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Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting millions worldwide, leading to cognitive and functional decline. Early detection and intervention are crucial for enhancing the quality of life of patients and their families. Remote Monitoring Technologies (RMTs) offer a promising solution for early detection by tracking changes in behavioral and cognitive functions, such as memory, language, and problem-solving skills. Timely detection of these symptoms can facilitate early intervention, potentially slowing disease progression and enabling appropriate treatment and care., Methods: The RADAR-AD study was designed to evaluate the accuracy and validity of multiple RMTs in detecting functional decline across various stages of AD in a real-world setting, compared to standard clinical rating scales. Our approach involved a univariate analysis using Analysis of Covariance (ANCOVA) to analyze individual features of six RMTs while adjusting for variables such as age, sex, years of education, clinical site, BMI and season. Additionally, we employed four machine learning classifiers - Logistic Regression, Decision Tree, Random Forest, and XGBoost - using a nested cross-validation approach to assess the discriminatory capabilities of the RMTs., Results: The ANCOVA results indicated significant differences between healthy and AD subjects regarding reduced physical activity, less REM sleep, altered gait patterns, and decreased cognitive functioning. The machine-learning-based analysis demonstrated that RMT-based models could identify subjects in the prodromal stage with an Area Under the ROC Curve of 73.0 %. In addition, our findings show that the Amsterdam iADL questionnaire has high discriminatory abilities., Conclusions: RMTs show promise in AD detection already in the prodromal stage. Using them could allow for earlier detection and intervention, thereby improving patients' quality of life. Furthermore, the Amsterdam iADL questionnaire holds high potential when employed remotely., Competing Interests: Declarations. Ethics approval and consent to participate: The RADAR-AD was ethically approved in each participating country and aligns with the Helsinki Declaration of 1975, revised in 2008. All participants and their informants provided written informed consent prior to any study procedures. Competing interests: Authors AA, AKB, AM, CH, DR, GF, GW, HF, IL, LH, MGk, MGr, ML, MTG, PC, SN, VA, and VN declare no financial or non-financial competing interests. DA has received research support and/ or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals, Evonik, Roche Diagnostics, and GE Health, and served as paid consultant for H. Lundbeck, Eisai, Heptares, Mentis Cura, Eli Lilly, Cognetivity, Enterin, Acadia, EIP Pharma, and Biogen. JC is an employee and a shareholder of Novartis. GS is an employee of Novartis. NC is employed by Novartis Pharma AG, Basel, Switzerland. Research of Alzheimer center Amsterdam (MM, CB) is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting Steun Alzheimercentrum Amsterdam. MB is an employee of the Ace Alzheimer Center and an advisory board member for Grifols, Roche, Eli Lilly, Araclon Biotech, Merck, Zambon, Biogen, Novo Nordisk, Bioiberica, Eisai, Servier, and Schwabe Pharma. SG declares support for this work through the Italian Ministry of Health (Ricerca Corrente). GW and SV are employees and shareholders of Johnson & Johnson., (© 2025. The Author(s).)

Background: The novel South London and Maudsley Brain Health Clinic (SLaM BHC) leverages advances in remote consultations and biomarkers to provide a timely, cost-efficient and accurate diagnosis in mild cognitive impairment (MCI)., Aims: To describe the organisation, patient cohort and acceptability of the remote diagnostic and interventional procedures., Method: We describe the recruitment, consultation set-up, the clinical and biomarker programme, and the two online group interventions for cognitive wellbeing and lifestyle change. We evaluate the acceptability of the remote consultations, lumbar puncture, saliva genotyping, and remote cognitive and functional assessments., Results: We present the results of the first 68 (mean age 73, 55% female, 43% minoritised ethnicity) of 146 people who enrolled for full remote clinical, cognitive, genetic, cerebrospinal fluid and neuroimaging phenotyping. A total of 86% were very satisfied/satisfied with the remote service. In all, 67% consented to lumbar puncture, and 95% of those were very satisfied, all having no significant complications. A total of 93% found taking saliva genotyping very easy/easy, and 93% found the cognitive assessments instructions clear. In all, 98% were satisfied with the Cognitive Wellbeing Group, and 90% of goals were achieved in the Lifestyle Intervention Group., Conclusions: The SLaM BHC provides a highly acceptable and safe clinical model for remote assessments and lumbar punctures in a representative, ethnically diverse population. This allows early and accurate diagnosis of Alzheimer's disease, differentiation from other MCI causes and targets modifiable risk factors. This is crucial for future disease modification, ensuring equitable access to research, and provides precise, timely and cost-efficient diagnoses in UK mental health services.

Background: Investigations of computerised cognitive training (CCT) show heterogeneous results in slowing age-related cognitive decline., Aims: To comprehensively evaluate the effectiveness of serious games-based CCT, integrating control conditions, neurophysiological and blood-based biomarkers, and subjective measures., Method: In this bi-centric randomised controlled trial with parallel groups, 160 participants (mean age 71.3 years) with cognitive impairment ranging from subjective decline to mild cognitive impairment, were pseudo-randomised to three arms: an intervention group receiving CCT immediately, an active control (watching documentaries) and a waitlist condition, which both started the CCT intervention after the control period. Both active arms entailed a 3-month intervention period comprising a total of 60 at-home sessions (five per week) and weekly on-site group meetings. In the intervention group, this was followed by additional 6 months of CCT, with monthly booster sessions to assess long-term training effects. Behavioural and subjective changes were assessed in 3-month intervals. Biological effects were measured by amyloid blood markers and magnetic resonance imaging obtained before and after training., Results: Adherence to the training protocol was consistently high across groups and time points (4.87 sessions per week). Domain-specific cognitive scores showed no significant interaction between groups and time points. Significant cognitive and subjective improvements were observed after long-term training. Voxel-based morphometry revealed no significant changes in grey matter volume following CCT, nor did amyloid levels moderate its effectiveness., Conclusions: Our study demonstrates no benefits of 3 months of CCT on cognitive or biological outcomes. However, positive effects were observed subjectively and after long-term CCT, warranting the inclusion of CCT in multicomponent interventions.

