Publications

2024

1. Pattern and mechanisms of atrophy progression in individuals with a family history of Alzheimer’s disease: a comparative study

   Christina Tremblay, Shady Rahayel, Alexandre Pastor-Bernier, and 10 more authors

   bioRxiv, Mar 2024

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   AbstractAlzheimer’s disease (AD) includes a long period of presymptomatic brain changes. Different risk factors are associated with AD development, including having a family history of AD (FHAD). The Braak scheme suggests that tau pathology, in synergy with amyloid-beta (Aβ), spreads along structural connections in AD, eventually leading to atrophy. Studying the pathways in which atrophy spreads early on, as well as the factors underpinning this pathway, is crucial for improving diagnostic accuracy and early interventions. However, the pattern of atrophy progression in people with a FHAD and the biological factors associated with this progression remain unclear. Here we used structural MRI from three databases (ADNI, PREVENT-AD and Montreal Adult Lifespan Study) to map the atrophy progression in FHAD and AD and assess the constraining effects of structural connectivity on atrophy progression. Cross-sectional and longitudinal data up to 4 years were used to perform atrophy progression analysis in FHAD and AD compared to controls. Positron emission tomography (PET) radiotracers were also used to quantify the distribution of tau and Aβ proteins at baseline. We first derived cortical atrophy progression maps using deformation-based morphometry from 153 FHAD, 156 AD, and 116 controls with similar age, education, and sex at baseline. We next examined the spatial relationship between atrophy progression and spatial patterns of tau and Aβ deposition, structural connectivity, and neurotransmitter receptor and transporter distributions. Our results show that there were similar patterns of atrophy progression in FHAD and AD, notably in the cingulate, temporal and parietal cortices, with more widespread and severe atrophy in AD. Both tau and Aβ pathology tended to accumulate in regions that were structurally connected in FHAD and AD. The pattern of atrophy and its progression also aligned with existing structural connectivity in FHAD. In AD, our findings suggest that atrophy progression results from propagating pathology that occurred much earlier, on an intact connectome. Moreover, a relationship was found between the serotonin 5-HT6 receptors spatial distribution and atrophy progression in AD, supporting an important role of these receptors in neurodegeneration. The current study demonstrates that regions showing atrophy progression in FHAD and AD present with specific connectivity and cellular characteristics, uncovering certain of the mechanisms involved in preclinical and clinical neurodegeneration.

2. Obesity and diffusion-weighted imaging of subcortical grey matter in young and older adults

   Max Tweedale, Filip Morys, Alexandre Pastor-Bernier, and 3 more authors

   Appetite, Sep 2024

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   Obesity and hypothalamic inflammation are causally related. It is unclear whether this neuroinflammation precedes or results from obesity. Animal studies show that an increase in food intake can lead to hypothalamic inflammation, but hypothalamic inflammation can create a feedback loop that further increases food intake. Internal and external factors mediate patterns of food intake and how it can affect the hypothalamus. Measures of water diffusivity in magnetic resonance imaging of the brain such as fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD) are associated with grey matter inflammation. Here, we investigated how those measures are associated with obesity-related variables in groups of young and older adults. We found relationships between decreased diffusivity and obesity markers in young adults. In older adults, obesity and comorbidities were also related to significant changes in diffusivity. Here, diffusivity was strongly associated with body mass index (BMI) and blood levels of C-reactive protein (CRP) in multiple subcortical regions, rather than only the hypothalamus. Our results suggest that diffusivity measures can be used to investigate obesity-associated changes in the brain that can potentially reflect neuroinflammation. The connection seen between subcortical inflammation and obesity opens the conversation on preventative interventions needed to reduce the effects of obesity at all stages in life.

3. Neural correlates of obesity across the lifespan

   F Morys, Christina Tremblay, S Rahayel, and 4 more authors

   Commun. Biol., May 2024

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   Associations between brain and obesity are bidirectional: changes in brain structure and function underpin over-eating, while chronic adiposity leads to brain atrophy. Investigating brain-obesity interactions across the lifespan can help better understand these relationships. This study explores the interaction between obesity and cortical morphometry in children, young adults, adults, and older adults. We also investigate the genetic, neurochemical, and cognitive correlates of the brain-obesity associations. Our findings reveal a pattern of lower cortical thickness in fronto-temporal brain regions associated with obesity across all age cohorts and varying age-dependent patterns in the remaining brain regions. In adults and older adults, obesity correlates with neurochemical changes and expression of inflammatory and mitochondrial genes. In children and older adults, adiposity is associated with modifications in brain regions involved in emotional and attentional processes. Thus, obesity might originate from cognitive changes during early adolescence, leading to neurodegeneration in later life through mitochondrial and inflammatory mechanisms.

2023

1. Associations between sleep-related symptoms, obesity, cardiometabolic conditions, brain structural alterations and cognition in the UK biobank

