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2. Resting state EEG power spectrum and functional connectivity in autism: a cross-sectional analysis

Author

Garcés, Pilar, Baumeister, Sarah, Mason, Luke, Chatham, Christopher, Holiga, Stefan, Dukart, Juergen, Jones, Emily, Banaschewski, Tobias, Baron-Cohen, Simon, Bölte, Sven, Buitelaar, Jan, Durston, Sarah, Oranje, Bob, Persico, Antonio, Beckmann, Christian, Bougeron, Thomas, Dell’acqua, Flavio, Ecker, Christine, Moessnang, Carolin, Charman, Tony, Tillmann, Julian, Murphy, Declan, Johnson, Mark, Loth, Eva, Brandeis, Daniel, Hipp, Joerg, Ahmad, Jumana, Ambrosino, Sara, Auyeung, Bonnie, Bourgeron, Thomas, Bours, Carsten, Brammer, Michael, Brogna, Claudia, de Bruijn, Yvette, Chakrabarti, Bhismadev, Cornelissen, Ineke, Crawley, Daisy, Dumas, Guillaume, Faulkner, Jessica, Frouin, Vincent, Goyard, David, Ham, Lindsay, Hayward, Hannah, Holt, Rosemary, Kundu, Prantik, Lai, Meng-Chuan, Ardhuy, Xavier Liogier D’, Lombardo, Michael, Lythgoe, David, Mandl, René, Marquand, Andre, Mennes, Maarten, Meyer-Lindenberg, Andreas, Mueller, Nico, Oakley, Bethany, O’dwyer, Laurence, Oldehinkel, Marianne, Pandina, Gahan, Ruggeri, Barbara, Ruigrok, Amber, Sabet, Jessica, Sacco, Roberto, Cáceres, Antonia San José, Simonoff, Emily, Spooren, Will, Toro, Roberto, Tost, Heike, Waldman, Jack, Williams, Steve, Wooldridge, Caroline, Zwiers, Marcel, Leap Group, The Eu-Aims, Garcés, Pilar [0000-0003-4989-0123], Apollo - University of Cambridge Repository, Roche Innovation Center [Basel, Switzerland], Heidelberg University, University Hospital Mannheim | Universitätsmedizin Mannheim, University of London [London], Institute of Neuroscience and Medicine, Brain and Behaviour [Jülich, Germany] (INM-7), Jülich Research Centre, Autism Research Centre [Cambridge, Royaume-Uni], University of Cambridge [UK] (CAM), Centre for Psychiatry Research [Stockholm], Karolinska Institutet [Stockholm], Curtin University [Perth], Planning and Transport Research Centre (PATREC), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], University Medical Center [Utrecht], Università degli Studi di Messina = University of Messina (UniMe), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), King‘s College London, Goethe-University Frankfurt am Main, Central Institute of Mental Health [Mannheim], This work was supported by EU-AIMS (European Autism Interventions), which receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, the resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (grant FP7/2007–2013), from the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contributions and from Autism Speaks. AIMS-2-TRIALS is funded by the Innovative Medicines Initiative 2 Joint Undertaking (IMI 2 JU) under grant agreement no. 777394. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program, EFPIA, Autism Speaks, Autistica, and SFARI. PG was supported by the Roche Postdoctoral Fellowship (RPF) program., European Project: 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS(2012), European Project: 777394,H2020-JTI-IMI2-2016-10-two-stage,AIMS-2-TRIALS(2018), and University of Zurich

Subjects
Adult, Adolescent, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], Autism spectrum disorder, EEG, Resting state, Power spectrum, Functional connectivity, 610 Medicine & health, 1309 Developmental Biology, 2806 Developmental Neuroscience, 2738 Psychiatry and Mental Health, Developmental Neuroscience, 130 000 Cognitive Neurology & Memory, 1312 Molecular Biology, Humans, ddc:610, 10064 Neuroscience Center Zurich, Autistic Disorder, Child, Molecular Biology, Brain Mapping, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Research, 220 Statistical Imaging Neuroscience, Brain, Reproducibility of Results, Electroencephalography, 10058 Department of Child and Adolescent Psychiatry, Magnetic Resonance Imaging, Psychiatry and Mental health, Cross-Sectional Studies, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Developmental Biology
Abstract

