated with the severity of the acute language deficit, but not predictive of later language outcomes over and above information on the initial language impairment. Concerning neuroplasticity, we observed white matter neurodegeneration in the first months after stroke, with changes in the AF being associated with worse language outcomes.In sum, the work that was carried out in the context of this dissertation highlights the potential importance of an individual’s (intact) cognitive capacity for compensation and corresponding neural correlates for obtaining a more reliable prediction of language recovery after stroke. Moreover, we have provided new insights in (changes in) connectivity of damaged and undamaged language pathways in patients with aphasia in the first months after stroke, as well as if/how such measures are related to language outcomes at different stages of recovery. Although the current observational and longitudinal data do not allow us to draw firm causal conclusions, they are a vital first step to explore the nature of brain-behavior associations over time. The ultimate end goal is to obtain evidence-based prognostic models which would be beneficial for patients, relatives, clinicians, and even society. " "Perturbed cortical hierarchies in Autism Spectrum Disorder: The case of high-level vision." "Johan Wagemans" "Brain and Cognition, Laboratory for Experimental Psychology" "While people with Autism Spectrum Disorder (ASD) show clear impairments in normal day-to-day behavior, they simultaneously outperform their Typically Developing (TD) counterparts on many perceptual tasks. This relative superiority in tasks requiring the processing of separate features rather than the stimulus configuration, evoked two competing theoretical frameworks: the Weak Central Coherence hypothesis (WCC) and the Enhanced Perceptional Functioning (EPF) theory. While the former explains these results by the absence of a normal bias towards the global structure in a visual display in people with ASD, the latter insists that generally increased attention for local elements in a scene is the cause. Although both theoretical frameworks (WCC and EPF) have been investigated for years, evidence for either line of theory remains mixed and ambiguously interpretable. To address this problem, we argue that the existing evidence on perceptual processing in ASD should be integrated within a unified theoretical framework, the Reverse Hierarchy Theory (RHT). Within this theory, both neurocognitive theories can be regarded as cases of hierarchy perturbations in the visual cortex. More precisely, people with ASD show a less efficient (slower) early-stage and pre-attentive global processing of visual information (in accordance with WCC) and a later-stage advantage in the attention-focused processing of local scene (or object) elements (in accordance with EPF).            In this PhD project, we evaluated previous research findings on coarse (global) and fine (local) visual processing in ASD and tested the critical ideas of the main neurocognitive theories (WCC and EPF) in innovative ways. We used a diverse set of time-dependent experimental paradigms to explore possible differences in high-level visual perception between adolescents and adults with and without ASD (12-25 years of age). More precisely, behavioral testing focused on specific combinations of five experimental topics of interest: (1) the use of more ecologically valid visual displays, (2) the role of attentional processes in perception, (3) the defining stimulus characteristics for coarse and fine visual processing, (4) the influence of socially relevant stimuli, and (5) the influence of implicit social inferences based on the perception of dynamic visual displays.            We believe that, by linking current neurocognitive models with state-of-the-art research on the processing sequence of coarse and fine information in TD participants, RHT provides an important addition to our current understanding of visual processing in ASD. Future research should continue to focus on systematically varying the time-course and content of stimulus presentation in behavioral paradigms and to link it with neuroimaging findings. As a result, we believe that the ASD-related literature will converge on a neurologically plausible and coherent theoretical framework for understanding the atypical visual perception in ASD." "On epigenetics and how 'environmental' factors contribute to the long-term legacy of pediatric critical illness" "Greet Van den Berghe" "Laboratory of Intensive Care Medicine" "Critically ill patients are patients who, due to a variety of triggering medical conditions, require vital organ support to avoid imminent death. Despite major progress in intensive care the patients still face a high mortality risk. Moreover, critical illness is hallmarked by features of accelerated aging where many patients experience an adverse legacy of the illness long after hospital discharge. This is mostly described for adults and includes muscle weakness, chronic renal failure despite resolution of acute renal damage, bone loss and fracture risk, neurocognitive impairment and post-traumatic stress disorders. Children, treated in the paediatric intensive care unit (PICU) during crucial developmental phases, show impaired long-term physical and neurocognitive/psychological development and reduced quality of life. The degree to which the developmental impairment was already present or predestined at PICU admission, how much of the legacy was evoked by critical illness and its management, and what the underlying biological mechanisms are, remained unclear.The main objective of this doctoral thesis was thus to gain more insight in the underlying biological processes and modifiable risk factors with regard to the long-term developmental deficit faced by critically ill children. We hypothesised that two intensive care-related interventions during PICU stay could potentially affect the long-term outcome of these critically ill children. These are the exposure to phthalates, which are toxic plasticisers shown to leach from indwelling medical devices, and the nutritional management early during the course of critical illness. We further hypothesised that this legacy of critical illness and its management could be brought about by damage-related changes in DNA methylation or by telomere length alterations.In a first part, we documented the impact of exposure to circulating phthalates during paediatric critical illness on long-term neurocognitive outcome of critically ill children. We demonstrated that plasma concentrations of several phthalate metabolites, which were virtually undetectable in healthy children, were extremely high in critically ill children upon PICU admission. They decreased rapidly, but remained markedly elevated at PICU discharge. Moreover, exposure to circulating phthalate metabolites was independently and robustly associated with the attention deficit observed years after PICU admission. These data underscore the importance to use, whenever possible, medical devices composed of alternative, safer plasticisers or with low phthalate release potential.In a second part, we focused on the nutritional management during PICU stay. Providing artificial nutritional support