   Jessica Yu, Filip Morys, Alain Dagher, and 5 more authors

   Sleep Med., Jan 2023

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   OBJECTIVES: Sleep disturbances are increasingly recognized as adversely affecting brain health in aging. Our aim was to investigate interrelations between subjective sleep-related symptoms, obesity, cardiometabolic disorders, brain structure and cognitive decline in a population-based aging sample. METHODS: Data were extracted from the UK Biobank for anthropometric and demographic information, self-reported sleep behaviours, cardiometabolic measures, structural brain magnetic resonance imaging and cognitive test scores. “Sleep-related symptoms” (SRS) were measured using four questionnaire items: loud snoring, daytime sleepiness, likelihood to nap and difficulty getting up in the morning. Associations were tested using a structural equation model (SEM), adjusted for confounders. Further, multiple regression analysis was used to test for direct relationships between SRS and specific cognitive domains. RESULTS: Among 36,468 participants with an average age of 63.6 (SD 7.5) years and 46.7% male, we found that SRS were associated with obesity and several pre-existing cardiometabolic disturbances. In turn, cardiometabolic disorders were associated with increased white matter hyperintensities and cortical thinning, which were related to cognitive dysfunction. SRS were also directly related to several structural brain changes and to cognitive dysfunction. Regression analyses showed that SRS were directly associated with slower reaction times, and lower scores in fluid intelligence, working memory and executive function. CONCLUSIONS: Self-reported sleep-related symptoms were associated with cognitive dysfunction directly and through pre-existing cardiometabolic disorders and brain structural alterations. These findings provide evidence that symptoms of sleep disturbances, here defined primarily by hypersomnolence and snoring, are important risk factors or markers for cognitive dysfunction in an aging population.

2. Self-reported intake of high-fat and high-sugar diet is not associated with cognitive stability and flexibility in healthy men

   Hendrik Hartmann, Lieneke K Janssen, Nadine Herzog, and 4 more authors

   Appetite, Feb 2023

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   Animal studies indicate that a high-fat/high-sugar diet (HFS) can change dopamine signal transmission in the brain, which could promote maladaptive behavior and decision-making. Such diet-induced changes may also explain observed alterations in the dopamine system in human obesity. Genetic variants that modulate dopamine transmission have been proposed to render some individuals more prone to potential effects of HFS. The objective of this study was to investigate the association of HFS with dopamine-dependent cognition in humans and how genetic variations might modulate this potential association. Using a questionnaire assessing the self-reported consumption of high-fat/high-sugar foods, we investigated the association with diet by recruiting healthy young men that fall into the lower or upper end of that questionnaire (low fat/sugar group: LFS, n = 45; high fat/sugar group: HFS, n = 41) and explored the interaction of fat and sugar consumption with COMT Val158Met and Taq1A genotype. During functional magnetic resonance imaging (fMRI) scanning, male participants performed a working memory (WM) task that probes distractor-resistance and updating of WM representations. Logistic and linear regression models revealed no significant difference in WM performance between the two diet groups, nor an interaction with COMT Val158Met or Taq1A genotype. Neural activation in task-related brain areas also did not differ between diet groups. Independent of diet group, higher BMI was associated with lower overall accuracy on the WM task. This cross-sectional study does not provide evidence for diet-related differences in WM stability and flexibility in men, nor for a predisposition of COMT Val158Met or Taq1A genotype to the hypothesized detrimental effects of an HFS diet. Previously reported associations of BMI with WM seem to be independent of HFS intake in our male study sample.

3. Obesity-Associated Neurodegeneration Pattern Mimics Alzheimer’s Disease in an Observational Cohort Study

   Filip Morys, Olivier Potvin, Yashar Zeighami, and 5 more authors

   J. Alzheimers. Dis., Feb 2023

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   BACKGROUND: Excess weight in adulthood leads to health complications such as diabetes, hypertension, or dyslipidemia. Recently, excess weight has also been related to brain atrophy and cognitive decline. Reports show that obesity is linked with Alzheimer’s disease (AD)-related changes, such as cerebrovascular damage or amyloid-βaccumulation. However, to date no research has conducted a direct comparison between brain atrophy patterns in AD and obesity. OBJECTIVE: Here, we compared patterns of brain atrophy and amyloid-β/tau protein accumulation in obesity and AD using a sample of over 1,300 individuals from four groups: AD patients, healthy controls, obese otherwise healthy individuals, and lean individuals. METHODS: We age- and sex-matched all groups to the AD-patients group and created cortical thickness maps of AD and obesity. This was done by comparing AD patients with healthy controls, and obese individuals with lean individuals. We then compared the AD and obesity maps using correlation analyses and permutation-based tests that account for spatial autocorrelation. Similarly, we compared obesity brain maps with amyloid-βand tau protein maps from other studies. RESULTS: Obesity maps were highly correlated with AD maps but were not correlated with amyloid-β/tau protein maps. This effect was not accounted for by the presence of obesity in the AD group. CONCLUSION: Our research confirms that obesity-related grey matter atrophy resembles that of AD. Excess weight management could lead to improved health outcomes, slow down cognitive decline in aging, and lower the risk for AD.

4. Neuroanatomical correlates of genetic risk for obesity in children

   Filip Morys, Eric Yu, Mari Shishikura, and 6 more authors

   Transl. Psychiatry, Jan 2023

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   Obesity has a strong genetic component, with up to 20% of variance in body mass index (BMI) being accounted for by common polygenic variation. Most genetic polymorphisms associated with BMI are related to genes expressed in the central nervous system. At the same time, higher BMI is associated with neurocognitive changes. However, the direct link between genetics of obesity and neurobehavioral mechanisms related to weight gain is missing. Here, we use a large sample of participants (n > 4000) from the Adolescent Brain Cognitive Development cohort to investigate how genetic risk for obesity, expressed as polygenic risk score for BMI (BMI-PRS), is related to brain and behavioral measures in adolescents. In a series of analyses, we show that BMI-PRS is related to lower cortical volume and thickness in the frontal and temporal areas, relative to age-expected values. Relatedly, using structural equation modeling, we find that lower overall cortical volume is associated with higher impulsivity, which in turn is related to an increase in BMI 1 year later. In sum, our study shows that obesity might partially stem from genetic risk as expressed in brain changes in the frontal and temporal brain areas, and changes in impulsivity.

