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Neuroimaging, genetic and clinical studies of oculomotor control
Donnerstag, 03.06.2021:
14:30 - 16:00

Chair der Sitzung: Ulrich Ettinger, Universität Bonn
Chair der Sitzung: Christoph Klein, Universitätsklinikum Freiburg
Ort: Clinical challenges and the ageing brain

Zusammenfassung der Sitzung

The oculomotor system provides a rich microcosm for the study of perception, cognition and motor control. In this symposium, we will provide a state-of-the-art overview of the neural and genetic correlates of eye movements as well as their disorders in psychiatric and neurological disorders. Rebekka Schröder (Psychology/Bonn) will present fMRI data of the neural networks underlying smooth pursuit eye movements in healthy volunteers. Functional connectivity analysis shows that key oculomotor areas display widespread, but only partly overlapping patterns of connectivity. Mark Greenlee (Psychology/Regensburg) will report on fMRI studies investigating the neural correlates of visually-guided and memory-guided saccades. Comparisons of BOLD response between these types of paradigms will be made. Annabell Coors (DZNE/Bonn) will present molecular genetic data on oculomotor endophenotypes for schizophrenia. In N=3000 adults, higher polygenic risk scores for schizophrenia were associated with higher antisaccade error rate, latency and smooth pursuit velocity gain, but lower antisaccade amplitude gain. Daniela Canu (Child and Adolescent Psychiatry/Freiburg) will talk about microsaccade and saccade generation in neurodevelopmental disorders, including early-onset schizophrenia, autism and ADHD. Results suggest the presence of inhibition deficits across clinical groups, suggesting common (pre-)frontal functional impairments. Finally, Chrystalina Antoniades (Clinical Neurosciences/Oxford) will present data from a movement disorders cohort including Parkinson’s disease and progressive supranuclear palsy (N=1400) to illustrate how eye movement parameters have proven a useful translational tool in aiding clinical diagnosis and following disease progression. Overall, this symposium will combine multiple methodological approaches to shed light on human oculomotor control as well as its alterations in disease.

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Functional connectivity during smooth pursuit eye movements

Rebekka Schröder1, Anna-Maria Kasparbauer1, Inga Meyhöfer1, Maria Steffens1, Peter Trautner2,3, Ulrich Ettinger1

1Department of Psychology, University of Bonn, Bonn, Germany; 2Institute for Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany; 3Core Facility MRI, Bonn Technology Campus, University of Bonn, Bonn, Germany

Smooth pursuit eye movements (SPEM) hold the image of a slowly moving stimulus on the fovea. The neural system underlying SPEM primarily includes visual, parietal, and frontal areas. In the present study, we investigated how these areas are functionally coupled and how these couplings are influenced by target motion frequency. To this end, healthy participants (N=57) were instructed to follow a sinusoidal target stimulus moving horizontally at two different frequencies (0.2Hz, 0.4Hz). Eye movements and blood oxygen level-dependent (BOLD) activity were recorded simultaneously. Functional connectivity of the key areas of the SPEM network was investigated with a psychophysiological interaction (PPI) approach. How activity in five eye movement-related seed regions (lateral geniculate nucleus, V1, V5, posterior parietal cortex, frontal eye fields) relates to activity in other parts of the brain during SPEM was analyzed. The behavioral results showed clear deterioration of SPEM performance at higher target frequency. BOLD activity during SPEM versus fixation occurred in a geniculo-occipito-parieto-frontal network, replicating previous findings. PPI analysis yielded widespread, partially overlapping networks. In particular, frontal eye fields and posterior parietal cortex showed task-dependent connectivity to large parts of the entire cortex, whereas other seed regions demonstrated more regionally focused connectivity. Higher target frequency was associated with stronger activations in visual areas but had no effect on functional connectivity. In summary, the results confirm and extend previous knowledge regarding the neural mechanisms underlying SPEM and provide a valuable basis for further investigations such as in patients with SPEM impairments and known alterations in brain connectivity.

Neural correlates of visually guided and memory guided saccades

Mark Greenlee

Universität Regensburg, Deutschland

We propose a new way to compare visually guided and memory guided saccades where visual processing is comparable in both types of task. On each trial of the visually guided task, a coloured bar is flashed at central fixation. After a brief delay, four stimuli were presented peripherally, one in each quadrant. The participants are instructed to saccade to the stimulus that matches the previously viewed target on both colour and orientation. In memory guided condition, the order of stimulus presentation is reversed: first four eccentric stimuli were presented and after a delay the central target. In the memory guided condition, the participant is instructed to execute a saccade to the remembered location of the stimulus that matched the central target in colour and orientation. The behavioural results indicate that the memory guided task is associated with prolonged saccadic reaction times. A general linear model of fMRI BOLD responses revealed regions in prefrontal cortex (left anterior insula, right superior and middle frontal gyrus, anterior medial cingulum), and the intraparietal sulcus extending into surrounding areas (precuneus, superior and inferior parietal lobe) that were more activated when participants performed the memory – compared to the visually – guided task. Multivariate pattern analysis revealed voxel clusters in the ventral visual pathway and the frontal eye fields that correctly classify the target location in both tasks. Our findings identify a cortical network that underlies the programming of visually and memory guided eye movements.

