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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Adianes Herrera-Diaz; Adianes Herrera-Diaz; Rober Boshra; Paniz Tavakoli; +18 Authors

    The mismatch negativity (MMN) is considered the electrophysiological change-detection response of the brain, and therefore a valuable clinical tool for monitoring functional changes associated with return to consciousness after severe brain injury. Using an auditory multi-deviant oddball paradigm, we tracked auditory MMN responses in seventeen healthy controls over a 12-h period, and in three comatose patients assessed over 24 h at two time points. We investigated whether the MMN responses show fluctuations in detectability over time in full conscious awareness, or whether such fluctuations are rather a feature of coma. Three methods of analysis were utilized to determine whether the MMN and subsequent event-related potential (ERP) components could be identified: traditional visual analysis, permutation t-test, and Bayesian analysis. The results showed that the MMN responses elicited to the duration deviant-stimuli are elicited and reliably detected over the course of several hours in healthy controls, at both group and single-subject levels. Preliminary findings in three comatose patients provide further evidence that the MMN is often present in coma, varying within a single patient from easily detectable to undetectable at different times. This highlights the fact that regular and repeated assessments are extremely important when using MMN as a neurophysiological predictor of coma emergence.

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    Frontiers in Neurology
    Article . 2023 . Peer-reviewed
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    Frontiers in Neurology
    Article . 2023
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Frontiers in Neurolo...arrow_drop_down
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      Frontiers in Neurology
      Article . 2023 . Peer-reviewed
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      Frontiers in Neurology
      Article . 2023
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    Authors: Arnaud Boujut; Arnaud Boujut; Lynn Valeyry Verty; Lynn Valeyry Verty; +11 Authors

    Background: Working memory (WM) capacity declines with advancing age, which impacts the ability to carry out complex cognitive activities in everyday life. Updating and inhibition processes have been identified as some of the most critical attentional control processes of WM and are linked to age-related WM decline. The general aim of the Attentional Control Training in Older People (ACTOP) study was to perform a side-by-side comparison of updating and inhibition training to examine their respective efficacy and transfer in cognitively healthy older adults.Method: The study was a three-arm, double-blind, randomized controlled trial registered with the US National Institutes of Health clinical trials registry. Ninety older adults were randomly assigned to 12 half-hour sessions of updating (N-back type exercises), inhibition (Stroop-like exercises) computerized training or active control (general knowledge quiz game). A group of thirty younger adults completed all proximal and WM transfer tasks without training to assess age-related deficits prior to training and whether training reduces these deficits.Results: Piecewise mixed models show quick improvement of performance during training for both updating and inhibition training. During updating training, the progression was more pronounced for the most difficult (3-back) than for the least (1-back) difficult level until the ninth session. Updating and inhibition training groups improved performance on all proximal and WM transfer measures but these improvements did not differ from the active control group. Younger adults outperformed older ones on all transfer tasks prior to training. However, this was no longer the case following training for two transfer tasks regardless of the training group.Conclusion: The overall results from this study suggest that attentional control training is effective in improving updating and inhibition performance on training tasks. The optimal dose to achieve efficacy is ~9 half-hour sessions and the dose effect was related to difficulty level for updating training. Despite an overall improvement of older adults on all transfer tasks, neither updating nor inhibition training provided additional improvements in comparison with the active control condition. This suggests that the efficacy of process-based training does not directly affect transfer tasks.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03532113

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    Frontiers in Neurology
    Article . 2020
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    Frontiers in Neurology
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    Frontiers in Neurology
    Article . 2020 . Peer-reviewed
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      Article . 2020
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      Frontiers in Neurology
      Article . 2020 . Peer-reviewed
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    Authors: Gabriela S. Gilmour; Davide Martino; Davide Martino; Karen Hunka; +5 Authors