2022

1. Mechanisms linking obesity and its metabolic comorbidities with cerebral grey and white matter changes

   Isabel Garcı́a-Garcı́a, Andréanne Michaud, · Marı́a, and 3 more authors

   Rev. Endocr. Metab. Disord., Jan 2022

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   Obesity is a preventable risk factor for cerebrovascular disorders and it is associated with cerebral grey and white matter changes. Specifically, individuals with obesity show diminished grey matter volume and thickness, which seems to be more prominent among fronto-temporal regions in the brain. At the same time, obesity is associated with lower microstructural white matter integrity, and it has been found to precede increases in white matter hyperintensity load. To date, however, it is unclear whether these findings can be attributed solely to obesity or whether they are a consequence of cardiometabolic complications that often co-exist with obesity, such as low-grade systemic inflammation, hypertension, insulin resistance, or dyslipidemia. In this narrative review we aim to provide a comprehensive overview of the potential impact of obesity and a number of its cardiometabolic consequences on brain integrity, both separately and in synergy with each other. We also identify current gaps in knowledge and outline recommendations for future research.

2. Brain response to food odors is not associated with body mass index and obesity-related metabolic health measures

   Maria Poessel, Filip Morys, Nora Breuer, and 3 more authors

   Appetite, Jan 2022

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   Smell perception plays a role in eating behavior and might be involved in the development of obesity. In fact, olfactory function is impaired in obesity and might depend on metabolic health factors. To date, the underlying neural mechanisms remain unclear. Here, we investigate neural processing of food-related odors in normal-weight, overweight and obese individuals. Fifty-three young and healthy participants (28.8 \pm 4.4 years, 27 female; 24 normal-weight, 10 overweight, and 19 obese) were presented with high- (chocolate, potato chips) and low-caloric (orange, cucumber) food odors during a functional magnetic resonance imaging (fMRI). We also assessed olfactory identification ability, body mass index (BMI), body fat percentage, insulin resistance, and leptin levels. In brief, olfactory perception of food odors was linked to brain activity in the entorhinal and piriform cortex, and the insula, hippocampus, and amygdala. Insulin resistance was negatively related to olfactory identification. Additionally, perception of sweet versus savory odors was related to a higher brain activity in the right middle/superior frontal gyrus. Finally, we found no effect of obesity status, BMI, metabolic factors, or body fat percentage on neural responses to food odors. Overall, this suggests that food odor processing might depend on factors other than body weight status or associated markers of metabolic health.

3. Relationship between impulsivity, uncontrolled eating and body mass index: a hierarchical model

   Isabel Garcı́a-Garcı́a, Selin Neseliler, Filip Morys, and 8 more authors

   Int. J. Obes., Jan 2022

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   Background: Impulsivity increases the risk for obesity and weight gain. However, the precise role of impulsivity in the aetiology of overeating behavior and obesity is currently unknown. Here we examined the relationships between personality-related measures of impulsivity, Uncontrolled Eating, body mass index (BMI), and longitudinal weight changes. In addition, we analyzed the associations between general impulsivity domains and cortical thickness to elucidate brain vulnerability factors related to weight gain. Methods: Students (N = 2318) in their first year of university—a risky period for weight gain—completed questionnaire measures of impulsivity and eating behavior at the beginning of the school year. We also collected their weight at the end of the term (N = 1177). Impulsivity was divided into three factors: stress reactivity, reward sensitivity and lack of self-control. Using structural equation models, we tested a hierarchical relationship, in which impulsivity traits were associated with Uncontrolled Eating, which in turn predicted BMI and weight change. Seventy-one participants underwent T1-weighted MRI to investigate the correlation between impulsivity and cortical thickness. Results: Impulsivity traits showed positive correlations with Uncontrolled Eating. Higher scores in Uncontrolled Eating were in turn associated with higher BMI. None of the impulsivity-related measurements nor Uncontrolled Eating were correlated with longitudinal weight gain. Higher stress sensitivity was associated with increased cortical thickness in the superior temporal gyrus. Lack of self-control was positively associated with increased thickness in the superior medial frontal gyrus. Finally, higher reward sensitivity was associated with lower thickness in the inferior frontal gyrus. Conclusion: The present study provides a comprehensive characterization of the relationships between different facets of impulsivity and obesity. We show that differences in impulsivity domains might be associated with BMI via Uncontrolled Eating. Our results might inform future clinical strategies aimed at fostering self-control abilities to prevent and/or treat unhealthy weight gain.

4. Population-based research in obesity – An overview of neuroimaging studies using big data approach

   Filip Morys, Mari Shishikura, and Alain Dagher

   Current Opinion in Endocrine and Metabolic Research, Apr 2022

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   In this review, we present research on neuroanatomical correlates of obesity using big data. This approach utilizes large sample sizes from population-based cohorts and is especially important for brain imaging research given the current replication crisis. Recent studies show that large sample sizes are needed to detect replicable associations between brain phenotypes and behavioral or anthropometric features, but previous brain imaging research on excess weight was often performed on samples including fewer than 100 participants. While smaller studies are crucial to investigate mechanistically fine-grained and more novel research questions, big data can be a tool to test some of the results generated by this research. Here, we present studies on adiposity-related brain changes, but also discuss genetic and environmental factors related to the excess weight development. We provide a summary of grey and white matter changes in obesity and conclude with recommendations for future studies investigating neurocognitive profiles of obesity.