Polygenic risk scores for schizophrenia are associated with oculomotor endophenotypes

Annabell Coors1, Mohammed-Aslam Imtiaz1, Meta M. Boenniger1, Ahmad Aziz1,2, Monique M. B. Breteler1,3,5, Ulrich Ettinger4,5

1Population Health Sciences, Deutsches Zentrum für Neurodegenerative Erkrankungen e.V., Bonn, Germany; 2Department of Neurology, Faculty of Medicine, University of Bonn, Germany; 3Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Germany; 4Department of Psychology, University of Bonn, Germany; 5These authors contributed equally to this work

Background:Schizophrenia is a heterogeneous disorder with substantial heritability. The use of endophenotypes can help clarify its aetiology. Measures from the smooth pursuit and antisaccade eye movement tasks have been identified as endophenotypes for schizophrenia in twin and family studies. However, the genetic basis of the overlap between schizophrenia and these oculomotor markers is largely unknown. Here, we tested whether schizophrenia polygenic risk scores (PRS) were associated with oculomotor performance in the general population.

Method:Analyses were based on data of 2,956 participants (aged 30-95) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Genotyping was performed on Omni-2.5 exome arrays. Using summary statistics from a recent meta-analysis based on the two largest schizophrenia genome-wide association studies to date, we quantified genetic risk for schizophrenia by creating PRS at different p-value thresholds for genetic markers. We examined associations between PRS and oculomotor performance using multivariable regression models.

Results:Higher PRS were associated with higher antisaccade error rate and latency, and lower antisaccade amplitude gain. PRS showed inconsistent patterns of associations with smooth pursuit velocity gain and were not associated with saccade rate during smooth pursuit or performance on a prosaccade control task.

Conclusions: There is overlap between genetic determinants of schizophrenia and oculomotor endophenotypes. Our findings suggest that the mechanisms that underlie schizophrenia also affect oculomotor function and, therefore, support the stronger linkage of the two research fields.

Eye movement-based process analysis: a simultaneous comparison of patients with schizophrenia, ADHD, ASD and healthy controls

Daniela Canu1, Chara Ioannou1, Katarina Müller2, Berthold Martin2, Christian Fleischhaker1, Monica Biscaldi1, André Beauducel3, Nikolaos Smyrnis4, Ludger Tebartz van Elst5, Christoph Klein1,6

1Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; 2Psychotherapeutisches Wohnheim für junge Menschen Leppermühle, Buseck, Germany; 3Institute of Psychology, University of Bonn, Bonn, Germany; 42nd Psychiatry Department, National and Kapodistrian University of Athens, Medical School, University General Hospital "ATTIKON", Athens, Greece; 5Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; 6Department of Child and Adolescent Psychiatry, Medical Faculty, University of Cologne, Cologne, Germany

Despite their phenotypic differences, schizophrenia, Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) share similarities at many levels of investigation. Coherently, based on the Neurodevelopmental Continuum model, neurodevelopmental disorders, including schizophrenia, should be re-conceptualised as lying on an aetiological, neurodevelopmental and clinical continuum. This concept requires their simultaneous comparison, which has not yet been accomplished.

Four groups of late adolescents were included: 26 ASD, 28 ADHD, 20 schizophrenia, 29 with typical development (TD). Eye movements were recorded while basic ocular-motor tasks (prosaccade, antisaccade, memory-guided saccade, fixation) and a visual-search task were administered.

Patients with schizophrenia manifested generalised deficits across tasks and domains of inhibition, processing speed and intra-subject variability (ISV) of response time and saccade dynamics, while sharing with ADHD and ASD deficits in inhibition, ISV of search initiation and fixation duration during search, only with ASD increased microsaccade frequency, ISV of saccade dynamics and post-search duration. In parallel, ASD presented the most speeded and least variable performance during search. Despite dissociations, similar profiles of impairments between clinical groups were revealed by vector correlations. If impairment is interpreted as a qualia, results could suggest the existence of one common neurodevelopmental continuum of performance for the three disorders, while quantitative differences appear in the level of impairment. Along such continuum, schizophrenia presented the greatest level of impairment, while the position of ASD and ADHD was interchangeable, depending on the group of tasks considered. Given the relevance of cognitive impairments in these three disorders, we argue in favour of overlapping pathophysiological mechanisms.

Quantification of eye movements and their use as a translational marker in clinical diagnosis

Chrystalina Antoniades

University of Oxford, United Kingdom

Parkinson’s disease (PD) is a progressive neurological disease and along with Alzheimer’s, one of the most common types of movement disorders. It primarily presents with motor symptoms such as bradykinesia, rigidity and tremor and has as part of its core pathology the degeneration of dopaminergic neurons in the substantia nigra pars compact. The pathways affected by Parkinson’s are also involved in the generation of eye movements and specifically in saccades.

For this talk, I will present saccadic data from both patients and healthy controls, part of the OxQUIP (Oxford Quantification in Parkinsonism study); this trial aims to identify and validate novel neurophysiological and cognitive biomarkers that have the potential to provide quantitative measures of disease state, supplanting the present need of clinical evaluation using rating scales.

Although oculomotor pathways have been extensively studied, PD treatment-induced changes in their parameters are not well known. There is currently no disease-modifying treatment for PD. Most cases are treated symptomatically with medication or surgery (such as Deep Brain Stimulation). One of the factors limiting the rate of development of new treatments, is the reliance on clinical rating scales which are subjective, insensitive and non-linear.

I will present data from a movement disorders cohort N=1400 datasets (focusing on Parkinson’s and Progressive Supranuclear Palsy - a tauopathy (atypical Parkinsonism) to illustrate how eye movement parameters have proven a useful translational tool especially in aiding clinical diagnosis and following disease progression.