Acoustic stimulation during sleep predicts long-lasting increases in memory performance and beneficial amyloid response in older adults.

BACKGROUND: Sleep and neurodegeneration are assumed to be locked in a bi-directional vicious cycle. Improving sleep could break this cycle and help to prevent neurodegeneration. We tested multi-night phase-locked acoustic stimulation (PLAS) during slow wave sleep (SWS) as a non-invasive method to improve SWS, memory performance and plasma amyloid levels. METHODS: 32 healthy older adults (agemean: 68.9) completed a between-subject sham-controlled three-night intervention, preceded by a sham-PLAS baseline night. RESULTS: PLAS induced increases in sleep-associated spectral-power bands as well as a 24% increase in slow wave-coupled spindles, known to support memory consolidation. There was no significant group-difference in memory performance or amyloid-beta between the intervention and control group. However, the magnitude of PLAS-induced physiological responses were associated with memory performance up to 3 months post intervention and beneficial changes in plasma amyloid. Results were exclusive to the intervention group. DISCUSSION: Multi-night PLAS is associated with long-lasting benefits in memory and metabolite clearance in older adults, rendering PLAS a promising tool to build upon and develop long-term protocols for the prevention of cognitive decline.

Re-fixation and perseveration patterns in neglect patients during free visual exploration.

The literature suggests that neglect patients not only show impairments in directing attention toward the left, contralesional space, but also present with perseverative behavior. Moreover, previous studies described re-fixations during visual search tasks, and interpreted this finding as an impairment of spatial working memory. The aim of the present study was to study re-fixations and perseverations (i.e., recurrent re-fixations to same locations) during free visual exploration, a task with high ecological validity. We hypothesized that: (1) neglect patient would perform re-fixations more frequently than healthy controls within the right hemispace; and, (2) the re-fixation behavior of neglect patients would be characterized by perseverative fixations. To test these hypotheses, we assessed 22 neglect patients and 23 healthy controls, measuring their eye movements during free exploration of naturalistic pictures. The results showed that neglect patients tend to re-fixate locations within the ipsilesional hemispace when they freely explore naturalistic pictures. Importantly, the saliency of discrete locations within the pictures has a stronger influence on fixation behavior within the contralesional than within the ipsilesional hemispace in neglect patients. Finally, the results indicated that, for re-fixations, saliency plays a more important role within the contralesional than the ipsilesional hemispace. Moreover, we found evidence that re-fixation behavior of neglect patients is characterized by frequent recurrent re-fixations back to the same spatial locations which may be interpreted as perseverations. Hence, with the present study, we could better elucidate the mechanism leading to re-fixations and perseverative behavior during free visual exploration in neglect patients.

Adaptive data-driven selection of sequences of biological and cognitive markers in pre-clinical diagnosis of dementia.

Effective clinical decision procedures must balance multiple competing objectives such as time-to-decision, acquisition costs, and accuracy. We describe and evaluate POSEIDON, a data-driven method for PrOspective SEquentIal DiagnOsis with Neutral zones to individualize clinical classifications. We evaluated the framework with an application in which the algorithm sequentially proposes to include cognitive, imaging, or molecular markers if a sufficiently more accurate prognosis of clinical decline to manifest Alzheimer's disease is expected. Over a wide range of cost parameter data-driven tuning lead to quantitatively lower total cost compared to ad hoc fixed sets of measurements. The classification accuracy based on all longitudinal data from participants that was acquired over 4.8 years on average was 0.89. The sequential algorithm selected 14 percent of available measurements and concluded after an average follow-up time of 0.74 years at the expense of 0.05 lower accuracy. Sequential classifiers were competitive from a multi-objective perspective since they could dominate fixed sets of measurements by making fewer errors using less resources. Nevertheless, the trade-off of competing objectives depends on inherently subjective prescribed cost parameters. Thus, despite the effectiveness of the method, the implementation into consequential clinical applications will remain controversial and evolve around the choice of cost parameters.

Investigating Compensatory Brain Activity in Older Adults with Subjective Cognitive Decline.