Objective: Attention Deficit Hyperactivity Disorder (ADHD) is defined as a persistent pattern of inattention and hyperactivity-impulsivity that interferes with functioning anofd development. Increased emotional reactivity and impaired emotion regulation are established findings in children with ADHD. Impairments in executive functions such as impulse control and working memory, in turn, have also been suggested to have a negative effect on emotion recognition. However, studies exploring suspected deficits in the ability to recognise facial emotions in ADHD have to date yielded controversial results. We sought to clarify the mechanism of possible emotion recognition dysfunction in children with ADHD., Methods: Sixty-one children diagnosed with ADHD (aged 10.36 ± 1.89 years) and a control group ( N  = 78; aged 9.6 ± 1.8 years) were evaluated with questionnaires and computerized tests for cognitive and facial emotion recognition capacity., Results: The ADHD group displayed more behavioural issues and performed worse in cognitive tests compared to the control group. Group status (i.e. ADHD vs. control group) did not predict facial emotion recognition when controlled for age, IQ and sex in linear regression models. Performance in Divided Attention predicted facial emotion recognition in linear regression in the ADHD group., Conclusions: Individuals with ADHD showed facial emotion recognition capacity similar to a typically developing control group. Good performance in a cognitive test assessing divided attention predicted capacity for facial emotion recognition, but only in the ADHD group.

Decision-making under unpredictable conditions can cause discomfort in autistic persons due to their preference for predictability. Decision-making impairments might furthermore be associated with a dysregulation of sex and stress hormones. This prospective, cross-sectional study investigated decision-making in 32 autistic participants (AP, 14 female) and 31 non-autistic participants (NAP, 20 female) aged 18-64 years. The Iowa Gambling Task (IGT) and the Cambridge Risk Task (CRT) were used to assess decision-making under ambiguity and under risk with known outcome probabilities, respectively. Cortisol, estradiol, and testosterone serum levels were related to decision-making performance. Groups did not differ in overall IGT and CRT performance, but compared with NAP, AP preferred less profitable card decks with predictable outcomes while avoiding those with unpredictable outcomes. AP required more time to reach decisions compared to NAP. Additionally, AP without comorbid depression performed significantly worse than NAP in the IGT. Estradiol and cortisol concentrations were significant predictors of CRT scores in NAP, but not in AP. The study results imply that AP are 'risk-averse' in decision-making under ambiguity as they avoided choice options with unpredictable losses in comparison to NAP. Our findings highlight the intolerance for uncertainty, particularly in ambiguous situations. Thus, we recommend being as transparent and precise as possible when interacting with autistic individuals. Future research should explore decision-making in social situations among individuals with ASD, factoring in person-dependent variables such as depression., (© 2024. The Author(s).)

Background: Neurocognitive functioning is a relevant transdiagnostic dimension in psychiatry. As pupil size dynamics track cognitive load during a working memory task, we aimed to explore if this parameter allows identification of psychophysiological subtypes in healthy participants and patients with affective and anxiety disorders., Methods: Our sample consisted of 226 participants who completed the n-back task during simultaneous functional magnetic resonance imaging and pupillometry measurements. We used latent class growth modeling to identify clusters based on pupil size in response to cognitive load. In a second step, these clusters were compared on affective and anxiety symptom levels, performance in neurocognitive tests, and functional magnetic resonance imaging activity., Results: The clustering analysis resulted in two distinct pupil response profiles: one with a stepwise increasing pupil size with increasing cognitive load (reactive group) and one with a constant pupil size across conditions (nonreactive group). A larger increase in pupil size was significantly associated with better performance in neurocognitive tests in executive functioning and sustained attention. Statistical maps of parametric modulation of pupil size during the n-back task showed the frontoparietal network in the positive contrast and the default mode network in the negative contrast. The pupil response profile of the reactive group was associated with more thalamic activity, likely reflecting better arousal upregulation and less deactivation of the limbic system., Conclusions: Pupil measurements have the potential to serve as a highly sensitive psychophysiological readout for detection of neurocognitive deficits in the core domain of executive functioning, adding to the development of valid transdiagnostic constructs in psychiatry., (Copyright © 2023. Published by Elsevier Inc.)

Background: Wrist-worn actigraphy can be an objective tool to assess sleep and other behavioral and psychological symptoms in dementia (BPSD). We investigated the feasibility of using wearable actigraphy in agitated late-stage dementia patients., Methods: Agitated, late-stage Alzheimer's dementia care home residents in Greater London area (n = 29; 14 females, mean age ± SD: 80.8 ± 8.2; 93.1% White) were recruited to wear an actigraphy watch for 4 weeks. Wearing time was extracted to evaluate compliance, and factors influencing compliance were explored., Results: A high watch-acceptance (96.6%) and compliance rate (88.0%) was noted. Non-compliance was not associated with age or BPSD symptomatology. However, participants with "better" cognitive function (R = 0.42, p = 0.022) and during nightshift (F 1.240, 33.475  = 8.075, p = 0.005) were less compliant. Female participants were also marginally less compliant (F 1, 26  = 3.790, p = 0.062)., Discussions: Wrist-worn actigraphy appears acceptable and feasible in late-stage agitated dementia patients. Accommodating the needs of both the patients and their carers may further improve compliance., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Remote monitoring technologies (RMTs) can measure cognitive and functional decline objectively at-home, and offer opportunities to measure passively and continuously, possibly improving sensitivity and reducing participant burden in clinical trials. However, there is skepticism that age and cognitive or functional impairment may render participants unable or unwilling to comply with complex RMT protocols. We therefore assessed the feasibility and usability of a complex RMT protocol in all syndromic stages of Alzheimer's disease and in healthy control participants., Methods: For 8 weeks, participants (N = 229) used two activity trackers, two interactive apps with either daily or weekly cognitive tasks, and optionally a wearable camera. A subset of participants participated in a 4-week sub-study (N = 45) using fixed at-home sensors, a wearable EEG sleep headband and a driving performance device. Feasibility was assessed by evaluating compliance and drop-out rates. Usability was assessed by problem rates (e.g., understanding instructions, discomfort, forgetting to use the RMT or technical problems) as discussed during bi-weekly semi-structured interviews., Results: Most problems were found for the active apps and EEG sleep headband. Problem rates increased and compliance rates decreased with disease severity, but the study remained feasible., Conclusions: This study shows that a highly complex RMT protocol is feasible, even in a mild-to-moderate AD population, encouraging other researchers to use RMTs in their study designs. We recommend evaluating the design of individual devices carefully before finalizing study protocols, considering RMTs which allow for real-time compliance monitoring, and engaging the partners of study participants in the research., Competing Interests: JC is an employee and shareholder of Novartis. AD is supported by the Welcome Trust [223100/Z/21/Z]. Research of Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting Steun Alzheimercentrum Amsterdam. DA has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals, Biogen, and GE Health, and served as paid consultant for H. Lundbeck, Eisai, Heptares, Mentis Cura, and Roche Diagnostics. IK declares support for this work through the National Institute of Health Research (personal award and Oxford Health Biomedical Research Centre) and the Medical Research Council (Dementias Platform UK grant), and is a paid medical advisor for digital healthcare technology companies (Five Lives SAS and Cognetivity Ltd). All other authors declare that there is no conflict of interest., (© The Author(s) 2024.)