Background Understanding the development of the neuronal circuitry underlying autism spectrum disorder (ASD) is critical to shed light into its etiology and for the development of treatment options. Resting state EEG provides a window into spontaneous local and long-range neuronal synchronization and has been investigated in many ASD studies, but results are inconsistent. Unbiased investigation in large and comprehensive samples focusing on replicability is needed. Methods We quantified resting state EEG alpha peak metrics, power spectrum (PS, 2–32 Hz) and functional connectivity (FC) in 411 children, adolescents and adults (n = 212 ASD, n = 199 neurotypicals [NT], all with IQ > 75). We performed analyses in source-space using individual head models derived from the participants’ MRIs. We tested for differences in mean and variance between the ASD and NT groups for both PS and FC using linear mixed effects models accounting for age, sex, IQ and site effects. Then, we used machine learning to assess whether a multivariate combination of EEG features could better separate ASD and NT participants. All analyses were embedded within a train-validation approach (70%–30% split). Results In the training dataset, we found an interaction between age and group for the reactivity to eye opening (p = .042 uncorrected), and a significant but weak multivariate ASD vs. NT classification performance for PS and FC (sensitivity 0.52–0.62, specificity 0.59–0.73). None of these findings replicated significantly in the validation dataset, although the effect size in the validation dataset overlapped with the prediction interval from the training dataset. Limitations The statistical power to detect weak effects—of the magnitude of those found in the training dataset—in the validation dataset is small, and we cannot fully conclude on the reproducibility of the training dataset’s effects. Conclusions This suggests that PS and FC values in ASD and NT have a strong overlap, and that differences between both groups (in both mean and variance) have, at best, a small effect size. Larger studies would be needed to investigate and replicate such potential effects., Molecular Autism, 13

Published
2022

3. Preference for biological motion is reduced in ASD: implications for clinical trials and the search for biomarkers

Author

Mason, L., Shic, F., Falck-Ytter, T., Chakrabarti, B., Charman, T., Loth, E., Tillmann, J., Banaschewski, T., Baron-Cohen, S., Bölte, S., Buitelaar, J., Durston, S., Oranje, B., Persico, A. M., Beckmann, C., Bougeron, T., Dell’Acqua, F., Ecker, C., Moessnang, C., Murphy, D., Johnson, M. H., Jones, E. J. H., Ahmad, Jumana, Ambrosino, Sara, Baumeister, Sarah, Bours, Carsten, Brammer, Michael, Brandeis, Daniel, Brogna, Claudia, de Bruijn, Yvette, Chatham, Chris, Cornelissen, Ineke, Crawley, Daisy, Dumas, Guillaume, Faulkner, Jessica, Frouin, Vincent, Garcés, Pilar, Goyard, David, Ham, Lindsay, Hipp, Joerg, Holt, Rosemary, Lai, Meng-Chuan, D’ardhuy, Xavier Liogier, Lombardo, Michael V., Lythgoe, David J., Mandl, René, Marquand, Andre, Mennes, Maarten, Meyer-Lindenberg, Andreas, Bast, Nico, Oakley, Bethany, O’Dwyer, Laurence, Oldehinkel, Marianne, Pandina, Gahan, Ruggeri, Barbara, Ruigrok, Amber, Sabet, Jessica, Sacco, Roberto, Cáceres, Antonia San José, Simonoff, Emily, Spooren, Will, Toro, Roberto, Tost, Heike, Waldman, Jack, Williams, Steve C. R., Wooldridge, Caroline, Zwiers, Marcel P., Mason, L [0000-0001-9978-7349], Baron-Cohen, Simon [0000-0001-9217-2544], Johnson, Mark [0000-0003-4229-2585], and Apollo - University of Cambridge Repository

Subjects
Eye tracking, Psykologi, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Adolescent, Autism Spectrum Disorder, Research, Autism, Biomarker, Biological motion, Development, Severity of Illness Index, Psychiatry and Mental health, Young Adult, Developmental Neuroscience, Case-Control Studies, Psychology, Humans, Neurology. Diseases of the nervous system, Autistic Disorder, Child, RC346-429, Molecular Biology, Biomarkers, Developmental Biology
Abstract