    Introduction: Essential tremor (ET) is a tremor syndrome characterized by bilateral, upper limb action tremor. Essential tremor-plus (ET-plus) describes ET patients with additional neurologic signs. It is unknown whether there is a difference in response to treatment with ventralis intermedius nucleus deep brain stimulation (VIM DBS) in patients with ET and ET-plus. Due to potential variability in underlying etiology in ET-plus, there is a concern that ET-plus patients may have worse outcomes. The aim of this study was to identify whether patients with ET-plus have worse tremor outcomes after VIM DBS than patients with ET.Methods: This is a retrospective chart and video review evaluating VIM DBS outcomes by comparing changes from baseline in the Fahn-Tolosa-Marin Tremor Rating Scale Part B (FTM-B) for the treated limb between patients with ET and ET-plus at follow-up examinations. Patients were re-classified as having ET or ET-plus using pre-operative examination videos by two independent movement disorders neurologists blinded to patient characteristics. As a secondary outcome, we evaluated for correlations and potential predictors of treatment response.Results: Twenty-six patients were included: 13 with ET, 13 with ET-plus. There were no significant differences in the change in FTM-B scores between the ET and ET-plus patients at each follow-up examination. None of the included patients developed new symptoms compatible with dystonia, parkinsonism or gait disturbances.Conclusions: Patients with ET-plus had tremor improvement from VIM DBS, with no differences when compared to those with ET, without emergence of postoperative neurological issues. Patients with ET-plus should still be considered good candidates for VIM DBS for treatment of tremor.

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    Frontiers in Neurology
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    Article . 2021
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    Frontiers in Neurology
    Article . 2021 . Peer-reviewed
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      Article . 2021
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      Frontiers in Neurology
      Article . 2021 . Peer-reviewed
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    Authors: Quincy J. Almeida; Matt J.N. Brown;

    Bradykinesia is a well-documented DOPA-responsive clinical feature of Parkinson’s disease (PD). While amplitude deficits (hypokinesia) are a key component of this slowness, it is important to consider how dopamine influences both the amplitude (hypokinesia) and frequency components of bradykinesia when a bimanually coordinated movement is required. Based on the notion that the basal ganglia are associated with sensory deficits, the influence of dopaminergic replacement on sensory feedback conditions during bimanual coordination was also evaluated. Bimanual movements were examined in PD and healthy comparisons in an unconstrained three-dimensional coordination task. PD were tested “off” (overnight withdrawal of dopaminergic treatment) and “on” (peak dose of dopaminergic treatment), while the healthy group was evaluated for practice effects across two sessions. Required cycle frequency (increased within each trial from 0.75 to 2 Hz), type of visual feedback (no vision, normal vision, and augmented vision), and coordination pattern (symmetrical in-phase and non-symmetrical anti-phase) were all manipulated. Overall, coordination (mean accuracy and standard deviation of relative phase) and amplitude deficits during bimanual coordination were confirmed in PD participants. In addition, significant correlations were identified between severity of motor symptoms as well as bradykinesia to greater coordination deficits (accuracy and stability) in PD “off” group. However, even though amplitude deficits (hypokinesia) improved with dopaminergic replacement, it did not improve bimanual coordination performance (accuracy or stability) in PD patients from “off” to “on.” Interestingly, while coordination performance in both groups suffered in the augmented vision condition, the amplitude of the more affected limb of PD was notably influenced. It can be concluded that DOPA-responsive hypokinesia contributes to, but is not directly responsible for bimanual coordination impairments in PD. It is likely that bimanual coordination deficits in PD are caused by the combination of dopaminergic system dysfunction as well as other neural impairments that may be DOPA-resistant or related to non-dopaminergic pathways.

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    Frontiers in Neurology
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    Frontiers in Neurology
    Article . 2013 . Peer-reviewed
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      Frontiers in Neurology
      Article . 2013 . Peer-reviewed
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    Authors: Brian D. Robertson; Abdullah S. Al Jaja; Abdullah S. Al Jaja; Alex A. MacDonald; +12 Authors

    In Parkinson's disease (PD), cognitive functions mediated by brain regions innervated by ventral tegmental area (VTA) worsen with dopamine replacement therapy, whereas processes relying on regions innervated by the substantia nigra pars compacta (SNc) improve. The SLC6A3 gene encodes the dopamine transporter (DAT). The common 9R polymorphism produces higher DAT concentrations and consequently lower baseline dopamine than SLC6A3 wildtype. Whether SLC6A3 genotype modulates the effect of dopaminergic therapy on cognition in PD is not known. We investigated the effect of dopaminergic therapy and SLC6A3 genotype on encoding and recall of abstract images using the Aggie Figures Learning Test in PD patients. Encoding depends upon brain regions innervated by the VTA, whereas recall is mediated by widespread brain regions, a number innervated by the SNc. We found that dopaminergic therapy worsened encoding of abstract images in 9R carriers only. In contrast, dopaminergic therapy improved recall of abstract images in all PD patients, irrespective of SLC6A3 genotype. Our findings suggest that 9R-carrier PD patients are more predisposed to dopamine overdose and medication-induced impairment of cognitive functions mediated by VTA-innervated brain regions. Interestingly, PD patients without the 9R polymorphism did not show such an impairment. SLC6A3 genotype does not modulate the dopaminergic therapy-induced improvement of functions mediated by SNc-innervated regions in PD patients.

