Computerized Physical and Cognitive Training Improves Functional Architecture of the Brain in Down Syndrome Adults: a Longitudin
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medRxiv preprint doi: https://doi.org/10.1101/2020.05.28.20115709; this version posted May 30, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Computerized physical and cognitive training improves functional architecture of the brain in Down Syndrome adults: a longitudinal network science EEG study Anagnostopoulou A.1*, Styliadis C.1*, Kartsidis P.1, Romanopoulou E.1, Zilidou V.1, Karali C.2, Karagianni M.1, Klados M.3, Paraskevopoulos E.1**, Bamidis P. D.1** 1 Medical Physics Laboratory, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece. 2 School of Biology, Faculty of Science, Aristotle University of Thessaloniki, Greece. 3 Department of Psychology, The University of Sheffield International Faculty, City College, Thessaloniki, Greece. * Joined first authorship. ** Joined senior authorship. Correspondence should be addressed to Charis Styliadis, PhD; [email protected] Keywords: Down Syndrome, Physical Training, Cognitive Training, Electroencephalography, Network Science Indices, Adaptive Neuroplasticity Abstract Understanding the neuroplastic capacity of people with Down Syndrome (PwDS) can reveal the cause-effect relationship between aberrant brain organization and phenotypic characteristics. Non-invasive, neuroplasticity-triggering, training protocols, coupled with conventional evaluation methods, have reported promising results. However, the, so far, sparse neurophysiological and network science evidence, are also crucial in quantifying the efficacy of therapeutic interventions. Using electroencephalography (EEG)-acquired data, as well as connectivity and graph-theory approach, we aim to evaluate the effect of a non-invasive intervention on PwDS and track neuroplastic shifts in the DS brain network. 12 PwDS (6 males, average age 29) completed our 10-week protocol (combined physical and cognitive training). Prior to and after the intervention, they underwent eyes-open, resting-state EEG measurements in conjunction with psychosomatometric assessments. After the short-term training, the evaluations reflect increases in physical and cognitive capabilities, while the functional connectivity analysis showed a significant reorganization of the brain network of PwDS (i.e., calibration of connection intensity) and graph-theory analysis indicated significantly increased global and local efficiency and clustering and decreased path length between nodes. These differences delineate the effects of adaptational neuroplasticity, revealing a transition to a healthier, more efficient, and flexible network architecture, with improved integration and segregation abilities and a possible deceleration of neurodegenerative processes in the brain of PwDS. This trial is registered with ClinicalTrials.gov Identifier NCT04390321. Author Summary People with DS (PwDS) have witnessed a steady increase in life expectancy over the past century (average life expectancy of 60 years) with the downside of an increased risk of losing their mental capacity. Though the effects of cognitive and physical training NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.05.28.20115709; this version posted May 30, 2020. 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. All rights reserved. No reuse allowed without permission. on the neuroplasticity attributes of people with and without cognitive impairment have been well documented via neurophysiological evaluations and network science indices, there is still insufficient evidence on PwDS. We investigated the effects of a combinational training protocol on the brain network organization of 12 adult PwDS (age: 29±11) using EEG and network indices (functional connectivity, graph-theoretical approach) coupled with traditional questionnaires. We report evidence of adaptational neuroplastic effects, pointing to a transitional state towards a healthier organization with an increased ability to integrate and segregate information. Our findings underline the ability of the DS brain to respond to the cognitive demands of external stimuli, reflecting the possibility of developing independent-living skills. Introduction Neuroplasticity can emerge in both typical and atypical brains and allows for either development (evolutionary plasticity), reaction (reactive plasticity), recovery (reparation plasticity), or adaptation to internal and external stimuli (adaptational plasticity)1. The different aspects of plasticity are suggested to have the same molecular basis1. In contrast to the brain of typically developed (TD) individuals, the down syndrome (DS) brain, because of gene over-expression, presents atypical levels of inhibition, which lead to prolonged failure of synaptic plasticity and a reduced capacity for remodeling2. These characteristics, along with morphogenetic modifications, have been identified as some of the leading causes of brain disability in people with DS (PwDS)3. Children and young adults with DS, in comparison to age-matched individuals of typical development, have smaller brain volumes (i.e., decreased volume in frontal, amygdalar and cerebellar structures but also increased parahippocampal volume)4,5, a pattern which over pronounces after their 50th year of age6. The current consensus has associated the cognitive capabilities and deficiencies of PwDS with several distinct brain regions (i.e., right parietal, temporal and occipital lobe, left temporal gyrus, bilateral orbitofrontal cortex, posterior cerebellum, and hippocampus) emphasizing an abnormal, less efficient DS brain organization7. Several other lines of electroencephalography (EEG) and magnetoencephalography (MEG) research have complemented the notion of atypical organization; PwDS, when compared to TD, exhibit slow brain wave, especially in the left posterior areas8,9, with higher delta band and lower alpha and beta band activity, a pattern evident in non-DS AD8–11. fMRI studies have shown that the DS network has a rather-simplified organization12, lacking the appropriate efficiency and flexibility13. Given the limited capacity of the DS brain to consolidate information due to its disorganized architecture of reduced segregation and impaired integration, diffused connectivity (hyper-synchrony), and decreased long-range connectivity12,13, the DS brain network’s potential for plasticity13 is in question. Despite these DS-related atypical deviations, which imply a possible limitation of neuroplasticity13, the DS brain does possess neuroplastic capabilities, at least in the form of compensatory events14–16. The emergence of AD-related characteristics (i.e., altered theta band activity and power) in PwDS, at least a decade before the manifestation of dementia and much earlier than in TD people11,17, reaffirm the possibility of compensatory mechanisms, and particularly neuro-plasticity, prior to and during the expression of AD14,16. Characterizing neuroplasticity in PwDS is vital in understanding causality between aberrant brain circuitry and the cognitive and behavioral phenotype. medRxiv preprint doi: https://doi.org/10.1101/2020.05.28.20115709; this version posted May 30, 2020. 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. All rights reserved. No reuse allowed without permission. This understanding would allow the quantification of the remodeling potential of evidence-based interventions that aim to reawake neural plasticity and permit improved cognition. Longitudinal and interventional studies are required to investigate whether it is possible to overcome, at least partially, the cognitive disability through novel therapies. Such interventional approaches have shifted from a pharmaceutical concept, with, so far, inconclusive results regarding beneficial effects 18–22, to non-pharmaceutical interventions of physical and behavioral components, aiming to trigger neuroplasticity and enhance brain health or to protect against neurodegenerative events14. Such interventions have shown promise in healthy aging, and populations with cognitive impairments, and provided mounting evidence for lifelong brain plasticity25–39. Up to date, research is based on cross-sectional brain imaging and graph theory investigations of DS phenotypes12,38–40, coupled with results focusing on cognitive7 and behavioral performance41, as well as evidence of subjective nature (questionnaires and performance on somatometric and psychometric tests). Several studies support the positive impact of exercise-based interventions on daily life activities for PwDS42, showing an effect on adopting a more active lifestyle, and enhancing social skills (provided that the training includes exercises with a social element) 42,43. DS cognitive protocols have so far offered limited evidence on executive functions for middle-aged individuals44, as well as on memory, behavior, and psychoeducation for elderly with DS41. Nonetheless, DS literature still features a substantial knowledge gap, and to our knowledge, there are no reports of neurophysiological investigations of the training-