BACKGROUND: Preclinical Alzheimer's disease (AD) is one possible cause of subjective cognitive decline (SCD). Normal task performance despite ongoing neurodegeneration is typically considered as neuronal compensation, which is reflected by greater neuronal activity. Compensatory brain activity has been observed in frontal as well as parietal regions in SCD, but data are scarce, especially outside the memory domain. OBJECTIVE: To investigate potential compensatory activity in SCD. Such compensatory activity is particularly expected in participants where blood-based biomarkers indicated amyloid positivity as this implies preclinical AD. METHODS: 52 participants with SCD (mean age: 71.00±5.70) underwent structural and functional neuroimaging (fMRI), targeting episodic memory and spatial abilities, and a neuropsychological assessment. The estimation of amyloid positivity was based on plasma amyloid-ß and phosphorylated tau (pTau181) measures. RESULTS: Our fMRI analyses of the spatial abilities task did not indicate compensation, with only three voxels exceeding an uncorrected threshold at p < 0.001. This finding was not replicated in a subset of 23 biomarker positive individuals. CONCLUSION: Our results do not provide conclusive evidence for compensatory brain activity in SCD. It is possible that neuronal compensation does not manifest at such an early stage as SCD. Alternatively, it is possible that our sample size was too small or that compensatory activity may be too heterogeneous to be detected by group-level statistics. Interventions based on the individual fMRI signal should therefore be explored.

Informant Questionnaires in Dedicated Memory Clinics: How Much Do They Contribute?

BACKGROUND/OBJECTIVES: The diagnostic process in a university memory clinic is based largely on cognitive testing. However, input from informants, acquired through interview or questionnaires, may significantly impact diagnosis. We sought to evaluate whether informant questionnaires for basic and instrumental activities of daily living, or for identifying progressive cognitive decline would improve diagnostic predictability of neurodegenerative disorders compared with either the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological test battery or the Mini-Mental State Examination score alone. DESIGN: Retrospective data analysis using logit models. SETTING: University hospital outpatient memory clinic. PARTICIPANTS: A total of 394 patients with dementia, mild cognitive impairment (MCI), depression, or subjective cognitive impairment were assessed. MEASUREMENTS: Bristol Activities of Daily Living Scale, Functional Activities Questionnaire, Informant Questionnaire on Cognitive Decline in the Elderly, and the Physical Self-Maintenance Scale questionnaires were obtained. Analyses through logit models were performed to predict outcome diagnoses, based on cognitive scores alone or in combination with one or more informant questionnaires. RESULTS: The four questionnaires were highly correlated (.31-.86). The addition of informant questionnaires improved diagnostic predictability between differential diagnoses of MCI and dementia, or dementia and depression. However, the misprediction rate was reduced by up to 6 percentage points only. Adding more than one questionnaire or all CERAD subtests instead of their sum score never improved prediction in regularized logit models to a clinically relevant extent. CONCLUSION: Although questionnaires contribute to a statistically better prediction of the outcome diagnosis, for some sets of differential diagnoses, the benefit may not be clinically pertinent when routine semistructured informant interviews are used by trained personnel. However, standardized assessment, particularly when patients are seen longitudinally, should not be underestimated.

Transcranial electrical stimulation improves cognitive training effects in healthy elderly adults with low cognitive performance.

OBJECTIVE: To investigate the efficacy of transcranial direct (tDCS) or alternating current stimulation (tACS) in boosting cognitive training efficiency in healthy older adults. We further explored whether such improvements depend on general cognitive performance or age. METHODS: In this randomized, sham-controlled study, 59 healthy elderly participants (mean age 71.7) were assigned to receive computer-based cognitive training (10 sessions, 50 min, twice weekly) combined with tDCS (2 mA), tACS (5 Hz), or sham stimulation over the left dorsolateral prefrontal cortex (20 minutes). Cognitive performance was assessed with the Montreal Cognitive Assessment (MoCA), and a cognitive composite score derived from a broad neuropsychological test battery before and immediately after the intervention as well as at 6 and 12 months follow-ups. RESULTS: Performance in the cognitive composite score improved significantly in all groups but was not further modulated by neurostimulation. Additional analyses revealed that participants with a low initial MoCA score (<1SD) improved significantly more in the tDCS than in the sham group. CONCLUSION: TDCS increased the efficacy of cognitive training, but only in participants with initially low general cognitive performance. SIGNIFICANCE: Cognitive interventions including tDCS should address baseline performance as modulating factor of cognitive outcomes.