Augmented reality (AR) apps, in which the virtual and real world are combined, can recreate instrumental activities of daily living (IADL) and are therefore promising to measure cognition needed for IADL in early Alzheimer's disease (AD) both in the clinic and in the home settings. The primary aim of this study was to distinguish and classify healthy controls (HC) from participants with AD pathology in an early AD stage using an AR app. The secondary aims were to test the association of the app with clinical cognitive and functional tests and investigate the feasibility of at-home testing using AR. We furthermore investigated the test-retest reliability and potential learning effects of the task. The digital score from the AR app could significantly distinguish HC from preclinical AD (preAD) and prodromal AD (proAD), and preAD from proAD, both with in-clinic and at-home tests. For the classification of the proAD group, the digital score (AUC clinic&#95;visit  = 0.84 [0.75-0.93], AUC at&#95;home  = 0.77 [0.61-0.93]) was as good as the cognitive score (AUC = 0.85 [0.78-0.93]), while for classifying the preAD group, the digital score (AUC clinic&#95;visit  = 0.66 [0.53-0.78], AUC at&#95;home  = 0.76 [0.61-0.91]) was superior to the cognitive score (AUC = 0.55 [0.42-0.68]). In-clinic and at-home tests moderately correlated (rho = 0.57, p < 0.001). The digital score was associated with the clinical cognitive score (rho = 0.56, p < 0.001). No learning effects were found. Here we report the AR app distinguishes HC from otherwise healthy Aβ-positive individuals, both in the outpatient setting and at home, which is currently not possible with standard cognitive tests., (© 2023. The Author(s).)

Computerized cognitive training (CCT) has been shown to improve cognition in older adults via targeted exercises for single or multiple cognitive domains. Combining CCT with non-invasive brain stimulation is thought to be even more effective due to synergistic effects in the targeted brain areas and networks. However, little is known about the moderating effects of sex, age, and education on cognitive outcomes. Here, we investigated these factors in a randomized, double-blind study in which we administered CCT either combined with transcranial direct (tDCS), alternating (tACS) current stimulation or sham stimulation. 59 healthy older participants (mean age 71.7 ± 6.1) received either tDCS (2 mA), tACS (5 Hz), or sham stimulation over the left dorsolateral prefrontal cortex during the first 20 min of a CCT (10 sessions, 50 min, twice weekly). Before and after the complete cognitive intervention, a neuropsychological assessment was performed, and the test scores were summarized in a composite score. Our results showed a significant three-way interaction between age, years of education, and stimulation technique ( F (6,52)  = 5.53, p  = 0.007), indicating that the oldest participants with more years of education particularly benefitted from tDCS compared to the sham group, while in the tACS group the youngest participants with less years of education benefit more from the stimulation. These results emphasize the importance of further investigating and taking into account sex, age, and education as moderating factors in the development of individualized stimulation protocols., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03475446., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Krebs, Peter, Brill, Klöppel and Brem.)

Alzheimer's disease (AD) and other neurodegenerative diseases such as Parkinson's disease (PD) and Huntington's disease (HD) are associated with progressive cognitive, motor, affective and consequently functional decline considerably affecting Activities of Daily Living (ADL) and quality of life. Standard assessments, such as questionnaires and interviews, cognitive testing, and mobility assessments, lack sensitivity, especially in early stages of neurodegenerative diseases and in the disease progression, and have therefore a limited utility as outcome measurements in clinical trials. Major advances in the last decade in digital technologies have opened a window of opportunity to introduce digital endpoints into clinical trials that can reform the assessment and tracking of neurodegenerative symptoms. The Innovative Health Initiative (IMI)-funded projects RADAR-AD ( Remote assessment of disease and relapse-Alzheimer's disease ), IDEA-FAST ( Identifying digital endpoints to assess fatigue, sleep and ADL in neurodegenerative disorders and immune-mediated inflammatory diseases ) and Mobilise-D ( Connecting digital mobility assessment to clinical outcomes for regulatory and clinical endorsement ) aim to identify digital endpoints relevant for neurodegenerative diseases that provide reliable, objective, and sensitive evaluation of disability and health-related quality of life. In this article, we will draw from the findings and experiences of the different IMI projects in discussing (1) the value of remote technologies to assess neurodegenerative diseases; (2) feasibility, acceptability and usability of digital assessments; (3) challenges related to the use of digital tools; (4) public involvement and the implementation of patient advisory boards; (5) regulatory learnings; and (6) the significance of inter-project exchange and data- and algorithm-sharing., Competing Interests: AP received grant support from Ministry of Health (MINSAL) and Ministry of Education, Research and University (MIUR), from Airalzh Foundation, LIMPE-DSIMOV society and MI H2020 initiative (MI2-2018-15-06); he received speaker honoraria from Abbvie, Bial, Biomarin, Roche and Zambon Pharmaceuticals. W-FN has consulted for Novartis, GlaxoSmithKline, Abbvie, BMS, Sanofi, MedImmune, Janssen, Resolve Therapeutics and UCB. LR receives consultancy from MJ Fox Foundation and grant support from the EU, NIHR, MRC, PDUK, Dunhill Medical Trust, Cure Parkinson’s Trust, EPSRC, MJ Fox Foundation. DA has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals, Evonik, Roche Diagnostics, and GE Health, and served as paid consultant for H. Lundbeck, Eisai, Heptares, Mentis Cura, Eli Lilly, Cognetivity, Enterin, Acadia, EIP Pharma, and Biogen. JC was employed by Novartis Institutes for Biomedical Research (NIBR), Basel, Switzerland and GE was employed by Novartis Pharmaceuticals Corporations, Cambridge, MA, United States. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Brem, Kuruppu, de Boer, Muurling, Diaz-Ponce, Gove, Curcic, Pilotto, Ng, Cummins, Malzbender, Nies, Erdemli, Graeber, Narayan, Rochester, Maetzler, Aarsland and on behalf of the RADAR-AD Consortium.)

Competing Interests: We declare no competing interests.

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-β 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.

Oxytocin (OT) has been extensively studied with regard to its socio-cognitive and -behavioral effects. Its potential as a therapeutic agent is being discussed for a range of neuropsychiatric conditions. However, there is limited evidence of its effects on non-social cognition in general and decision-making in particular, despite the importance of these functions in neuropsychiatry. Using a crossover/within-subject, blinded, randomized design, we investigated for the first time if intranasal OT (24 IU) affects decision-making differently depending on outcome predictability/ambiguity in healthy males. The Iowa Gambling Task (IGT) and the Cambridge Risk Task (CRT) were used to assess decision-making under low outcome predictability/high ambiguity and under high outcome probability/low ambiguity, respectively. After administration of OT, subjects performed worse and exhibited riskier performance in the IGT (low outcome predictability/high ambiguity), whereas they made borderline-significant less risky decisions in the CRT (high outcome probability/low ambiguity) as compared to the control condition. Decision-making in healthy males may therefore be influenced by OT and adjusted as a function of contextual information, with implications for clinical trials investigating OT in neuropsychiatric conditions.