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    Frontiers in Neurology
    Article . 2018
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    Frontiers in Neurology
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    Frontiers in Neurology
    Article . 2018 . Peer-reviewed
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      Frontiers in Neurology
      Article . 2018
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      Frontiers in Neurology
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      Frontiers in Neurology
      Article . 2018 . Peer-reviewed
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    Authors: Todd Nelson; Todd Nelson; Lan-Xin Zhang; Lan-Xin Zhang; +6 Authors

    Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multisystem medical condition with heterogeneous symptom expression. Currently, there is no effective cure or treatment for the standard care of patients. A variety of ME/CFS symptoms can be linked to the vital life functions of the brainstem, the lower extension of the brain best known as the hub relaying information back and forth between the cerebral cortex and various parts of the body.Objective/Methods: Over the past decade, Magnetic Resonance Imaging (MRI) studies have emerged to understand ME/CFS with interesting findings, but there has lacked a synthesized evaluation of what has been found thus far regarding the involvement of the brainstem. We conducted this study to review and evaluate the recent MRI findings via a literature search of the MEDLINE database, from which 11 studies met the eligibility criteria.Findings: Data showed that MRI studies frequently reported structural changes in the white and gray matter. Abnormalities of the functional connectivity within the brainstem and with other brain regions have also been found. The studies have suggested possible mechanisms including astrocyte dysfunction, cerebral perfusion impairment, impaired nerve conduction, and neuroinflammation involving the brainstem, which may at least partially explain a substantial portion of the ME/CFS symptoms and their heterogeneous presentations in individual patients.Conclusions: This review draws research attention to the role of the brainstem in ME/CFS, helping enlighten future work to uncover the pathologies and mechanisms of this complex medical condition, for improved management and patient care.

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    Frontiers in Neurology
    Article . 2021 . Peer-reviewed
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    Authors: Shahin Basiratzadeh; Ramtin Hakimjavadi; Natalie Baddour; Wojtek Michalowski; +14 Authors

    BackgroundConducting clinical trials for traumatic spinal cord injury (tSCI) presents challenges due to patient heterogeneity. Identifying clinically similar subgroups using patient demographics and baseline injury characteristics could lead to better patient-centered care and integrated care delivery.PurposeWe sought to (1) apply an unsupervised machine learning approach of cluster analysis to identify subgroups of tSCI patients using patient demographics and injury characteristics at baseline, (2) to find clinical similarity within subgroups using etiological variables and outcome variables, and (3) to create multi-dimensional labels for categorizing patients.Study designRetrospective analysis using prospectively collected data from a large national multicenter SCI registry.MethodsA method of spectral clustering was used to identify patient subgroups based on the following baseline variables collected since admission until rehabilitation: location of the injury, severity of the injury, Functional Independence Measure (FIM) motor, and demographic data (age, and body mass index). The FIM motor score, the FIM motor score change, and the total length of stay were assessed on the subgroups as outcome variables at discharge to establish the clinical similarity of the patients within derived subgroups. Furthermore, we discussed the relevance of the identified subgroups based on the etiological variables (energy and mechanism of injury) and compared them with the literature. Our study also employed a qualitative approach to systematically describe the identified subgroups, crafting multi-dimensional labels to highlight distinguishing factors and patient-focused insights.ResultsData on 334 tSCI patients from the Rick Hansen Spinal Cord Injury Registry was analyzed. Five significantly different subgroups were identified (p-value ≤0.05) based on baseline variables. Outcome variables at discharge superimposed on these subgroups had statistically different values between them (p-value ≤0.05) and supported the notion of clinical similarity of patients within each subgroup.ConclusionUtilizing cluster analysis, we identified five clinically similar subgroups of tSCI patients at baseline, yielding statistically significant inter-group differences in clinical outcomes. These subgroups offer a novel, data-driven categorization of tSCI patients which aligns with their demographics and injury characteristics. As it also correlates with traditional tSCI classifications, this categorization could lead to improved personalized patient-centered care.