Background The neurocognitive mechanisms underlying autism spectrum disorder (ASD) remain unclear. Progress has been largely hampered by small sample sizes, variable age ranges and resulting inconsistent findings. There is a pressing need for large definitive studies to delineate the nature and extent of key case/control differences to direct research towards fruitful areas for future investigation. Here we focus on perception of biological motion, a promising index of social brain function which may be altered in ASD. In a large sample ranging from childhood to adulthood, we assess whether biological motion preference differs in ASD compared to neurotypical participants (NT), how differences are modulated by age and sex and whether they are associated with dimensional variation in concurrent or later symptomatology. Methods Eye-tracking data were collected from 486 6-to-30-year-old autistic (N = 282) and non-autistic control (N = 204) participants whilst they viewed 28 trials pairing biological (BM) and control (non-biological, CTRL) motion. Preference for the biological motion stimulus was calculated as (1) proportion looking time difference (BM-CTRL) and (2) peak look duration difference (BM-CTRL). Results The ASD group showed a present but weaker preference for biological motion than the NT group. The nature of the control stimulus modulated preference for biological motion in both groups. Biological motion preference did not vary with age, gender, or concurrent or prospective social communicative skill within the ASD group, although a lack of clear preference for either stimulus was associated with higher social-communicative symptoms at baseline. Limitations The paired visual preference we used may underestimate preference for a stimulus in younger and lower IQ individuals. Our ASD group had a lower average IQ by approximately seven points. 18% of our sample was not analysed for various technical and behavioural reasons. Conclusions Biological motion preference elicits small-to-medium-sized case–control effects, but individual differences do not strongly relate to core social autism associated symptomatology. We interpret this as an autistic difference (as opposed to a deficit) likely manifest in social brain regions. The extent to which this is an innate difference present from birth and central to the autistic phenotype, or the consequence of a life lived with ASD, is unclear.

Published
2021

4. The EU-AIMS Longitudinal European Autism Project (LEAP): clinical characterisation

Author

Charman, Tony, primary, Loth, Eva, additional, Tillmann, Julian, additional, Crawley, Daisy, additional, Wooldridge, Caroline, additional, Goyard, David, additional, Ahmad, Jumana, additional, Auyeung, Bonnie, additional, Ambrosino, Sara, additional, Banaschewski, Tobias, additional, Baron-Cohen, Simon, additional, Baumeister, Sarah, additional, Beckmann, Christian, additional, Bölte, Sven, additional, Bourgeron, Thomas, additional, Bours, Carsten, additional, Brammer, Michael, additional, Brandeis, Daniel, additional, Brogna, Claudia, additional, de Bruijn, Yvette, additional, Chakrabarti, Bhismadev, additional, Cornelissen, Ineke, additional, Acqua, Flavio Dell’, additional, Dumas, Guillaume, additional, Durston, Sarah, additional, Ecker, Christine, additional, Faulkner, Jessica, additional, Frouin, Vincent, additional, Garcés, Pilar, additional, Ham, Lindsay, additional, Hayward, Hannah, additional, Hipp, Joerg, additional, Holt, Rosemary J., additional, Isaksson, Johan, additional, Johnson, Mark H., additional, Jones, Emily J. H., additional, Kundu, Prantik, additional, Lai, Meng-Chuan, additional, D’ardhuy, Xavier Liogier, additional, Lombardo, Michael V., additional, Lythgoe, David J, additional, Mandl, René, additional, Mason, Luke, additional, Meyer-Lindenberg, Andreas, additional, Moessnang, Carolin, additional, Mueller, Nico, additional, O’Dwyer, Laurence, additional, Oldehinkel, Marianne, additional, Oranje, Bob, additional, Pandina, Gahan, additional, Persico, Antonio M., additional, Ruggeri, Barbara, additional, Ruigrok, Amber N. V., additional, Sabet, Jessica, additional, Sacco, Roberto, additional, Cáceres, Antonia San Jóse, additional, Simonoff, Emily, additional, Toro, Roberto, additional, Tost, Heike, additional, Waldman, Jack, additional, Williams, Steve C. R., additional, Zwiers, Marcel P., additional, Spooren, Will, additional, Murphy, Declan G. M., additional, and Buitelaar, Jan K., additional

Published
2017
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5. The EU-AIMS Longitudinal European Autism Project (LEAP): design and methodologies to identify and validate stratification biomarkers for autism spectrum disorders