The prevalence of dementia is increasing and poses a health challenge for individuals and society. Despite the desire to know their risks and the importance of initiating early therapeutic options, large parts of the population do not get access to memory clinic-based assessments. Remote memory clinics facilitate low-level access to cognitive assessments by eschewing the need for face-to-face meetings. At the same time, patients with detected impairment or increased risk can receive non-pharmacological treatment remotely. Sensor technology can evaluate the efficiency of this remote treatment and identify cognitive decline. With remote and (partly) automatized technology the process of cognitive decline can be monitored but more importantly also modified by guiding early interventions and a dementia preventative lifestyle. We highlight how sensor technology aids the expansion of assessments beyond cognition and to other domains, e.g., depression. We also illustrate applications for aiding remote treatment and describe how remote tools can facilitate health education which is the cornerstone for long-lasting lifestyle changes. Tools such as transcranial electric stimulation or sleep-based interventions have currently mostly been used in a face-to-face context but have the potential of remote deployment-a step already taken with memory training apps. Many of the presented methods are readily scalable and of low costs and there is a range of target populations, from the worried well to late-stage dementia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Owens, Krebs, Kuruppu, Brem, Kowatsch, Aarsland and Klöppel.)

As transcranial electrical stimulation (tES) protocols advance, assumptions underlying the technique need to be retested to ensure they still hold. Whilst the safety of stimulation has been demonstrated mainly for a small number of sessions, and small sample size, adverse events (AEs) following multiple sessions remain largely untested. Similarly, whilst blinding procedures are typically assumed to be effective, the effect of multiple stimulation sessions on the efficacy of blinding procedures also remains under question. This is especially relevant in multisite projects where small unintentional variations in protocol could lead to inter-site difference. We report AE and blinding data from 1,019 participants who received up to 11 semi-consecutive sessions of active or sham transcranial alternating current stimulation (tACS), direct current stimulation (tDCS), and random noise stimulation (tRNS), at 4 sites in the UK and US. We found that AEs were often best predicted by factors other than tES, such as testing site or session number. Results from the blinding analysis suggested that blinding was less effective for tDCS and tACS than tRNS. The occurrence of AEs did not appear to be linked to tES despite the use of smaller electrodes or repeated delivery. However, blinding efficacy was impacted in tES conditions with higher cutaneous sensation, highlighting a need for alternative stimulation blinding protocols. This may be increasingly necessary in studies wishing to deliver stimulation with higher intensities., Competing Interests: Declaration of competing interest Alvaro Pascual-Leone serves on the scientific advisory boards for Starlab Neuroscience, Neuroelectrics, Constant Therapy, Cognito, and Neosync; and is listed as an inventor on several issued and pending patents on the real-time integration of transcranial magnetic stimulation (TMS) with electroencephalography (EEG) and magnetic resonance imaging (MRI). Roi Cohen Kadosh serves on the scientific advisory boards for Neuroelectrics and Innosphere, and is the founder, director and shareholder of Cognite Neurotechnology and listed as an inventor on a pending patent that allows personalisation of neuromodulation. There are no other known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Alzheimer's disease (AD) is a major public health issue. Cognitive interventions such as computerized cognitive trainings (CCT) are effective in attenuating cognitive decline in AD. However, in those at risk of dementia related to AD, results are heterogeneous. Efficacy and feasibility of CCT needs to be explored in depth. Moreover, underlying mechanisms of CCT effects on the three cognitive domains typically affected by AD (episodic memory, semantic memory and spatial abilities) remain poorly understood., Methods: In this bi-centric, randomized controlled trial (RCT) with parallel groups, participants (planned N = 162, aged 60-85 years) at risk for AD and with at least subjective cognitive decline will be randomized to one of three groups. We will compare serious game-based CCT against a passive wait list control condition and an active control condition (watching documentaries). Training will consist of daily at-home sessions for 10 weeks (50 sessions) and weekly on-site group meetings. Subsequently, the CCT group will continue at-home training for an additional twenty-weeks including monthly on-site booster sessions. Investigators conducting the cognitive assessments will be blinded. Group leaders will be aware of participants' group allocations. Primarily, we will evaluate change using a compound value derived from the comprehensive cognitive assessment for each of three cognitive domains. Secondary, longitudinal functional and structural magnetic resonance imaging (MRI) and evaluation of blood-based biomarkers will serve to investigate neuronal underpinnings of expected training benefits., Discussion: The present study will address several shortcomings of previous CCT studies. This entails a comparison of serious game-based CCT with both a passive and an active control condition while including social elements crucial for training success and adherence, the combination of at-home and on-site training, inclusion of booster sessions and assessment of physiological markers. Study outcomes will provide information on feasibility and efficacy of serious game-based CCT in older adults at risk for AD and will potentially generalize to treatment guidelines. Moreover, we set out to investigate physiological underpinnings of CCT induced neuronal changes to form the grounds for future individually tailored interventions and neuro-biologically informed trainings., Trial Registration: This RCT was registered 1st of July 2020 at clinicaltrials.gov (Identifier NCT04452864)., (© 2022. The Author(s).)

Attempts to enhance human memory and learning ability have a long tradition in science. This topic has recently gained substantial attention because of the increasing percentage of older individuals worldwide and the predicted rise of age-associated cognitive decline in brain functions. Transcranial brain stimulation methods, such as transcranial magnetic (TMS) and transcranial electric (tES) stimulation, have been extensively used in an effort to improve cognitive functions in humans. Here we summarize the available data on low-intensity tES for this purpose, in comparison to repetitive TMS and some pharmacological agents, such as caffeine and nicotine. There is no single area in the brain stimulation field in which only positive outcomes have been reported. For self-directed tES devices, how to restrict variability with regard to efficacy is an essential aspect of device design and function. As with any technique, reproducible outcomes depend on the equipment and how well this is matched to the experience and skill of the operator. For self-administered non-invasive brain stimulation, this requires device designs that rigorously incorporate human operator factors. The wide parameter space of non-invasive brain stimulation, including dose (e.g., duration, intensity (current density), number of repetitions), inclusion/exclusion (e.g., subject's age), and homeostatic effects, administration of tasks before and during stimulation, and, most importantly, placebo or nocebo effects, have to be taken into account. The outcomes of stimulation are expected to depend on these parameters and should be strictly controlled. The consensus among experts is that low-intensity tES is safe as long as tested and accepted protocols (including, for example, dose, inclusion/exclusion) are followed and devices are used which follow established engineering risk-management procedures. Devices and protocols that allow stimulation outside these parameters cannot claim to be "safe" where they are applying stimulation beyond that examined in published studies that also investigated potential side effects. Brain stimulation devices marketed for consumer use are distinct from medical devices because they do not make medical claims and are therefore not necessarily subject to the same level of regulation as medical devices (i.e., by government agencies tasked with regulating medical devices). Manufacturers must follow ethical and best practices in marketing tES stimulators, including not misleading users by referencing effects from human trials using devices and protocols not similar to theirs., (© 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.)