2021

1. Brain atrophy progression in Parkinson’s disease is shaped by connectivity and local vulnerability

   Christina Tremblay, Shady Rahayel, Andrew Vo, and 7 more authors

   Brain Commun, Nov 2021

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   Brain atrophy has been reported in the early stages of Parkinson’s disease, but there have been few longitudinal studies. How intrinsic properties of the brain, such as anatomical connectivity, local cell-type distribution and gene expression combine to determine the pattern of disease progression also remains unknown. One hypothesis proposes that the disease stems from prion-like propagation of misfolded alpha-synuclein via the connectome that might cause varying degrees of tissue damage based on local properties. Here, we used MRI data from the Parkinson Progression Markers Initiative to map the progression of brain atrophy over 1, 2 and 4 years compared with baseline. We derived atrophy maps for four time points using deformation-based morphometry applied to T1-weighted MRI from 120 de novo Parkinson’s disease patients, 74 of whom had imaging at all four time points (50 Men: 24 Women) and 157 healthy control participants (115 Men: 42 Women). In order to determine factors that may influence neurodegeneration, we related atrophy progression to brain structural and functional connectivity, cell-type expression and gene ontology enrichment analyses. After regressing out the expected age and sex effects associated with normal ageing, we found that atrophy significantly progressed over 2 and 4 years in the caudate, nucleus accumbens, hippocampus and posterior cortical regions. This progression was shaped by both structural and functional brain connectivity. Also, the progression of atrophy was more pronounced in regions with a higher expression of genes related to synapses and was inversely related to the prevalence of oligodendrocytes and endothelial cells. In sum, we demonstrate that the progression of atrophy in Parkinson’s disease is in line with the prion-like propagation hypothesis of alpha-synuclein and provide evidence that synapses may be especially vulnerable to synucleinopathy. In addition to identifying vulnerable brain regions, this study reveals different factors that may be implicated in the neurotoxic mechanisms leading to progression in Parkinson’s disease. All brain maps generated here are available on request.

2. Association Between Midlife Obesity and Its Metabolic Consequences, Cerebrovascular Disease, and Cognitive Decline

   Filip Morys, Mahsa Dadar, and Alain Dagher

   J. Clin. Endocrinol. Metab., Sep 2021

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   CONTEXT: Chronic obesity is associated with several complications, including cognitive impairment and dementia. However, we have only piecemeal knowledge of the mechanisms linking obesity to central nervous system damage. Among candidate mechanisms are other elements of obesity-associated metabolic syndrome, such as hypertension, dyslipidemia, and diabetes, but also systemic inflammation. While there have been several neuroimaging studies linking adiposity to changes in brain morphometry, a comprehensive investigation of the relationship has so far not been done. OBJECTIVE: To identify links between adiposity and cognitive dysfunction. METHODS: This observational cohort study (UK Biobank), with an 8-year follow-up, included more than 20 000 participants from the general community, with a mean age of 63 years. Only participants with data available on both baseline and follow-up timepoints were included. The main outcome measures were cognitive performance and mediator variables: hypertension, diabetes, systemic inflammation, dyslipidemia, gray matter measures, and cerebrovascular disease (volume of white matter hyperintensities on magnetic resonance imaging). RESULTS: Using structural equation modeling, we found that body mass index, waist-to-hip ratio, and body fat percentage were positively related to higher plasma C-reactive protein, dyslipidemia, hypertension, and diabetes. In turn, hypertension and diabetes were related to cerebrovascular disease. Finally, cerebrovascular disease was associated with lower cortical thickness and volume and higher subcortical volumes, but also cognitive deficits (largest significant pcorrected = 0.02). CONCLUSIONS: We show that adiposity is related to poor cognition, with metabolic consequences of obesity and cerebrovascular disease as potential mediators. The outcomes have clinical implications, supporting a role for the management of adiposity in the prevention of late-life dementia and cognitive decline.

3. Brain Responses to High-Calorie Visual Food Cues in Individuals with Normal-Weight or Obesity: An Activation Likelihood Estimation Meta-Analysis

   Yingkai Yang, Qian Wu, and Filip Morys

   Brain Sciences 2021, Vol. 11, Page 1587, Nov 2021

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   Overconsumption of high-calorie or unhealthy foods commonly leads to weight gain. Understanding people’s neural responses to high-calorie food cues might help to develop better interventions for preventing or reducing overeating and weight gain. In this review, we conducted a coordinate-based meta-analysis of functional magnetic resonance imaging studies of viewing high-calorie food cues in both normal-weight people and people with obesity. Electronic databases were searched for relevant articles, retrieving 59 eligible studies containing 2410 unique participants. The results of an activation likelihood estimation indicate large clusters in a range of structures, including the orbitofrontal cortex (OFC), amygdala, insula/frontal operculum, culmen, as well as the middle occipital gyrus, lingual gyrus, and fusiform gyrus. Conjunction analysis suggested that both normal-weight people and people with obesity activated OFC, supporting that the two groups share common neural substrates of reward processing when viewing high-calorie food cues. The contrast analyses did not show significant activations when comparing obesity with normal-weight. Together, these results provide new important evidence for the neural mechanism underlying high-calorie food cues processing, and new insights into common and distinct brain activations of viewing high-calorie food cues between people with obesity and normal-weight people.

4. Pilot study of food-specific go/no-go training for overweight individuals: brain imaging data suggest inhibition shapes food evaluation

   Yingkai Yang, Filip Morys, Qian Wu, and 2 more authors

   Soc. Cogn. Affect. Neurosci., Dec 2021

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   Food-specific go/no-go training might reduce overeating and facilitate weight loss. In this pilot study, we examined whether a food-specific go/no-go training over five weeks, as compared to a non-food-specific training, could produce changes in behavioral and neural responses to food images and body weight. Here, we used a sample of 51 overweight participants divided into training and control groups whose brain activity and food evaluation were measured before and after the training. Compared with the control group, in the training group we found significant reductions in high-calorie food evaluation. We also found lower activations in inhibitory control- and reward-related brain regions in response to high-calorie food images. Further, activation change of the mid-insula in response to the high-calorie food images was positively associated with change in the evaluation of those images. However, we found no evidence for a significant effect of food-specific go/no-go training on body weight change. Our findings highlight that food-specific go/no-go training in overweight individuals can reduce high-calorie food evaluation, but also neural activations in inhibitory control- and reward- related brain regions.