Author

Loth, Eva, primary, Charman, Tony, additional, Mason, Luke, additional, Tillmann, Julian, additional, Jones, Emily J. H., additional, Wooldridge, Caroline, additional, Ahmad, Jumana, additional, Auyeung, Bonnie, additional, Brogna, Claudia, additional, Ambrosino, Sara, additional, Banaschewski, Tobias, additional, Baron-Cohen, Simon, additional, Baumeister, Sarah, additional, Beckmann, Christian, additional, Brammer, Michael, additional, Brandeis, Daniel, additional, Bölte, Sven, additional, Bourgeron, Thomas, additional, Bours, Carsten, additional, de Bruijn, Yvette, additional, Chakrabarti, Bhismadev, additional, Crawley, Daisy, additional, Cornelissen, Ineke, additional, Acqua, Flavio Dell’, additional, Dumas, Guillaume, additional, Durston, Sarah, additional, Ecker, Christine, additional, Faulkner, Jessica, additional, Frouin, Vincent, additional, Garces, Pilar, additional, Goyard, David, additional, Hayward, Hannah, additional, Ham, Lindsay M., additional, Hipp, Joerg, additional, Holt, Rosemary J., additional, Johnson, Mark H., additional, Isaksson, Johan, additional, Kundu, Prantik, additional, Lai, Meng-Chuan, additional, D’ardhuy, Xavier Liogier, additional, Lombardo, Michael V., additional, Lythgoe, David J., additional, Mandl, René, additional, Meyer-Lindenberg, Andreas, additional, Moessnang, Carolin, additional, Mueller, Nico, additional, O’Dwyer, Laurence, additional, Oldehinkel, Marianne, additional, Oranje, Bob, additional, Pandina, Gahan, additional, Persico, Antonio M., additional, Ruigrok, Amber N. V., additional, Ruggeri, Barbara, additional, Sabet, Jessica, additional, Sacco, Roberto, additional, Cáceres, Antonia San José, additional, Simonoff, Emily, additional, Toro, Roberto, additional, Tost, Heike, additional, Waldman, Jack, additional, Williams, Steve C. R., additional, Zwiers, Marcel P., additional, Spooren, Will, additional, Murphy, Declan G. M., additional, and Buitelaar, Jan K., additional

Published
2017
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6. Identification and validation of biomarkers for autism spectrum disorders

Author

Loth, Eva, primary, Spooren, Will, additional, Ham, Lindsay M., additional, Isaac, Maria B., additional, Auriche-Benichou, Caroline, additional, Banaschewski, Tobias, additional, Baron-Cohen, Simon, additional, Broich, Karl, additional, Bölte, Sven, additional, Bourgeron, Thomas, additional, Charman, Tony, additional, Collier, David, additional, de Andres-Trelles, Fernando, additional, Durston, Sarah, additional, Ecker, Christine, additional, Elferink, Andre, additional, Haberkamp, Marion, additional, Hemmings, Robert, additional, Johnson, Mark H., additional, Jones, Emily J. H., additional, Khwaja, Omar S., additional, Lenton, Sabine, additional, Mason, Luke, additional, Mantua, Valentina, additional, Meyer-Lindenberg, Andreas, additional, Lombardo, Michael V., additional, O'Dwyer, Laurence, additional, Okamoto, Koichi, additional, Pandina, Gahan J., additional, Pani, Luca, additional, Persico, Antonio M., additional, Simonoff, Emily, additional, Tauscher-Wisniewski, Sitra, additional, Llinares-Garcia, Jordi, additional, Vamvakas, Spiros, additional, Williams, Steve, additional, Buitelaar, Jan K., additional, and Murphy, Declan G. M., additional

Published
2015
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8. Religiousness and Levels of Hazardous Alcohol Use: A Latent Profile Analysis

Author

Jankowski, Peter J., primary, Hardy, Sam A., additional, Zamboanga, Byron L., additional, Ham, Lindsay S., additional, Schwartz, Seth J., additional, Kim, Su Yeong, additional, Forthun, Larry F., additional, Bersamin, Melina M., additional, Donovan, Roxanne A., additional, Whitbourne, Susan Krauss, additional, Hurley, Eric A., additional, and Cano, Miguel Ángel, additional

Published
2015
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12. Examining the Light and Dark Sides of Emerging Adults’ Identity: A Study of Identity Status Differences in Positive and Negative Psychosocial Functioning

