Investigating the neural mechanisms of transcranial direct current stimulation effects on human cognition: current issues and potential solutions.

Transcranial direct current stimulation (tDCS) has been studied extensively for its potential to enhance human cognitive functions in healthy individuals and to treat cognitive impairment in various clinical populations. However, little is known about how tDCS modulates the neural networks supporting cognition and the complex interplay with mediating factors that may explain the frequently observed variability of stimulation effects within and between studies. Moreover, research in this field has been characterized by substantial methodological variability, frequent lack of rigorous experimental control and small sample sizes, thereby limiting the generalizability of findings and translational potential of tDCS. The present manuscript aims to delineate how these important issues can be addressed within a neuroimaging context, to reveal the neural underpinnings, predictors and mediators of tDCS-induced behavioral modulation. We will focus on functional magnetic resonance imaging (fMRI), because it allows the investigation of tDCS effects with excellent spatial precision and sufficient temporal resolution across the entire brain. Moreover, high resolution structural imaging data can be acquired for precise localization of stimulation effects, verification of electrode positions on the scalp and realistic current modeling based on individual head and brain anatomy. However, the general principles outlined in this review will also be applicable to other imaging modalities. Following an introduction to the overall state-of-the-art in this field, we will discuss in more detail the underlying causes of variability in previous tDCS studies. Moreover, we will elaborate on design considerations for tDCS-fMRI studies, optimization of tDCS and imaging protocols and how to assure high-level experimental control. Two additional sections address the pressing need for more systematic investigation of tDCS effects across the healthy human lifespan and implications for tDCS studies in age-associated disease, and potential benefits of establishing large-scale, multidisciplinary consortia for more coordinated tDCS research in the future. We hope that this review will contribute to more coordinated, methodologically sound, transparent and reproducible research in this field. Ultimately, our aim is to facilitate a better understanding of the underlying mechanisms by which tDCS modulates human cognitive functions and more effective and individually tailored translational and clinical applications of this technique in the future.

PSYCHOLOGICAL GENERAL WELL-BEING, COGNITIVE FAILURE, AND INFLAMMATION BIOMARKERS AMONG WORKERS FOUR MONTHS AFTER A MILD/ASYMPTOMATIC SARS-CoV-2 INFECTION.

OBJECTIVE: To investigate the relationship between cognitive complaints, systemic inflammatory biomarkers and psychological general well-being (PGWB) after mild/asymptomatic SARS-CoV-2 infection, according to the presence of long COVID and work tasks. METHODS: University employees and metal workers were recruited in a cross-sectional study four months after SARS-CoV-2 infection to assess cognitive impairment, individual PGWB index, inflammatory biomarkers, namely platelet-lymphocyte, neutrophil-lymphocyte and lymphocyte-monocyte ratios, and the presence of long COVID symptoms. RESULTS: A significant increase in the levels of inflammatory biomarkers was observed in subjects with long COVID. Furthermore, the PGWB index was influenced by long COVID symptoms and subjective cognitive and depressive symptoms, but not by work activity. CONCLUSIONS: In occupational settings, it is crucial to detect the presence of long COVID symptoms and systemic inflammation early, as they may be associated with lower PGWB.

Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS.

Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials.

The role of frontal cortex in novel-word learning and consolidation: Evidence from focal transcranial direct current stimulation.

Previous studies have demonstrated that conventional transcranial direct current stimulation (tDCS) can enhance novel-word learning. However, because of the widespread current that is induced by these setups and lack of appropriate control conditions, little is known about the underlying neural mechanisms. In the present double-blinded and sham-tDCS controlled study, we investigated for the first time if regionally precise focal tDCS targeting two key nodes of the novel-word learning network at different time points would result in regionally and temporally distinct effects. 156 participants completed a contextual novel-word-learning paradigm and learning success was probed immediately after the acquisition period and 30-min later. Participants were randomly assigned to six stimulation conditions: Active tDCS (1.5 mA) was administered to left inferior frontal (IFG) or middle temporal gyrus (MTG), either during acquisition or delayed recall. Control groups received sham-tDCS either during acquisition or delayed recall (50% IFG/MTG). Data were analyzed with a generalized linear mixed model with a binomial link function in a Bayesian framework. Our results showed that frontal tDCS selectively increased accuracy gains from immediate to delayed recall, irrespective of timing of the stimulation. There was no evidence for beneficial effects of middle temporal gyrus tDCS. Our findings confirm that IFG tDCS can enhance novel-word learning in a regionally, but not timing specific way. Tentatively, this may be explained by enhancement of semantic selection processes resulting in more effective consolidation and/or retrieval. Future studies using longer time intervals between assessments are required to clarify the potential contribution of neurophysiological after-effects of IFG tDCS administered during acquisition to enhanced consolidation.

Non-pharmacological interventions for improving language and communication in people with primary progressive aphasia.