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    Frontiers in Neurology
    Article . 2023 . Peer-reviewed
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    Authors: Cody Rex; Marie-Josée Nadeau; Renée Douville; Renée Douville; +1 Authors

    Background: Spinal and Bulbar Muscular Atrophy (SBMA) is caused by the extension of the polyglutamine tract within the androgen receptor (AR) gene, and results in a multisystem presentation, including the degeneration of lower motor neurons. The androgen receptor (AR) is known to modulate the expression of endogenous retrovirus-K (ERVK), a pathogenic viral genomic symbiont. Since ERVK is associated with motor neuron disease, such as Amyotrophic Lateral Sclerosis (ALS), we sought to determine if patients with SBMA exhibit evidence of ERVK reactivation. Results: Data from a pilot study demonstrate that peripheral blood mononuclear cell (PBMC) samples from controls and patients with SBMA were examined ex vivo for the expression of ERVK viral transcripts and proteins. No differences in ERVK RNA expression was observed between the clinical groups. In contrast, enhancement of processed ERVK Gag and integrase proteins were observed in SBMA-derived PBMC as compared to healthy control specimens. Increased ERVK protein maturation co-occurred with elevation in the expression of the pro-inflammatory transcription factor IRF1 in SBMA. Conclusions: Our findings indicate that ERVK viral protein maturation in SBMA is an unrecognized biomarker and facet of the disease. We discuss how our current understanding of ERVK-driven pathology may tie into key aspects of multi-system dysfunction in SBMA, with a focus on inflammation, proteinopathy, as well as DNA damage and repair.

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      Article . 2019
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      Frontiers in Neurology
      Article . 2019 . Peer-reviewed
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    Authors: Adam C. Gravitis; Uilki Tufa; Katherine Zukotynski; Katherine Zukotynski; +10 Authors

    IntroductionPrevious case-control studies of sudden unexpected death in epilepsy (SUDEP) patients failed to identify ECG features (peri-ictal heart rate, heart rate variability, corrected QT interval, postictal heart rate recovery, and cardiac rhythm) predictive of SUDEP risk. This implied a need to derive novel metrics to assess SUDEP risk from ECG.MethodsWe applied Single Spectrum Analysis and Independent Component Analysis (SSA-ICA) to remove artifact from ECG recordings. Then cross-frequency phase-phase coupling (PPC) was applied to a 20-s mid-seizure window and a contour of −3 dB coupling strength was determined. The contour centroid polar coordinates, amplitude (alpha) and angle (theta), were calculated. Association of alpha and theta with SUDEP was assessed and a logistic classifier for alpha was constructed.ResultsAlpha was higher in SUDEP patients, compared to non-SUDEP patients (p < 0.001). Theta showed no significant difference between patient populations. The receiver operating characteristic (ROC) of a logistic classifier for alpha resulted in an area under the ROC curve (AUC) of 94% and correctly classified two test SUDEP patients.DiscussionThis study develops a novel metric alpha, which highlights non-linear interactions between two rhythms in the ECG, and is predictive of SUDEP risk.

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    Frontiers in Neurology
    Article . 2023 . Peer-reviewed
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    Frontiers in Neurology
    Article . 2023
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      Frontiers in Neurology
      Article . 2023 . Peer-reviewed
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      Frontiers in Neurology
      Article . 2023
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    Authors: Maryam Tayyab; Maryam Tayyab; Luanne M. Metz; David K.B. Li; +8 Authors