Author

Schwartz, Seth J., primary, Beyers, Wim, additional, Luyckx, Koen, additional, Soenens, Bart, additional, Zamboanga, Byron L., additional, Forthun, Larry F., additional, Hardy, Sam A., additional, Vazsonyi, Alexander T., additional, Ham, Lindsay S., additional, Kim, Su Yeong, additional, Whitbourne, Susan Krauss, additional, and Waterman, Alan S., additional

Published
2010
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18. The EU-AIMS Longitudinal European Autism Project (LEAP): design and methodologies to identify and validate stratification biomarkers for autism spectrum disorders

Author

Loth, Eva, Charman, Tony, Mason, Luke, Tillmann, Julian, Jones, Emily JH, Wooldridge, Caroline, Ahmad, Jumana, Auyeung, Bonnie, Brogna, Claudia, Ambrosino, Sara, Banaschewski, Tobias, Baron-Cohen, Simon, Baumeister, Sarah, Beckmann, Christian, Brammer, Michael, Brandeis, Daniel, Bölte, Sven, Bourgeron, Thomas, Bours, Carsten, De Bruijn, Yvette, Chakrabarti, Bhismadev, Crawley, Daisy, Cornelissen, Ineke, Acqua, Flavio Dell', Dumas, Guillaume, Durston, Sarah, Ecker, Christine, Faulkner, Jessica, Frouin, Vincent, Garces, Pilar, Goyard, David, Hayward, Hannah, Ham, Lindsay M, Hipp, Joerg, Holt, Rosemary J, Johnson, Mark H, Isaksson, Johan, Kundu, Prantik, Lai, Meng-Chuan, D'ardhuy, Xavier Liogier, Lombardo, Michael V, Lythgoe, David J, Mandl, René, Meyer-Lindenberg, Andreas, Moessnang, Carolin, Mueller, Nico, O'Dwyer, Laurence, Oldehinkel, Marianne, Oranje, Bob, Pandina, Gahan, Persico, Antonio M, Ruigrok, Amber NV, Ruggeri, Barbara, Sabet, Jessica, Sacco, Roberto, Cáceres, Antonia San José, Simonoff, Emily, Toro, Roberto, Tost, Heike, Waldman, Jack, Williams, Steve CR, Zwiers, Marcel P, Spooren, Will, Murphy, Declan GM, and Buitelaar, Jan K

Subjects
Adult, Male, Autism Spectrum Disorder, Individuality, Neuroimaging, Genetic Heterogeneity, Cognition, Genetics, Humans, EEG, Longitudinal Studies, Precision Medicine, Child, Saliva, Eye Movement Measurements, Patient Selection, Siblings, Brain, Magnetic Resonance Imaging, 3. Good health, Phenotype, FOS: Biological sciences, Female, Eye-tracking, Biomarkers, MRI, Hair
Abstract

BACKGROUND: The tremendous clinical and aetiological diversity among individuals with autism spectrum disorder (ASD) has been a major obstacle to the development of new treatments, as many may only be effective in particular subgroups. Precision medicine approaches aim to overcome this challenge by combining pathophysiologically based treatments with stratification biomarkers that predict which treatment may be most beneficial for particular individuals. However, so far, we have no single validated stratification biomarker for ASD. This may be due to the fact that most research studies primarily have focused on the identification of mean case-control differences, rather than within-group variability, and included small samples that were underpowered for stratification approaches. The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study worldwide that aims to identify and validate stratification biomarkers for ASD. METHODS: LEAP includes 437 children and adults with ASD and 300 individuals with typical development or mild intellectual disability. Using an accelerated longitudinal design, each participant is comprehensively characterised in terms of clinical symptoms, comorbidities, functional outcomes, neurocognitive profile, brain structure and function, biochemical markers and genomics. In addition, 51 twin-pairs (of which 36 had one sibling with ASD) are included to identify genetic and environmental factors in phenotypic variability. RESULTS: Here, we describe the demographic characteristics of the cohort, planned analytic stratification approaches, criteria and steps to validate candidate stratification markers, pre-registration procedures to increase transparency, standardisation and data robustness across all analyses, and share some 'lessons learnt'. A clinical characterisation of the cohort is given in the companion paper (Charman et al., accepted). CONCLUSION: We expect that LEAP will enable us to confirm, reject and refine current hypotheses of neurocognitive/neurobiological abnormalities, identify biologically and clinically meaningful ASD subgroups, and help us map phenotypic heterogeneity to different aetiologies.

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