The prefrontal cortex is a key player in stress response regulation. Electroencephalographic (EEG) responses, such as a decrease in frontal alpha and an increase in frontal beta power, have been proposed to reflect stress-related brain activity. However, the stress response is likely composed of different parts such as cognitive effort, time pressure, and social-evaluative threat, which have not been distinguished in previous studies. This distinction, however, is crucial if we aim to establish reliable tools for early detection of stress-related conditions and monitoring of stress responses throughout treatment. This randomized cross-over study (N = 38) aimed to disentangle EEG correlates of stress. With linear mixed models accounting for missing values in some conditions, we found a decrease in frontal alpha and increase in beta power when performing the Paced Auditory Serial Addition Test (PASAT; cognitive effort; n = 32) compared to resting state (n = 33). No change in EEG power was found when the PASAT was performed under time pressure (n = 29) or when adding social-evaluative threat (video camera; n = 29). These findings suggest that frontal EEG power can discriminate stress from resting state but not more fine-grained differences of the stress response., (© 2021 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The neuropeptide oxytocin (OT) has been associated with a broad range of human behaviors, particularly in the domain of social cognition, and is being discussed to play a role in a range of psychiatric disorders. Studies using the Reading The Mind In The Eyes Test (RMET) to investigate the role of OT in mental state recognition reported inconsistent outcomes. The present study applied a randomized, double-blind, cross-over design, and included measures of serum OT. Twenty healthy males received intranasal placebo or OT (24 IU) before performing the RMET. Frequentist and Bayesian analyses showed that contrary to previous studies (Domes et al., 2007; Radke & de Bruijn, 2015), individuals performed worse in the OT condition compared to the placebo condition (p = 0.023, Cohen's d = 0.55, 95% confidence interval [CI] [0.08, 1.02], BF 10 = 6.93). OT effects did not depend on item characteristics (difficulty, valence, intensity, sex) of the RMET. Furthermore, OT serum levels did not change after intranasal OT administration. Given that similar study designs lead to heterogeneous outcomes, our results highlight the complexity of OT effects and support evidence that OT might even interfere with social cognitive abilities. However, the Bayesian analysis approach shows that there is only moderate evidence that OT influences mind-reading, highlighting the need for larger-scale studies considering the discussed aspects that might have led to divergent study results., (© 2021. The Author(s).)

How a letter addressing the lack of women invited to speak at a conference in brain stimulation encouraged researchers to take action., Competing Interests: KH, BF, AB No competing interests declared, (© 2021, Hoy et al.)

Cognitive deficits and negative symptoms in schizophrenia are associated with poor functional outcomes and limited in terms of treatment. The Schizophrenia Treatment With Electric Transcranial Stimulation (STARTS) trial has shown efficacy of transcranial direct current stimulation (tDCS) for improving negative symptoms. In this secondary analysis, we investigate its effects on cognitive performance. In STARTS, a double-blinded, sham-controlled, randomized clinical trial, patients were treated with twice-daily, 20-min, 2-mA fronto-temporal tDCS over 5 days or sham-tDCS. In 90 patients, we evaluated the cognitive performance up to 12 weeks post-treatment. We found that active-tDCS showed no beneficial effects over sham-tDCS in any of the tests. Based on a 5-factor cognitive model, improvements of executive functions and delayed memory were observed in favor of sham-tDCS. Overall, the applied active-tDCS protocol, primarily designed to improve negative symptoms, did not promote cognitive improvement. We discuss possible protocol modification potentially required to increase tDCS effects on cognition. ClinicalTrials.gov identifier: NCT02535676., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Aging is associated with a decline in attentional and executive abilities, which are linked to physiological, structural, and functional brain changes. A variety of novel non-invasive brain stimulation methods have been probed in terms of their neuroenhancement efficacy in the last decade; one that holds significant promise is transcranial random noise stimulation (tRNS) that delivers an alternate current at random amplitude and frequency. The aim of this study was to investigate whether repeated sessions of tRNS applied as an add-on to cognitive training (CT) may induce long-term near and far transfer cognitive improvements. Methods: In this sham-controlled, randomized, double-blinded study forty-two older adults (age range 60-86 years) were randomly assigned to one of three intervention groups that received 20 min of 0.705 mA tRNS ( N = 14), 1 mA tRNS ( N = 14), or sham tRNS ( N = 19) combined with 30 min of CT of executive functions (cognitive flexibility, inhibitory control, working memory). tRNS was applied bilaterally over the dorsolateral prefrontal cortices for five sessions. The primary outcome (non-verbal logical reasoning) and other cognitive functions (attention, memory, executive functions) were assessed before and after the intervention and at a 1-month follow-up. Results: Non-verbal logical reasoning, inhibitory control and reaction time improved significantly over time, but stimulation did not differentially affect this improvement. These changes occurred during CT, while no further improvement was observed during follow-up. Performance change in logical reasoning was significantly correlated with age in the group receiving 1 mA tRNS, indicating that older participants profited more from tRNS than younger participants. Performance change in non-verbal working memory was significantly correlated with age in the group receiving sham tRNS, indicating that in contrast to active tRNS, older participants in the sham group declined more than younger participants. Interpretation: CT induced cognitive improvements in all treatment groups, but tRNS did not modulate most of these cognitive improvements. However, the effect of tRNS depended on age in some cognitive functions. We discuss possible explanations leading to this result that can help to improve the design of future neuroenhancement studies in older populations., Competing Interests: RC serves on the scientific advisory boards for Neuroelectrics and Innosphere and filed a UK Patent Application Number 2000874.4 (“method for obtaining personalized parameters for transcranial stimulation, transcranial system, method of applying transcranial stimulation”). This patent does not relate to this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Brambilla, Dinkelbach, Bigler, Williams, Zokaei, Cohen Kadosh and Brem.)