5. Investigating the genetic and environmental basis of head micromovements during MRI

   Frauke Beyer, Katrin Horn, S Frenzel, and 24 more authors

   bioRxiv, Oct 2021

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   Introduction Head motion during magnetic resonance imaging is heritable. Further, it shares phenotypical and genetic variance with body mass index (BMI) and impulsivity. Yet, to what extent this trait is related to single genetic variants and physiological or behavioral features is unknown. We investigated the genetic basis of head motion in a meta-analysis of genome-wide association studies. Further, we tested whether physiological or psychological measures, such as respiratory rate or impulsivity, mediated the relationship between BMI and head motion. Methods We conducted a genome-wide association meta-analysis for mean and maximal framewise head displacement (FD) in seven population neuroimaging cohorts (UK Biobank, LIFE-Adult, Rotterdam Study cohort 1-3, Austrian Stroke Prevention Family Study, Study of Health in Pomerania; total N = 35.109). We performed a pre-registered analysis to test whether respiratory rate, respiratory volume, self-reported impulsivity and heart rate mediated the relationship between BMI and mean FD in LIFE-Adult. Results No variant reached genome-wide significance for neither mean nor maximal FD. Neither physiological nor psychological measures mediated the relationship between BMI and head motion. Conclusion Based on these findings from a large meta-GWAS and pre-registered follow-up study, we conclude that the previously reported genetic correlation between BMI and head motion relies on polygenic variation, and that neither psychological nor simple physiological parameters explain a substantial amount of variance in the association of BMI and head motion. Future imaging studies should thus rigorously control for head motion at acquisition and during preprocessing. ### Competing Interest Statement The authors have declared no competing interest.

6. Inter-individual body mass variations relate to fractionated functional brain hierarchies

   Bo Yong Park, Hyunjin Park, Filip Morys, and 7 more authors

   Communications Biology 2021 4:1, Jun 2021

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   Variations in body mass index (BMI) have been suggested to relate to atypical brain organization, yet connectome-level substrates of BMI and their neurobiological underpinnings remain unclear. Studying 325 healthy young adults, we examined associations between functional connectivity and inter-individual BMI variations. We utilized non-linear connectome manifold learning techniques to represent macroscale functional organization along continuous hierarchical axes that dissociate low level and higher order brain systems. We observed an increased differentiation between unimodal and heteromodal association networks in individuals with higher BMI, indicative of a disrupted modular architecture and hierarchy of the brain. Transcriptomic decoding and gene enrichment analyses identified genes previously implicated in genome-wide associations to BMI and specific cortical, striatal, and cerebellar cell types. These findings illustrate functional connectome substrates of BMI variations in healthy young adults and point to potential molecular associations. Bo-yong Park et al. use non-linear connectome manifold learning to examine the association between brain connectivity and inter-individual body mass index (BMI) in 325 young adults. They supplement these analyses with existing transcriptomic data, altogether suggesting several neural and molecular associations that may underlie BMI variations in healthy young adults.

2020

1. Nucleus accumbens volume is related to obesity measures in an age-dependent fashion

   Isabel Garcı́a-Garcı́a, Filip Morys, and Alain Dagher

   J. Neuroendocrinol., Dec 2020

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   Motivation theories of obesity suggest that one of the brain mechanisms underlying pathological eating and weight gain is the dysregulation of dopaminergic circuits. Although these dysregulations likely occur at the microscopic level, studies on grey matter volume report macroscopic differences associated with obesity. One region suggested to play a key role in the pathophysiology of obesity is the nucleus accumbens (NAcc). We performed a meta-analysis of findings regarding NAcc volume and overweight/obesity. We additionally examined whether grey matter volume in the NAcc and other mesolimbic areas depends on the longitudinal trajectory of obesity, using the UK Biobank dataset. To this end, we analysed the data using a latent growth model, which identifies whether a certain variable of interest (eg, NAcc volume) is related to another variable’s (body mass index [BMI]) initial values or longitudinal trajectories. Our meta-analysis showed that, overall, NAcc volume is positively related to BMI. However, further analyses revealed that the relationship between NAcc volume and BMI is dependent on age. For younger individuals, such a relationship is positive, whereas, for older adults, it is negative. This was corroborated by our analysis in the UK Biobank dataset, which includes older adults, where we found that a higher BMI was associated with a lower NAcc and thalamus volume. Overall, the present study suggests that increased NAcc volume at a young age might be a vulnerability factor for obesity, whereas, at an older age, decreased NAcc volume with increased BMI might be an effect of prolonged influences of neuroinflammation on the brain.

2. Food addiction, skating on thin ice. A critical overview of neuroimaging findings

   Isabel Garcia-Garcia, Filip Morys, Andreanne Michaud, and 1 more author

   Curr. Addict. Rep., Dec 2020

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   Purpose of Review The food addiction model suggests the compelling hypothesis that compulsive overeating and drug addictions share common neurobiological underpinnings. However, neuroimaging results are inconsistent, and they are difficult to integrate with each other. This mini-review provides a critical overview of the human neuroimaging literature in food addiction and binge eating symptoms. Recent Findings Neuroanatomical studies suggest the involvement of the orbitofrontal cortex in food addiction. Functional imaging studies have examined whether food addiction is associated with alterations during reward processing, cognitive control, or emotion regulation. However, these results have provided limited consistency so far. Summary To overcome the limitations of current research, we suggest that future studies on food addiction should address four main points: (a) disentangle between the effects of food addiction and obesity; (b) discriminate between causes and consequences of food addiction; (c) address the heterogeneity of food addiction; (d) prevent overinterpretation of results and facilitate replicability.