Transcranial Electric Current Stimulation During Associative Memory Encoding: Comparing tACS and tDCS Effects in Healthy Aging.

Associative memory is one of the first cognitive functions negatively affected by healthy and pathological aging processes. Non-invasive brain stimulation (NIBS) techniques are easily administrable tools to support memory. However, the optimal stimulation parameters inducing a reliable positive effect on older adult's memory performance remain mostly unclear. In our randomized, double-blind, cross-over study, 28 healthy older adults (16 females; 71.18 + 6.42 years of age) received anodal transcranial direct (tDCS), alternating current in the theta range (tACS), and sham stimulation over the left ventrolateral prefrontal cortex (VLPFC) each once during encoding. We tested associative memory performance with cued recall and recognition tasks after a retention period and again on the following day. Overall, neither tDCS nor tACS showed effects on associative memory performance. Further analysis revealed a significant difference for performance on the cued recall task under tACS compared to sham when accounting for age. Our results suggest that tACS might be more effective to improve associative memory performance than tDCS in higher aged samples.

Investigating a new tablet-based telerehabilitation app in patients with aphasia: a randomised, controlled, evaluator-blinded, multicentre trial protocol.

INTRODUCTION: Aphasia is a common language disorder acquired after stroke that reduces the quality of life of affected patients. The impairment is frequently accompanied by a deficit in cognitive functions. The state-of-the-art therapy is speech and language therapy but recent findings highlight positive effects of high-frequency therapy. Telerehabilitation has the potential to enable high-frequency therapy for patients at home. This study investigates the effects of high-frequency telerehabilitation speech and language therapy (teleSLT) on language functions in outpatients with aphasia compared with telerehabilitative cognitive training. We hypothesise that patients training with high-frequency teleSLT will show higher improvement in language functions and quality of life compared with patients with high-frequency tele-rehabilitative cognitive training (teleCT). METHODS AND ANALYSIS: This study is a randomised controlled, evaluator-blinded multicentre superiority trial comparing the outcomes following either high-frequency teleSLT or teleCT. A total of 100 outpatients with aphasia will be recruited and assigned in a 1:1 ratio stratified by trial site and severity of impairment to one of two parallel groups. Both groups will train over a period of 4 weeks for 2 hours per day. Patients in the experimental condition will devote 80% of their training time to teleSLT and the remaining 20% (24 min/day) to teleCT, vice versa for patients in the control condition. The primary outcome measure is the understandability of verbal communication on the Amsterdam Nijmegen Everyday Language Test and secondary outcome measures are intelligibility of the verbal communication, impairment of receptive and expressive language functions, confrontation naming. Other outcomes measures are quality of life and acceptance (usability and subjective experience) of the teleSLT system. ETHICS AND DISSEMINATION: This study is approved by the Ethics Committee Bern (ID 2016-01577). Results will be submitted to a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT03228264.

Therapist-Guided Tablet-Based Telerehabilitation for Patients With Aphasia: Proof-of-Concept and Usability Study.