Background: Major depressive disorder represents (MDD) a major cause of disability and disease burden. Beside antidepressant medication, psychotherapy is a key approach of treatment. Schema therapy has been shown to be effective in the treatment of psychiatric disorders, especially personality disorders, in a variety of settings and patient groups. Nevertheless, there is no evidence on its effectiveness for MDD in an inpatient nor day clinic setting and little is known about the factors that drive treatment response in such a target group., Methods: In the current protocol, we outline OPTIMA (OPtimized Treatment Identification at the MAx Planck Institute): a single-center randomized controlled trial of schema therapy as a treatment approach for MDD in an inpatient and day clinic setting. Over the course of 7 weeks, we compare schema therapy with cognitive behavioral therapy and individual supportive therapy, conducted in individual and group sessions and with no restrictions regarding concurrent antidepressant medication, thus approximating real-life treatment conditions. N = 300 depressed patients are included. All study therapists undergo a specific training and supervision and therapy adherence is assessed. Primary outcome is depressive symptom severity as self-assessment (Beck Depression Inventory-II) and secondary outcomes are clinical ratings of MDD (Montgomery-Asberg Depression Rating Scale), recovery rates after 7 weeks according to the Munich-Composite International Diagnostic Interview, general psychopathology (Brief Symptom Inventory), global functioning (World Health Organization Disability Assessment Schedule), and clinical parameters such as dropout rates. Further parameters on a behavioral, cognitive, psychophysiological, and biological level are measured before, during and after treatment and in 2 follow-up assessments after 6 and 24 months after end of treatment., Discussion: To our knowledge, the OPTIMA-Trial is the first to investigate the effectiveness of schema therapy as a treatment approach of MDD, to investigate mechanisms of change, and explore predictors of treatment response in an inpatient and day clinic setting by using such a wide range of parameters. Insights from OPTIMA will allow more integrative approaches of psychotherapy of MDD. Especially, the identification of intervention-specific markers of treatment response can improve evidence-based clinical decision for individualizing treatment., Trial Registration: Identifier on clinicaltrials.gov : NCT03287362 ; September, 12, 2017.

Current first-line treatments for major depressive disorder (MDD) include pharmacotherapy and cognitive-behavioral therapy. However, one-third of depressed patients do not achieve remission after multiple medication trials, and psychotherapy can be costly and time-consuming. Although non-implantable neuromodulation (NIN) techniques such as transcranial magnetic stimulation, transcranial direct current stimulation, electroconvulsive therapy, and magnetic seizure therapy are gaining momentum for treating MDD, the efficacy of non-convulsive techniques is still modest, whereas use of convulsive modalities is limited by their cognitive side effects. In this context, we propose that NIN techniques could benefit from a precision-oriented approach. In this review, we discuss the challenges and opportunities in implementing such a framework, focusing on enhancing NIN effects via a combination of individualized cognitive interventions, using closed-loop approaches, identifying multimodal biomarkers, using computer electric field modeling to guide targeting and quantify dosage, and using machine learning algorithms to integrate data collected at multiple biological levels and identify clinical responders. Though promising, this framework is currently limited, as previous studies have employed small samples and did not sufficiently explore pathophysiological mechanisms associated with NIN response and side effects. Moreover, cost-effectiveness analyses have not been performed. Nevertheless, further advancements in clinical trials of NIN could shift the field toward a more "precision-oriented" practice.

Objective: To investigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training for treatment of cognitive symptoms in patients with Alzheimer's disease (AD). A secondary objective was to analyze associations between brain plasticity and cognitive effects of treatment., Methods: In this randomized, sham-controlled, multicenter clinical trial, 34 patients with AD were assigned to three experimental groups receiving 30 daily sessions of combinatory intervention. Participants in the real/real group ( n = 16) received 10 Hz repetitive transcranial magnetic stimulation (rTMS) delivered separately to each of six cortical regions, interleaved with computerized cognitive training. Participants in the sham rTMS group ( n = 18) received sham rTMS combined with either real (sham/real group, n = 10) or sham (sham/sham group, n = 8) cognitive training. Effects of treatment on neuropsychological (primary outcome) and neurophysiological function were compared between the 3 treatment groups. These, as well as imaging measures of brain atrophy, were compared at baseline to 14 healthy controls (HC)., Results: At baseline, patients with AD had worse cognition, cerebral atrophy, and TMS measures of cortico-motor reactivity, excitability, and plasticity than HC. The real/real group showed significant cognitive improvement compared to the sham/sham, but not the real/sham group. TMS-induced plasticity at baseline was predictive of post-intervention changes in cognition, and was modified across treatment, in association with changes of cognition., Interpretation: Combined rTMS and cognitive training may improve the cognitive status of AD patients, with TMS-induced cortical plasticity at baseline serving as predictor of therapeutic outcome for this intervention, and potential mechanism of action., Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01504958., (Copyright © 2020 Brem, Di Iorio, Fried, Oliveira-Maia, Marra, Profice, Quaranta, Schilberg, Atkinson, Seligson, Rossini and Pascual-Leone.)

Background: A major research finding in the field of Biological Psychiatry is that symptom-based categories of mental disorders map poorly onto dysfunctions in brain circuits or neurobiological pathways. Many of the identified (neuro) biological dysfunctions are "transdiagnostic", meaning that they do not reflect diagnostic boundaries but are shared by different ICD/DSM diagnoses. The compromised biological validity of the current classification system for mental disorders impedes rather than supports the development of treatments that not only target symptoms but also the underlying pathophysiological mechanisms. The Biological Classification of Mental Disorders (BeCOME) study aims to identify biology-based classes of mental disorders that improve the translation of novel biomedical findings into tailored clinical applications., Methods: BeCOME intends to include at least 1000 individuals with a broad spectrum of affective, anxiety and stress-related mental disorders as well as 500 individuals unaffected by mental disorders. After a screening visit, all participants undergo in-depth phenotyping procedures and omics assessments on two consecutive days. Several validated paradigms (e.g., fear conditioning, reward anticipation, imaging stress test, social reward learning task) are applied to stimulate a response in a basic system of human functioning (e.g., acute threat response, reward processing, stress response or social reward learning) that plays a key role in the development of affective, anxiety and stress-related mental disorders. The response to this stimulation is then read out across multiple levels. Assessments comprise genetic, molecular, cellular, physiological, neuroimaging, neurocognitive, psychophysiological and psychometric measurements. The multilevel information collected in BeCOME will be used to identify data-driven biologically-informed categories of mental disorders using cluster analytical techniques., Discussion: The novelty of BeCOME lies in the dynamic in-depth phenotyping and omics characterization of individuals with mental disorders from the depression and anxiety spectrum of varying severity. We believe that such biology-based subclasses of mental disorders will serve as better treatment targets than purely symptom-based disease entities, and help in tailoring the right treatment to the individual patient suffering from a mental disorder. BeCOME has the potential to contribute to a novel taxonomy of mental disorders that integrates the underlying pathomechanisms into diagnoses., Trial Registration: Retrospectively registered on June 12, 2019 on ClinicalTrials.gov (TRN: NCT03984084).