3. DRD2/ANKK1 Taq1A but not COMT single nucleotide polymorphisms contribute to the link between temporal impulsivity and obesity in men

   Filip Morys, Jakob Simmank, and Annette Horstmann

   bioRxiv, Jun 2020

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   Temporal impulsivity, the tendency to choose a smaller, sooner over a larger, delayed reward, is associated with single nucleotide polymorphisms (SNPs) in COMT and DRD2-related ANKK1 genes, whose products regulate dopaminergic transmission in the brain. Temporal impulsivity is also consistently associated with obesity, sometimes in a genderdependent fashion. Further, there seems to be no direct association between these SNPs and obesity. In this study, we investigated an interaction between BMI, COMT, and DRD2/ANKK1 SNPs, and temporal impulsivity. We tested three plausible models of associations between those variables: (1) genetic variability influencing BMI through temporal impulsivity and gender interactions, (2) genetic variability interacting with temporal impulsivity to influence BMI, (3) interaction of BMI and genetic variability influencing temporal impulsivity. We found evidence for the second model: in men, BMI was dependent on temporal impulsivity and the DRD2/ANKK1 SNP. It shows that increased temporal impulsivity combined with a disadvantageous DRD2/ANKK1 genotype might be a vulnerability factor for the development of obesity. Our study, even though cross-sectional, adds to the body of literature regarding the influence of the dopaminergic system on obesity measures. Our results point to a factor explaining discrepancies in results regarding associations of temporal impulsivity and BMI in women and men. ### Competing Interest Statement The authors have declared no competing interest.

4. Is obesity related to enhanced neural reactivity to visual food cues? A review and meta-analysis

   Filip Morys, Isabel Garcı́a-Garcı́a, and Alain Dagher

   Soc. Cogn. Affect. Neurosci., Jun 2020

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   Theoretical work suggests that obesity is related to enhanced incentive salience of food cues. However, evidence from both behavioral and neuroimaging studies on the topic is mixed. In this work we review the literature on cue reactivity in obesity and perform a preregistered meta-analysis of studies investigating effects of obesity on brain responses to passive food pictures viewing. Further, we examine whether age influences brain responses to food cues in obesity. In the meta-analysis we included 13 studies of children and adults that investigated group differences (obese vs. lean) in responses to food vs. non-food pictures viewing. While we found no significant differences in the overall meta-analysis, we show that age significantly influences brain response differences to food cues in the left insula and the left fusiform gyrus. In the left insula, obese vs. lean brain differences in response to food cues decreased with age, while in the left fusiform gyrus the pattern was opposite. Our results suggest that there is little evidence for obesity-related differences in responses to food cues and that such differences might be mediated by additional factors that are often not considered.

5. Whole‐brain functional connectivity correlates of obesity phenotypes

   Bo‐yong Park, Kyoungseob Byeon, Mi Ji Lee, and 6 more authors

   Hum. Brain Mapp., Dec 2020

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   Dysregulated neural mechanisms in reward and somatosensory circuits result in an increased appetitive drive for and reduced inhibitory control of eating, which in turn causes obesity. Despite many studies investigating the brain mechanisms of obesity, the role of macroscale whole-brain functional connectivity remains poorly understood. Here, we identified a neuroimaging-based functional connectivity pattern associated with obesity phenotypes by using functional connectivity analysis combined with machine learning in a large-scale (n   2,400) dataset spanning four independent cohorts. We found that brain regions containing the reward circuit positively associated with obesity phenotypes, while brain regions for sensory processing showed negative associations. Our study introduces a novel perspective for understanding how the whole-brain functional connectivity correlates with obesity phenotypes. Furthermore, we demonstrated the generalizability of our findings by correlating the functional connectivity pattern with obesity phenotypes in three independent datasets containing subjects of multiple ages and ethnicities. Our findings suggest that obesity phenotypes can be understood in terms of macroscale whole-brain functional connectivity and have important implications for the obesity neuroimaging community.

6. Metabolic syndrome increases COVID-19-related mortality in the UK Biobank sample

   F Morys, and A Dagher

   Dec 2020

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   The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license. Previous studies link obesity and individual components of metabolic syndrome to increased hospitalisations and death rates of patients with COVID-19. Here, in two overlapping samples of over 1,000 individuals from the UK Biobank we investigate whether metabolic syndrome, and its constituent components, increased waist circumference, dyslipidaemia, hypertension, diabetes, and systemic inflammation, are related to increased COVID-19 infection and mortality rates. Using logistic regression and controlling for confounding variables such as socioeconomic status, age, sex or ethnicity, we find that individuals with pre-existing metabolic syndrome (measured on average eleven years prior to 2020) have an increased risk for COVID-19-related death (odds ratio 1.67). We also find that specific factors contributing to increased mortality are serum glucose levels, systolic blood pressure and waist circumference.