BACKGROUND: Aphasia is the loss or impairment of language functions and affects everyday social life. The disorder leads to the inability to understand and be understood in both written and verbal communication and affects the linguistic modalities of auditory comprehension, verbal expression, reading, and writing. Due to heterogeneity of the impairment, therapy must be adapted individually and dynamically to patient needs. An important factor for successful aphasia therapy is dose and intensity of therapy. Tablet computer-based apps are a promising treatment method that allows patients to train independently at home, is well accepted, and is known to be beneficial for patients. In addition, it has been shown to ease the burden of therapists. OBJECTIVE: The aim of this project was to develop an adaptive multimodal system that enables aphasic patients to train at home using language-related tasks autonomously, allows therapists to remotely assign individualized tasks in an easy and time-efficient manner, and tracks the patient's progress as well as creation of new individual exercises. METHODS: The system consists of two main parts: (1) the patient's interface, which allows the patient to exercise, and (2) the therapist's interface, which allows the therapist to assign new exercises to the patient and supervise the patient's progress. The pool of exercises is based on a hierarchical language structure. Using questionnaires, therapists and patients evaluated the system in terms of usability (ie, System Usability Scale) and motivation (ie, adapted Intrinsic Motivation Inventory). RESULTS: A total of 11 speech and language therapists (age: mean 28, SD 7 years) and 15 patients (age: mean 53, SD 10 years) diagnosed with aphasia participated in this study. Patients rated the Bern Aphasia App in terms of usability (scale 0-100) as excellent (score >70; Z=-1.90; P=.03) and therapists rated the app as good (score >85; Z=-1.75; P=.04). Furthermore, patients enjoyed (scale 0-6) solving the exercises (score>3; mean 3.5, SD 0.40; Z=-1.66; P=.049). CONCLUSIONS: Based on the questionnaire scores, the system is well accepted and simple to use for patients and therapists. Furthermore, the new tablet computer-based app and the hierarchical language exercise structure allow patients with different types of aphasia to train with different doses and intensities independently at home. Thus, the novel system has potential for treatment of patients with aphasia as a supplement to face-to-face therapy.

Attentional reorienting triggers spatial asymmetries in a search task with cross-modal spatial cueing.

Cross-modal spatial cueing can affect performance in a visual search task. For example, search performance improves if a visual target and an auditory cue originate from the same spatial location, and it deteriorates if they originate from different locations. Moreover, it has recently been postulated that multisensory settings, i.e., experimental settings, in which critical stimuli are concurrently presented in different sensory modalities (e.g., visual and auditory), may trigger asymmetries in visuospatial attention. Thereby, a facilitation has been observed for visual stimuli presented in the right compared to the left visual space. However, it remains unclear whether auditory cueing of attention differentially affects search performance in the left and the right hemifields in audio-visual search tasks. The present study investigated whether spatial asymmetries would occur in a search task with cross-modal spatial cueing. Participants completed a visual search task that contained no auditory cues (i.e., unimodal visual condition), spatially congruent, spatially incongruent, and spatially non-informative auditory cues. To further assess participants' accuracy in localising the auditory cues, a unimodal auditory spatial localisation task was also administered. The results demonstrated no left/right asymmetries in the unimodal visual search condition. Both an additional incongruent, as well as a spatially non-informative, auditory cue resulted in lateral asymmetries. Thereby, search times were increased for targets presented in the left compared to the right hemifield. No such spatial asymmetry was observed in the congruent condition. However, participants' performance in the congruent condition was modulated by their tone localisation accuracy. The findings of the present study demonstrate that spatial asymmetries in multisensory processing depend on the validity of the cross-modal cues, and occur under specific attentional conditions, i.e., when visual attention has to be reoriented towards the left hemifield.

What Older People Like to Play: Genre Preferences and Acceptance of Casual Games.