    IntroductionMachine learning (ML) has great potential for using health data to predict clinical outcomes in individual patients. Missing data are a common challenge in training ML algorithms, such as when subjects withdraw from a clinical study, leaving some samples with missing outcome labels. In this study, we have compared three ML models to determine whether accounting for label uncertainty can improve a model’s predictions.MethodsWe used a dataset from a completed phase-III clinical trial that evaluated the efficacy of minocycline for delaying the conversion from clinically isolated syndrome to multiple sclerosis (MS), using the McDonald 2005 diagnostic criteria. There were a total of 142 participants, and at the 2-year follow-up 81 had converted to MS, 29 remained stable, and 32 had uncertain outcomes. In a stratified 7-fold cross-validation, we trained three random forest (RF) ML models using MRI volumetric features and clinical variables to predict the conversion outcome, which represented new disease activity within 2 years of a first clinical demyelinating event. One RF was trained using subjects with the uncertain labels excluded (RFexclude), another RF was trained using the entire dataset but with assumed labels for the uncertain group (RFnaive), and a third, a probabilistic RF (PRF, a type of RF that can model label uncertainty) was trained on the entire dataset, with probabilistic labels assigned to the uncertain group.ResultsProbabilistic random forest outperformed both the RF models with the highest AUC (0.76, compared to 0.69 for RFexclude and 0.71 for RFnaive) and F1-score (86.6% compared to 82.6% for RFexclude and 76.8% for RFnaive).ConclusionMachine learning algorithms capable of modeling label uncertainty can improve predictive performance in datasets in which a substantial number of subjects have unknown outcomes.

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    Frontiers in Neurology
    Article . 2023
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    Frontiers in Neurology
    Article . 2023 . Peer-reviewed
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      Frontiers in Neurology
      Article . 2023
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      Frontiers in Neurology
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    Authors: Adianes Herrera-Diaz; Adianes Herrera-Diaz; Rober Boshra; Paniz Tavakoli; +18 Authors

    The mismatch negativity (MMN) is considered the electrophysiological change-detection response of the brain, and therefore a valuable clinical tool for monitoring functional changes associated with return to consciousness after severe brain injury. Using an auditory multi-deviant oddball paradigm, we tracked auditory MMN responses in seventeen healthy controls over a 12-h period, and in three comatose patients assessed over 24 h at two time points. We investigated whether the MMN responses show fluctuations in detectability over time in full conscious awareness, or whether such fluctuations are rather a feature of coma. Three methods of analysis were utilized to determine whether the MMN and subsequent event-related potential (ERP) components could be identified: traditional visual analysis, permutation t-test, and Bayesian analysis. The results showed that the MMN responses elicited to the duration deviant-stimuli are elicited and reliably detected over the course of several hours in healthy controls, at both group and single-subject levels. Preliminary findings in three comatose patients provide further evidence that the MMN is often present in coma, varying within a single patient from easily detectable to undetectable at different times. This highlights the fact that regular and repeated assessments are extremely important when using MMN as a neurophysiological predictor of coma emergence.

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    Frontiers in Neurology
    Article . 2023 . Peer-reviewed
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    Frontiers in Neurology
    Article . 2023
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      Frontiers in Neurology
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      Frontiers in Neurology
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    Authors: Arnaud Boujut; Arnaud Boujut; Lynn Valeyry Verty; Lynn Valeyry Verty; +11 Authors

    Background: Working memory (WM) capacity declines with advancing age, which impacts the ability to carry out complex cognitive activities in everyday life. Updating and inhibition processes have been identified as some of the most critical attentional control processes of WM and are linked to age-related WM decline. The general aim of the Attentional Control Training in Older People (ACTOP) study was to perform a side-by-side comparison of updating and inhibition training to examine their respective efficacy and transfer in cognitively healthy older adults.Method: The study was a three-arm, double-blind, randomized controlled trial registered with the US National Institutes of Health clinical trials registry. Ninety older adults were randomly assigned to 12 half-hour sessions of updating (N-back type exercises), inhibition (Stroop-like exercises) computerized training or active control (general knowledge quiz game). A group of thirty younger adults completed all proximal and WM transfer tasks without training to assess age-related deficits prior to training and whether training reduces these deficits.Results: Piecewise mixed models show quick improvement of performance during training for both updating and inhibition training. During updating training, the progression was more pronounced for the most difficult (3-back) than for the least (1-back) difficult level until the ninth session. Updating and inhibition training groups improved performance on all proximal and WM transfer measures but these improvements did not differ from the active control group. Younger adults outperformed older ones on all transfer tasks prior to training. However, this was no longer the case following training for two transfer tasks regardless of the training group.Conclusion: The overall results from this study suggest that attentional control training is effective in improving updating and inhibition performance on training tasks. The optimal dose to achieve efficacy is ~9 half-hour sessions and the dose effect was related to difficulty level for updating training. Despite an overall improvement of older adults on all transfer tasks, neither updating nor inhibition training provided additional improvements in comparison with the active control condition. This suggests that the efficacy of process-based training does not directly affect transfer tasks.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03532113

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