2019

1. Unhealthy yet avoidable — how cognitive bias modification alters behavioral and brain responses

   Nora Mehl, Filip Morys, Arno Villringer, and 1 more author

   Nutrients, Dec 2019

   Abs

   Obesity is associated with automatically approaching problematic stimuli, such as unhealthy food. Cognitive bias modification (CBM) could beneficially impact problematic approach behavior. However, it is unclear which mechanisms are targeted by CBM in obesity. Candidate mechanisms include: (1) altering reward value of food stimuli; and (2) strengthening inhibitory abilities. Thirty-three obese adults completed either CBM or sham training during functional magnetic resonance imaging (fMRI) scanning. CBM consisted of implicit training to approach healthy and avoid unhealthy foods. At baseline, approach tendencies towards food were present in all participants. Avoiding vs. approaching food was associated with higher activity in the right angular gyrus (rAG). CBM resulted in a diminished approach bias towards unhealthy food, decreased activation in the rAG, and increased activation in the anterior cingulate cortex. Relatedly, functional connectivity between the rAG and right superior frontal gyrus increased. Analysis of brain connectivity during rest revealed training-related connectivity changes of the inferior frontal gyrus and bilateral middle frontal gyri. Taken together, CBM strengthens avoidance tendencies when faced with unhealthy foods and alters activity in brain regions underpinning behavioral inhibition.

2. Characterizing impulsivity and resting-state functional connectivity in normal-weight binge eaters

   R Oliva, F Morys, A Horstmann, and 2 more authors

   Int. J. Eat. Disord., Dec 2019

   Abs

   \copyright 2019 Wiley Periodicals, Inc. Objective: Binge eating is characterized by episodes of uncontrolled eating, within discrete periods of time. Although it is usually described in obese individuals or as a symptom of Binge Eating Disorder (BED), this behavior can also occur in the normal-weight (NW) population. An interesting premise suggests that impulsivity might contribute to the onset of binge eating and the progression toward weight gain. Drawing upon this evidence, here we explored impulsivity in NW individuals reporting binge-eating episodes through a functional connectivity approach. We hypothesized that, even in the absence of an eating disorder, NW binge eaters would be characterized by connectivity pattern changes in corticostriatal regions implicated in impulsivity, similarly to the results described in BED individuals. Methods: A resting-state functional magnetic resonance imaging study tested 39 NW men and women, with and without binge eating (binge eaters, BE and non-BE). Brain functional connectivity was explored by means of graph theoretic centrality measures and traditional seed-based analysis; trait impulsivity was assessed with self-report questionnaires. Results: The BE group was characterized by a higher degree of trait impulsivity. Brain functional connectivity measures revealed lower degree centrality within the right middle frontal gyrus, left insula/putamen and left temporoparietal regions and a lower functional connectivity between the right middle frontal gyrus and right insula in the BE group. Discussion: The results support previous evidence on BED of altered functional connectivity and higher impulsivity at the roots of overeating behavior, but further extend this concept excluding any potential confounding effect exerted by the weight status.

3. Hemispheric asymmetries in resting-state EEG and fMRI are related to approach and avoidance behaviour, but not to eating behaviour or BMI

   Filip Morys, L K Janssen, E Cesnaite, and 14 more authors

   Hum. Brain Mapp., Dec 2019

   Abs

   Much of our behaviour is driven by two motivational dimensions—approach and avoidance. These have been related to frontal hemispheric asymmetries in clinical and resting-state EEG studies: Approach was linked to higher activity of the left relative to the right hemisphere, while avoidance was related to the opposite pattern. Increased approach behaviour, specifically towards unhealthy foods, is also observed in obesity and has been linked to asymmetry in the framework of the right-brain hypothesis of obesity. Here, we aimed to replicate previous EEG findings of hemispheric asymmetries for self-reported approach/avoidance behaviour and to relate them to eating behaviour. Further, we assessed whether resting fMRI hemispheric asymmetries can be detected and whether they are related to approach/avoidance, eating behaviour and BMI. We analysed three samples: Sample 1 (n = 117) containing EEG and fMRI data from lean participants, and Samples 2 (n = 89) and 3 (n = 152) containing fMRI data from lean, overweight and obese participants. In Sample 1, approach behaviour in women was related to EEG, but not to fMRI hemispheric asymmetries. In Sample 2, approach/avoidance behaviours were related to fMRI hemispheric asymmetries. Finally, hemispheric asymmetries were not related to either BMI or eating behaviour in any of the samples. Our study partly replicates previous EEG findings regarding hemispheric asymmetries and indicates that this relationship could also be captured using fMRI. Our findings suggest that eating behaviour and obesity are likely to be mediated by mechanisms not directly relating to frontal asymmetries in neuronal activation quantified with EEG and fMRI.

4. MIS – A new scoring method for the operation span task that accounts for Math, remembered Items and Sequence

   Mathis Lammert, Filip Morys, Hendrik Hartmann, and 2 more authors

   Aug 2019

   Abs

   The operation span task is a well-validated measure of the executive component of working memory. Previous scoring systems of this task focus predominantly on the span part of the task, while the distractor – math task – serves as an exclusion criterion for test assessment only. Here, we propose a new Math-Item-Sequence (MIS) system to score performance on the Ospan based on both the span and math part. This new system provides three main improvements: 1) it eliminates the need to introduce arbitrary exclusion thresholds based on performance on the distractor task; 2) it takes into account remembered letters, and their relative position in the sequence separately; 3) it considers performance on the math task in the scoring of the Ospan task as a downweighing factor. In 6 independent samples we show that MIS score correlates highly with previously recommended scoring methods, suggesting that it measures the same underlying concepts. We also show that internal consistency of MIS is very good and comparable to or higher than the previous methods. We argue that MIS could be used in all samples, but might be of particular interest for small samples, where exclusions of participants are especially costly.