Neural activity related to language can be modulated within widespread networks following learning or in response to disruption-including the experimental application of noninvasive brain stimulation. However, the spatiotemporal characteristics of such modulation remain insufficiently explored. The present study combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to explore the modulation of activity across the language network following continuous theta-burst stimulation (cTBS) of the left pars opercularis. In 10 healthy subjects (21 ± 2 years old, four females), neuronavigated cTBS was delivered over the left pars opercularis of the frontal operculum (part of the traditional Broca's area) at 80% of active motor threshold (AMT) stimulation intensity. Real cTBS and sham cTBS were performed in two different visits separated by at least 48 h. Before, immediately, and 10 min after cTBS, 30 single pulses of TMS were delivered to the left pars opercularis at 80% of the resting motor threshold (RMT), whereas EEG was simultaneously recorded. We examined the cTBS-induced modulation of phase locking values (PLVs) between the TMS-evoked potentials (TEPs) recorded over the pars opercularis and those recorded over its right-hemispheric homolog area, the left supramarginal area, and the left superior temporal area in different EEG frequency bands and different time windows following cTBS. cTBS to the left pars opercularis induced within the gamma band: (1) a significant increase in TEP phase synchronization between the left and right pars opercularis at an early time window (250-350 ms) following cTBS; and (2) significantly increased PLV with the left supramarginal area and the left superior temporal area at a later time window (600-700 ms). In the theta and delta band, cTBS to the left pars opercularis induced significantly increased phase synchronization of TEPs between the left pars opercularis and the posterior left hemispheric language areas at a late time window. In sham condition, there was a significant decrease in TEP phase synchronization of the high beta band between left pars opercularis and left superior temporal area at 200-300 ms. These results contribute to characterize the dynamics of the language network and may have implications in the development of noninvasive stimulation protocols to promote the language rehabilitation in aphasia patients., (Copyright © 2020 Yoo, Vernet, Kim, Brem, Bashir, Ifert-Miller, Im, Eldaief and Pascual-Leone.)

Visuospatial neglect constitutes a supramodal cognitive deficit characterized by reduction or loss of spatial awareness for the contralesional space. It occurs in over 40% of right- and 20% of left-brain-lesioned stroke patients with lesions located mostly in parietal, frontal and subcortical brain areas. Visuospatial neglect is a multifaceted syndrome - symptoms can be divided into sensory, motor and representational neglect - and therefore requires an individually adapted diagnostic and therapeutic approach. Several models try to explain the origins of visuospatial neglect, of which the "interhemispheric rivalry model" is strongly supported by animal and human research. This model proposes that allocation of spatial attention is balanced by transcallosal inhibition and both hemispheres compete to direct attention to the contralateral hemi-space. Accordingly, a brain lesion causes an interhemispheric imbalance, which may be re-installed by activation of lesioned, or deactivation of unlesioned (over-activated) brain areas through noninvasive brain stimulation. Research in larger patient samples is needed to confirm whether noninvasive brain stimulation can improve long-term outcomes and whether these also affect activities of daily living and discharge destination.

Purpose of Review: After three decades of clinical research on repetitive transcranial magnetic stimulation (rTMS), major depressive disorder (MDD) has proven to be the primary field of application. MDD poses a major challenge for health systems worldwide, emphasizing the need for improving clinical efficacy of existing rTMS applications and promoting the development of novel evidence-based rTMS treatment approaches., Recent Findings: Several promising new avenues have been proposed: novel stimulation patterns, targets, and coils; combinatory treatments and maintenance; and personalization and stratification of rTMS parameters, and treatment of subpopulations., Summary: This opinion review summarizes current knowledge in the field and addresses the future direction of rTMS treatment in MDD, facilitating the establishment of this clinical intervention method as a standard treatment option and continuing to improve response and remission rates, and take the necessary steps to personalize rTMS-based treatment approaches.

The present study introduces a novel cognitive intervention aimed at improving fluid intelligence (G f ), based on a framework we refer to as FAST: Flexible, Adaptive, Synergistic Training. FAST leverages a combination of novel game-based executive function (EF) training-designed specifically to enhance the likelihood of transfer-and transcranial electrical stimulation (tES), with aims to synergistically activate and strengthen mechanisms of cognitive control critical to G f . To test our intervention, we collected three G f measures from 113 participants [the advanced short Bochumer Matrizen-Test (BOMAT), Raven's Advanced Progressive Matrices (APM), and matrices similar to Raven's generated by Sandia labs], prior to and following one of three interventions: (1) the FAST + tRNS intervention, a combination of 30 min of daily training with our novel training game, Robot Factory, and 20 min of concurrent transcranial random noise stimulation applied to bilateral dorsolateral prefrontal cortex (DLPFC); (2) an adaptively difficult Active Control intervention comprised of visuospatial tasks that specifically do not target G f ; or (3) a no-contact control condition. Analyses of changes in a G f factor from pre- to post-test found numerical increases for the FAST + tRNS group compared to the two control conditions, with a 0.3 SD increase relative to Active Control ( p = 0.07), and a 0.19 SD increase relative to a No-contact control condition ( p = 0.26). This increase was found to be largely driven by significant differences in pre- and post-test G f as measured on the BOMAT test. Progression through the FAST training game (Robot Factory) was significantly correlated with changes in G f . This is in contrast with progress in the Active Control condition, as well as with changes in individual EFs during FAST training, which did not significantly correlate with changes in G f . Taken together, this research represents a useful step forward in providing new insights into, and new methods for studying, the nature of G f and its malleability. Though our results await replication and extension, they provide preliminary evidence that the crucial characteristic of G f may, in fact, be the ability to combine EFs rapidly and adaptively according to changing demand, and that G f may be susceptible to targeted training.

Primary aldosteronism is a natural model for chronic aldosterone excess in humans and associated with symptoms of anxiety and depression. Cognitive deficits are inherent to the symptomatology of depression and anxiety disorders. Mineralocorticoid receptors and aldosterone appear to play a role in memory. Aldosterone was additionally supposed to be a risk factor for cognitive decline in patients with essential hypertension. The objective of this study was to investigate possible effects of chronically high aldosterone concentrations on cognitive function. A range of cognitive dimensions were assessed in 19 patients (9 males, 10 females); mean age 47.1 (12.5) under standardized treatment and several rating scales for anxiety, depression, quality of life and sleep were administered. Cognitive parameters were compared to standard norms from a large, healthy standardization sample. Patients showed increased levels of anxiety and depression without meeting diagnostic criteria for a disorder. Besides a numerically lower attention score, patients did not show any significant differences in the cognitive dimensions. Anxiety and depression were negatively correlated with quantitative performance in males. In females, a negative correlation between sleep disturbances and abstract reasoning and a positive correlation with quantitative performance were found. Our data showed no specific effect of chronic aldosterone in the tested cognitive parameters overall at least in younger patients, but they indicate sexually dimorphic regulation processes.

