Cognitive training gain transfer in cognitively healthy aging: per protocol results of the German AgeGain study

Florian Udo Fischer^1,2*Bianca Kollmann^3,4Dominik Wolf²Alexandra Sebastian^2,3Kristel Knaepen⁵David Riedel⁵Andreas Mierau^5,6Nicolas Ruffini^2,3Kristina Endres^2,7Jennifer Winter⁸Heiko K. Strüder⁵Gerard Nisal Bischof^10,9Sofia Faraza^11,12Bernhard Baier¹³Harald Binder¹⁴Alexander Drzezga^10,15,9Stefan Teipel^11,12Andreas Fellgiebel^16,2Oliver Tüscher^{17,18,19,2,3*}

• ¹University Clinic and Polyclinic for Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, Martin Luther University of Halle-Wittenberg, Halle, Germany
• ²Department of Psychiatry and Psychotherapy, University Medical Centre, Johannes Gutenberg University Mainz, Mainz, Rhineland-Palatinate, Germany
• ³Leibniz Institute for Resilience Research, Johannes Gutenberg University Mainz, Mainz, Rhineland-Palatinate, Germany
• ⁴Department of Neuropsychology and Psychological Resilience Research, Central Institute of Mental Health (ZI), Mannheim, Mannheim, Germany
• ⁵Institute for Movement and Neuroscience, German Sport University Cologne, Cologne, North Rhine-Westphalia, Germany
• ⁶Department of Sport, LUNEX, Differdange, Luxembourg, Differdange, Luxembourg
• ⁷Faculty of Computer Sciences and Microsystems Technology, Kaiserslautern University of Applied Sciences, Zweibrücken, Germany, Zweibrücken, Germany
• ⁸Institute for Human Genetics, University Medical Centre, Johannes Gutenberg University Mainz, Mainz, Rhineland-Palatinate, Germany
• ⁹Department of Nuclear Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany, Cologne, Germany
• ¹⁰Molecular Organization of the Brain (INM-2), Institute of Neuroscience and Medicine, Julich Research Center, Helmholtz Association of German Research Centres (HZ), Jülich, North Rhine-Westphalia, Germany
• ¹¹Department of Psychosomatic Medicine and Psychotherapy, University Hospital Rostock, Rostock, Mecklenburg-Vorpommern, Germany
• ¹²German Center for Neurodegenerative Diseases (DZNE), Rostock/Greifswald, Germany, Rostock/Greifswald, Germany
• ¹³Department of Neurology, University Medical Centre, Johannes Gutenberg University Mainz, Mainz, Rhineland-Palatinate, Germany
• ¹⁴Institute of Medical Biometry and Statistics, University Medical Center Freiburg, Freiburg, Germany
• ¹⁵German Center for Neurodegenerative Diseases (DZNE), Bonn-Cologne, Germany, Bonn/Cologne, Germany
• ¹⁶Clinic for Psychiatry, Psychosomatics and Psychotherapy, AGAPLESION Elisabethenstift, Darmstadt, Germany, Darmstadt, Germany
• ¹⁷University Clinic and Polyclinic for Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, Martin Luther University of Halle-Wittenberg, Halle, Saxony-Anhalt, Germany
• ¹⁸German Center for Mental Health (DZPG), Site Halle-Jena-Magdeburg, Halle (Saale), Germany, Halle/Jena/Magdeburg, Germany
• ¹⁹Institute of Molecular Biology (IMB) Mainz gGmbH, Mainz, Germany, Mainz, Rhineland-Palatinate, Germany

Introduction Cognitive decline is part of the normal aging process, but also a major risk factor for dementia. Cognitive training interventions aim to attenuate cognitive decline, but training gains need to be transferable to untrained cognitive abilities to influence everyday function. Furthermore, the neurobiological basis of cognitive training gain transfer remains elusive. A possible candidate is increased bilateral hemisphere usage enabled by efficient structural connectivity, especially of prefrontal regions. Therefore, the present multicentric study used a cognitive training intervention to demonstrate training transfer and identify neurobiological modulators of successful transfer. Methods In total 235 subjects were enrolled in AgeGain; 180 underwent a broad 4-week cognitive training intervention at three study sites. Pre-and post-training neuropsychological testing was conducted and successful transferers were identified according to preregistered definitions. Pretraining, subjects underwent diffusion and functional MRI to assess interhemispheric connectivity, measured as microstructural integrity of the corpus callosum and lateralization of functional activation patterns during a cognitive control task. Logistic regression models were estimated to predict successful transfer based on structural connectivity and bilateralization of activation patterns. Results Out of 180 subjects, 74 showed short-term training gain transfer that was maintained over 3 months in 19 subjects. Neither microstructural integrity of the corpus callosum, nor bilateralized activation predicted training gain transfer alone. However, their interaction was associated with long-term transfer over 3 months: subjects with higher mean diffusivity of the corpus callosum and more bilateral functional activity or conversely with lower diffusivity of the corpus callosum and more lateral functional activity were more likely successful long-term transferers. Conclusion We demonstrated successful training gain transfer in 41.1% of subjects, among whom 25.7% maintained the transfer over 3 months. Successful long-term transfer of training gains may depend on divergent mechanisms of structural and functional connectivity, which may explain previous heterogeneous results in the literature. Trial register: German Clinical Trials Register (DRKS), ID: DRKS00013077. Registered on November 19th 2017.