BACKGROUND: In recent computerized cognitive training studies, video games have emerged as a promising tool that can benefit cognitive function and well-being. Whereas most video game training studies have used first-person shooter (FPS) action video games, subsequent studies found that older adults dislike this type of game and generally prefer casual video games (CVGs), which are a subtype of video games that are easy to learn and use simple rules and interfaces. Like other video games, CVGs are organized into genres (eg, puzzle games) based on the rule-directed interaction with the game. Importantly, game genre not only influences the ease of interaction and cognitive abilities CVGs demand, but also affects whether older adults are willing to play any particular genre. To date, studies looking at how different CVG genres resonate with older adults are lacking. OBJECTIVE: The aim of this study was to investigate how much older adults enjoy different CVG genres and how favorably their CVG characteristics are rated. METHODS: A total of 16 healthy adults aged 65 years and above playtested 7 CVGs from 4 genres: casual action, puzzle, simulation, and strategy video games. Thereafter, they rated casual game preference and acceptance of casual game characteristics using 4 scales from the Core Elements of the Gaming Experience Questionnaire (CEGEQ). For this, participants rated how much they liked the game (enjoyment), understood the rules of the game (game-play), learned to manipulate the game (control), and make the game their own (ownership). RESULTS: Overall, enjoyment and acceptance of casual game characteristics was high and significantly above the midpoint of the rating scale for all CVG genres. Mixed model analyses revealed that ratings of enjoyment and casual game characteristics were significantly influenced by CVG genre. Participants' mean enjoyment of casual puzzle games (mean 0.95 out of 1.00) was significantly higher than that for casual simulation games (mean 0.75 and 0.73). For casual game characteristics, casual puzzle and simulation games were given significantly higher game-play ratings than casual action games. Similarly, participants' control ratings for casual puzzle games were significantly higher than that for casual action and simulation games. Finally, ownership was rated significantly higher for casual puzzle and strategy games than for casual action games. CONCLUSIONS: The findings of this study show that CVGs have characteristics that are suitable and enjoyable for older adults. In addition, genre was found to influence enjoyment and ratings of CVG characteristics, indicating that puzzle games are particularly easy to understand, learn, and play, and are enjoyable. Future studies should continue exploring the potential of CVG interventions for older adults in improving cognitive function, everyday functioning, and well-being. We see particular potential for CVGs in people suffering from cognitive impairment due to dementia or brain injury.

Evaluation of a novel Serious Game based assessment tool for patients with Alzheimer's disease.

Despite growing interest in developing ecological assessment of difficulties in patients with Alzheimer's disease new methods assessing the cognitive difficulties related to functional activities are missing. To complete current evaluation, the use of Serious Games can be a promising approach as it offers the possibility to recreate a virtual environment with daily living activities and a precise and complete cognitive evaluation. The aim of the present study was to evaluate the usability and the screening potential of a new ecological tool for assessment of cognitive functions in patients with Alzheimer's disease. Eighteen patients with Alzheimer's disease and twenty healthy controls participated to the study. They were asked to complete six daily living virtual tasks assessing several cognitive functions: three navigation tasks, one shopping task, one cooking task and one table preparation task following a one-day scenario. Usability of the game was evaluated through a questionnaire and through the analysis of the computer interactions for the two groups. Furthermore, the performances in terms of time to achieve the task and percentage of completion on the several tasks were recorded. Results indicate that both groups subjectively found the game user friendly and they were objectively able to play the game without computer interactions difficulties. Comparison of the performances between the two groups indicated a significant difference in terms of percentage of achievement of the several tasks and in terms of time they needed to achieve the several tasks. This study suggests that this new Serious Game based assessment tool is a user-friendly and ecological method to evaluate the cognitive abilities related to the difficulties patients can encounter in daily living activities and can be used as a screening tool as it allowed to distinguish Alzheimer's patient's performance from healthy controls.

Visuo-acoustic stimulation that helps you to relax: A virtual reality setup for patients in the intensive care unit.

After prolonged stay in an intensive care unit (ICU) patients often complain about cognitive impairments that affect health-related quality of life after discharge. The aim of this proof-of-concept study was to test the feasibility and effects of controlled visual and acoustic stimulation in a virtual reality (VR) setup in the ICU. The VR setup consisted of a head-mounted display in combination with an eye tracker and sensors to assess vital signs. The stimulation consisted of videos featuring natural scenes and was tested in 37 healthy participants in the ICU. The VR stimulation led to a reduction of heart rate (p = 0. 049) and blood pressure (p = 0.044). Fixation/saccade ratio (p < 0.001) was increased when a visual target was presented superimposed on the videos (reduced search activity), reflecting enhanced visual processing. Overall, the VR stimulation had a relaxing effect as shown in vital markers of physical stress and participants explored less when attending the target. Our study indicates that VR stimulation in ICU settings is feasible and beneficial for critically ill patients.