5. Liking and left amygdala activity during food versus nonfood processing are modulated by emotional context

   Isabel Garcı́a-Garcı́a, Jana Kube, Filip Morys, and 7 more authors

   Cogn. Affect. Behav. Neurosci., Nov 2019

   Abs

   \copyright 2019, The Psychonomic Society, Inc. Emotions can influence our eating behaviors. Facing an acute stressor or being in a positive mood are examples of situations that tend to modify appetite. However, the question of how the brain integrates these emotion-related changes in food processing remains elusive. Here, we designed an emotional priming fMRI task to test if amygdala activity during food pictures differs depending on the emotional context. Fifty-eight female participants completed a novel emotional priming task, in which emotional images of negative, neutral, or positive situations were followed by pictures of either foods or objects. After priming in each trial, participants rated how much they liked the shown foods or objects. We analyzed how brain activity during the contrast “foods > objects” changed according to the emotional context—in the whole brain and in the amygdala. We also examined the potential effect of adiposity (i.e., waist circumference). We observed a higher difference between liking scores for foods and objects after positive priming than after neutral priming. In the left amygdala, activity in the contrast “foods > objects” was higher after neutral priming relative to negative priming. Waist circumference was not significantly related to this emotional priming effect on food processing. Our results suggest that emotional context alters food and nonfood perception, both in terms of liking scores and with regard to engagement of the left amygdala. Moreover, our findings indicate that emotional context has an impact on the salience advantage of food, possibly affecting eating behavior.

6. Unhealthy yet Avoidable—How Cognitive Bias Modification Alters Behavioral and Brain Responses to Food Cues in Individuals with Obesity

   N Mehl, F Morys, A Villringer, and 1 more author

   Nutrients, Nov 2019

   Abs

   \copyright 2019 by the authors. Licensee MDPI, Basel, Switzerland. Obesity is associated with automatically approaching problematic stimuli, such as unhealthy food. Cognitive bias modification (CBM) could beneficially impact problematic approach behavior. However, it is unclear which mechanisms are targeted by CBM in obesity. Candidate mechanisms include: (1) altering reward value of food stimuli; and (2) strengthening inhibitory abilities. Thirty-three obese adults completed either CBM or sham training during functional magnetic resonance imaging (fMRI) scanning. CBM consisted of implicit training to approach healthy and avoid unhealthy foods. At baseline, approach tendencies towards food were present in all participants. Avoiding vs. approaching food was associated with higher activity in the right angular gyrus (rAG). CBM resulted in a diminished approach bias towards unhealthy food, decreased activation in the rAG, and increased activation in the anterior cingulate cortex. Relatedly, functional connectivity between the rAG and right superior frontal gyrus increased. Analysis of brain connectivity during rest revealed training-related connectivity changes of the inferior frontal gyrus and bilateral middle frontal gyri. Taken together, CBM strengthens avoidance tendencies when faced with unhealthy foods and alters activity in brain regions underpinning behavioral inhibition.

7. The impulsive brain: Neural underpinnings of binge eating behavior in normal-weight adults

   R Oliva, F Morys, A Horstmann, and 2 more authors

   Appetite, Nov 2019

   Abs

   Converging evidence suggests that dysfunctional inhibitory control might be at the roots of overeating and binge eating disorder (BED). The majority of these results stems from studies on obese populations, however we hypothesized that potential prodromes might be evident also in non-clinical conditions, when binge eating episodes are present (without a diagnosis of BED) and a normal Body Mass Index is preserved. To explore this issue, brain activity of 42 normal weight individuals with and without binge eating episodes (21 binge eaters and 21 non-binge eaters, BE and non-BE respectively) was assessed by means of functional magnetic resonance imaging (fMRI) during response inhibition tasks. We adopted a food-modified version of a go/no-go (GNG) and stop signal task (SST): these tasks investigate different aspects of inhibitory control (action restraint and cancellation) that have been rarely studied in the same individuals but that are known to involve different neural networks. In addition, impulsivity traits were assessed with self-report instruments. Despite similar behavioral performances, the two groups differed in trait impulsivity and brain activity. The fMRI results revealed differential engagement of fronto-striatal regions between the groups during the tasks. The BE group, compared to non-BE, showed lower activation of the right middle frontal gyrus (MFG) and Putamen during the GNG task, and higher activation of the left MFG during the SST. These findings provide evidence of a dissociation of the neural underpinnings of action restraint and cancellation in impulsive individuals. Moreover, they add support to the hypothesis that impulsivity may be a possible hallmark of binge eating behavior (in the absence of weight or full-blown eating disorders) and yield new insights on the role of regions typically involved in response inhibition and selection as possible substrates of impulsive eating.

2018

1. Dorsolateral and medial prefrontal cortex mediate the influence of incidental priming on economic decision making in obesity

   Filip Morys, Stefan Bode, and Annette Horstmann

   Sci. Rep., Dec 2018

   Abs

   Obese individuals discount future rewards to a higher degree than lean individuals, which is generally considered disadvantageous. Moreover, their decisions are altered more easily by decision-irrelevant cues. Here, we investigated neural correlates of this phenomenon using functional MRI. We tested 30 lean and 26 obese human subjects on a primed delay discounting paradigm using gustatory and visual cues of positive, neutral and negative valence to bias their intertemporal preferences. We hypothesised that activation differences in reward-related and behavioural control areas, and changes in connectivity between these areas, would reflect the effect of these cues. Here, obese subjects were more susceptible to priming with negative gustatory cues towards delayed choices as opposed to lean subjects. This was related to lower activity in the left dorsolateral prefrontal cortex during priming. Modulation of functional connectivity between the dlPFC and the ventromedial PFC by the behavioural priming effect correlated negatively with BMI. This might indicate that default goals of obese individuals were different from those of lean participants, as the dlPFC has been suggested to be involved in internal goal pursuit. The present results further our understanding of the role of the PFC in decision-making and might inform future weight-management approaches based on non-invasive brain stimulation.