Aging-related cognitive decline represents a critical risk factor for the development of dementia and is associated with global neurophysiological changes. It is imperative to act early, while the neural reserve is still sufficient, to prevent or postpone cognitive decline. Given that no significant modifying pharmacological intervention is available, a focus on pharmacological agents alone seems insufficient. We argue that combinations of different approaches are most effective in stimulating long-lasting molecular changes that restore, promote, and preserve cognition through the modulation of cognitively relevant neurotransmitter systems that ultimately converge in driving neurotrophic signaling. Considering recent technological advances, several interventions apart from cognitive enhancing drugs, including noninvasive brain stimulation, physical exercise/vascular interventions, and cognitive training, seem well positioned to possibly prolong optimal brain functioning upon aging., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

It is debated whether cognitive training of specific executive functions leads to far transfer effects, such as improvements in fluid intelligence (Gf). Within this context, transcranial direct current stimulation and recently also novel protocols such as transcranial random noise and alternating current stimulation are being investigated with regards to their ability to enhance cognitive training outcomes. We compared the effects of four different transcranial electrical brain stimulation protocols in combination with nine daily computerized training sessions on Gf. 82 participants were randomly assigned to receive transcranial direct current stimulation (tDCS), random noise stimulation (tRNS), multifocal alternating current stimulation at 40 Hz (mftACS), or multifocal tDCS (mftDCS) in combination with an adaptive and synergistic executive function (EF) training, or to a no-contact control group. EF training consisted of gamified tasks drawing on isolated as well as integrated executive functions (working memory, inhibition, cognitive flexibility). Transfer was assessed with a combined measure of Gf including three established tests (Bochumer Matrizentest - BOMAT, Raven's Advanced Progressive Matrices - RAPM, and Sandia Matrices). We found significant improvements in Gf for the tDCS, mftDCS, and tRNS groups when compared with the no-contact group. In contrast, the mftACS group did not improve significantly and showed a similar pattern as the no-contact group. Mediation analyses indicated that the improvement in Gf was mediated through game progression in the mftDCS and tRNS group. Electrical brain stimulation in combination with sustained EF training can lead to transfer effects in Gf, which are mediated by training progression., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Sleep disturbance is suggested to contribute to the development of dementia. However, prospective longitudinal data from middle-aged populations are scarce., Methods: We investigated a population-based sample of 2386 men aged 42-62 years at baseline during 1984-1989. Participants having a history of mental illnesses, psychiatric medication, Parkinson's disease or dementia within 2 years after baseline (n=296) were excluded. Difficulty falling asleep or maintaining sleep, sleep duration and daytime tiredness were enquired. Dementia diagnoses (n=287) between 1984 and 2014 were obtained through linkage with hospital discharge, national death and special reimbursement registers. Cox proportional hazards analyses were performed for all dementias, and separately for Alzheimer's disease (n=234) and other phenotypes (n=53). Additional analyses were performed on a subsample of an apolipoprotein E ( APOE ) genotype-tested population (n=1199)., Results: The risk ratio for dementia was 1.58 (95% CI 1.10 to 2.27) in men with frequent sleep disturbance after adjustments for age, examination year, elevated depressive symptoms, physical activity, alcohol consumption, cumulative smoking history, systolic blood pressure, body mass index, low-density lipoprotein and high-density lipoprotein cholesterol, high-sensitivity C reactive protein, cardiovascular disease history, education years and living alone. Daytime tiredness and sleep duration were not associated with dementia in adjusted analysis. In the APOE subsample, both APOE ε4 genotype and frequent sleep disturbance were associated with increased dementia risk, but in the interaction analysis they had no joint effect., Conclusions: Self-reported frequent sleep disturbance in middle-aged men may relate to the development of dementia in later life. Having an APOE ε4 genotype did not affect the relationship., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Cognitive impairments and depression are common non-motor manifestations in Parkinson's disease (PD). Recent evidence suggests that both partially arise via the same frontostriatal network, opening the opportunity for concomitant treatment with non-invasive brain stimulation (NIBS) techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). In this systematic review, we evaluate the effects of NIBS on cognition and/or mood in 19 placebo-controlled studies involving 561 PD patients. Outcomes depended on the area stimulated and the technique used. rTMS over the dorsolateral-prefrontal cortex (DLPFC) resulted in significant reductions in scores of depressive symptoms with moderate to large effect sizes along with increased performance in several tests of cognitive functions. tDCS over the DLPFC improved performance in several cognitive measures, including executive functions with large effect sizes. Additional effects of tDCS on mood were not detectable; however, only non-depressed patients were assessed. Further confirmatory research is needed to clarify the contribution that NIBS could make in the care of PD patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Type-2 diabetes mellitus (T2DM) accelerates cognitive aging and increases risk of Alzheimer's disease. Rodent models of T2DM show altered synaptic plasticity associated with reduced learning and memory. Humans with T2DM also show cognitive deficits, including reduced learning and memory, but the relationship of these impairments to the efficacy of neuroplastic mechanisms has never been assessed., Objective: Our primary objective was to compare mechanisms of cortical plasticity in humans with and without T2DM. Our secondary objective was to relate plasticity measures to standard measures of cognition., Methods: A prospective cross-sectional cohort study was conducted on 21 adults with T2DM and 15 demographically-similar non-diabetic controls. Long-term potentiation-like plasticity was assessed in primary motor cortex by comparing the amplitude of motor evoked potentials (MEPs) from single-pulse transcranial magnetic stimulation before and after intermittent theta-burst stimulation (iTBS). Plasticity measures were compared between groups and related to neuropsychological scores., Results: In T2DM, iTBS-induced modulation of MEPs was significantly less than controls, even after controlling for potential confounds. Furthermore, in T2DM, modulation of MEPs 10-min post-iTBS was significantly correlated with Rey Auditory Verbal Learning Task (RAVLT) performance., Conclusion: Humans with T2DM show abnormal cortico-motor plasticity that is correlated with reduced verbal learning. Since iTBS after-effects and the RAVLT are both NMDA receptor-dependent measures, their relationship in T2DM may reflect brain-wide alterations in the efficacy of NMDA receptors. These findings offer novel mechanistic insights into the brain consequences of T2DM and provide a reliable means to monitor brain health and evaluate the efficacy of clinical interventions.