is thought to be of major importance in an intensive care setting, as the vast majority of critically ill patients are unable to eat normally, particularly while being mechanically ventilated. Observational data have associated malnutrition during critical illness with muscle wasting, weakness and delayed recovery. Consequently, many clinicians have assumed that artificial nutrition via the parenteral route is beneficial for patients’ outcome. However, a large randomised controlled clinical study (the “PEPaNIC” trial) showed that withholding of such supplemental parenteral nutrition during the first week of paediatric intensive care reduced the incidence of new infections and accelerated recovery, allowing an earlier PICU discharge. Despite these beneficial short-term effects, concerns have been raised about long-term developmental consequences, possibly mediated by DNA methylation changes or telomere length alterations, of tolerating such a macronutrient deficit. Hence, assessment of the impact on long-term outcome of the children was crucial. In this second part we therefore documented the impact of critical illness and of early initiation of supplemental parenteral nutrition on telomere length alterations and DNA methylation changes during PICU stay, and on long-term health risks, and physical and neurocognitive outcome of PICU survivors.As accelerated telomere shortening could theoretically explain part of the legacy of paediatric critical illness, we quantified telomere length in repeated white blood cell DNA harvested in PICU from patients who were enrolled in the PEPaNIC-trial, as compared with healthy children who never needed intensive care. We found that shorter than normal leukocyte telomeres are present in critically ill children admitted to the PICU. Duration of stay in PICU and early initiation of parenteral nutrition further shortened telomeres, effects that were independent of other determinants and which could predispose these children to adverse long-term health sequelae.As DNA methylation is essential for diverse biological processes such as development and cognition, and nutrition may have a major impact on the epigenome, we investigated whether DNA methylation changes arise during the course of PICU stay and remain present until PICU discharge, and whether these could be affected by the nutritional management strategy in PICU. After adjusting for pre-admission DNA methylation changes and critical illness-induced changes in cell type composition, several genes of potentially high relevance to the long-term legacy of critical illness, such as genes involved in neuronal migration, differentiation and growth, brain development and signaling, processing of amyloid-beta precursor protein, transcriptional regulation, energy metabolism and multiple cellular signalling pathways, were found to be differentially methylated between patients upon PICU discharge and matched controls. Severity of illness and early initiation of parenteral nutrition, independent of its slowing effect on recovery, were found to be significantly associated with a large proportion of the aberrant DNA methylation changes that arose during PICU stay.In a last study, we investigated whether withholding parenteral nutrition during the first week in PICU, an intervention that clearly improved short-term PICU outcome, has an impact on long-term health risks and physical and neurocognitive development. Two years after inclusion in the PEPaNIC randomised controlled trial, we assessed health risks, and physical and neurocognitive development of 786 PICU-survivors who were randomly allocated to late or early initiation of parenteral nutrition in the PICU, in comparison with 405 matched healthy children. Late initiation of parenteral nutrition did not adversely affect survival, physical and neurocognitive development, but improved overall executive functioning, more specifically inhibition, working memory, and meta-cognition. Also externalising behavioural problems and visual-motor integration were improved. Moreover, we found that omitting supplemental parenteral nutrition early during PICU stay partially normalised the long-term neurocognitive legacy of paediatric critical illness. The protective effect of withholding parenteral nutrition was most pronounced in the youngest children.In conclusion, we demonstrated that exposure to phthalates leaching from indwelling plastic medical devices could induce an attention deficit in PICU survivors. Secondly, we showed that telomeres shortened and DNA methylation changes in genes important for neurocognitive development arose during PICU stay, partly explained by early initiation of parenteral nutrition. These changes may predispose critically ill children to adverse long-term health sequelae. Finally, we found that withholding parenteral nutrition during the first week in the PICU did not negatively affect survival, growth or health status 2 years later, and significantly improved several domains of neurocognitive development, hereby partially normalising the long-term neurocognitive legacy of paediatric critical illness. Hence, these data increase our understanding of the factors and the underlying biological processes that may contribute to the impaired development of critically ill children. They will hopefully lead to a change in legislation concerning the use of plasticisers in medical devices and to a change in clinical guidelines in favour of withholding early use of PN during paediatric critical illness, both in order to improve long-term developmental outcomes of millions of PICU survivors worldwide." "“Money for nothing”? Dissociating pro-active, re-active, and automatic reward influences on conflict processing and response inhibition" "Nico Böhler" "Department of Experimental psychology" "Reward effects on cognitive functions have recently inspired a lot of research, not least because they offer a controllable window into neurocognitive effects of motivation in general, which is disturbed in a wide range of prominent brain-related disorders. Importantly, different traditions exist wherein reward effects on sensory and attentional processing are often ascribed to an automatic process that circumvents active top-down control processes based on gradually enhancing the salience of reward-related sensory features. In contrast, reward effects on cognitivecontrol processes are usually conceived of as effortful control operations, often in the form of enhanced preparation for an upcoming task (pro-actively); yet, such processes can likely also be engaged on the spot when needed (re-actively). The key aim of the present proposal is to investigate the relationship between these automatic and control-related processes. The planned studies will use classical control tasks, like the Stroop and the Stop-signal task, systematically varying how reward is associated to the task. The latter will furthermore allow to separately associate reward to the execution versus the inhibition of motor responses, which have been suggested to bedifferentially susceptible to reward influences. Together, the proposed studies will substantially advance our understanding of neurocognitive reward effects, hence contributing to basic science and to applied and clinical psychological work alike."