BACKGROUND: Primary progressive aphasia (PPA) accounts for approximately 43% of frontotemporal dementias and is mainly characterised by a progressive impairment of speech and communication abilities. Three clinical variants have been identified: (a) non-fluent/agrammatic, (b) semantic, and (c) logopenic/phonological PPA variants. There is currently no curative treatment for PPA, and the disease progresses inexorably over time, with devastating effects on speech and communication ability, functional status, and quality of life. Several non-pharmacological interventions that may improve symptoms (e.g. different forms of language training and non-invasive brain stimulation) have been investigated in people with PPA. OBJECTIVES: To assess the effects of non-pharmacological interventions for people with PPA on word retrieval (our primary outcome), global language functions, cognition, quality of life, and adverse events. SEARCH METHODS: We searched the Cochrane Dementia and Cognitive Improvement Group's trial register, MEDLINE (Ovid SP), Embase (Ovid SP), four other databases and two other trial registers. The latest searches were run on 26 January 2024. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating the effects of non-pharmacological interventions in people with PPA. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: There were insufficient data available to conduct the network meta-analyses that we had originally planned (due to trial data being insufficiently reported or not reported at all, as well as the heterogeneous content of the included interventions). Therefore, we provide a descriptive summary of the included studies and results. We included 10 studies, with a total of 132 participants, evaluating non-pharmacological interventions. These were: transcranial direct current stimulation (tDCS) or repetitive transcranial magnetic stimulation (rTMS) as stand-alone treatments (used by two and one studies, respectively); tDCS combined with semantic and phonological word-retrieval training (five studies); tDCS combined with semantic word-retrieval training (one study); and tDCS combined with phonological word-retrieval training (one study). Results for our primary outcome of word retrieval were mixed. For the two studies that investigated the effects of tDCS as stand-alone treatment compared to placebo ("sham") tDCS, we rated the results as having very low-certainty evidence. One study found a significant beneficial effect on word retrieval after active tDCS; one study did not report any significant effects in favour of the active tDCS group. Five studies investigated tDCS administered to the dorsolateral prefrontal cortex, inferior frontal cortex, left frontotemporal region, or the temporoparietal cortex, combined with semantic and phonological word-retrieval training. The most consistent finding was enhancement of word-retrieval ability for trained items immediately after the intervention, when behavioural training was combined with active tDCS compared to behavioural training plus sham tDCS. We found mixed effects for untrained items and maintenance of treatment effects during follow-up assessments. We rated the certainty of the evidence as very low in all studies. One study investigated tDCS combined with semantic word-retrieval training. Training was provided across 15 sessions with a frequency of three to five sessions per week, depending on the personal preferences of the participants. tDCS targeted the left frontotemporal region. The study included three participants: two received 1 mA stimulation and one received 2 mA stimulation. The study showed mixed results. We rated it as very low-certainty evidence. One study investigated tDCS combined with phonological word-retrieval training. Training was again provided across 15 sessions over a period of three weeks. tDCS targeted the left inferior frontal gyrus. This study showed a significantly more pronounced improvement for trained and untrained words in favour of the group that had received active tDCS, but we rated the certainty of the evidence as very low. One study compared active rTMS applied to an individually determined target site to active rTMS applied to a control site (vertex) for effects on participants' word retrieval. This study demonstrated better word retrieval for active rTMS administered to individually determined target brain regions than in the control intervention, but we rated the results as having a very low certainty of evidence. Four studies assessed overall language ability, three studies assessed cognition, five studies assessed potential adverse effects of brain stimulation, and one study investigated quality of life. AUTHORS' CONCLUSIONS: There is currently no high-certainty evidence to inform clinical decision-making regarding non-pharmacological treatment selection for people with PPA. Preliminary evidence suggests that the combination of active tDCS with specific language therapy may improve impaired word retrieval for specifically trained items beyond the effects of behavioural treatment alone. However, more research is needed, including high-quality RCTs with detailed descriptions of participants and methods, and consideration of outcomes such as quality of life, depressive symptoms, and overall cognitive functioning. Moreover, studies assessing optimal treatments (i.e. behavioural interventions, brain stimulation interventions, and their combinations) for individual patients and PPA subtypes are needed. We were not able to conduct the planned (network) meta-analyses due to missing data that could not be obtained from most of the authors, a general lack of RCTs in the field, and heterogeneous interventions in eligible trials. Journals should implement a mandatory data-sharing requirement to assure transparency and accessibility of data from clinical trials.

No Object-Location Memory Improvement through Focal Transcranial Direct Current Stimulation over the Right Temporoparietal Cortex.

Remembering objects and their associated location (object-location memory; OLM), is a fundamental cognitive function, mediated by cortical and subcortical brain regions. Previously, the combination of OLM training and transcranial direct current stimulation (tDCS) suggested beneficial effects, but the evidence remains heterogeneous. Here, we applied focal tDCS over the right temporoparietal cortex in 52 participants during a two-day OLM training, with anodal tDCS (2 mA, 20 min) or sham (40 s) on the first day. The focal stimulation did not enhance OLM performance on either training day (stimulation effect: -0.09, 95%CI: [-0.19; 0.02], p = 0.08). Higher electric field magnitudes in the target region were not associated with individual performance benefits. Participants with content-related learning strategies showed slightly superior performance compared to participants with position-related strategies. Additionally, training gains were associated with individual verbal learning skills. Consequently, the lack of behavioral benefits through focal tDCS might be due to the involvement of different cognitive processes and brain regions, reflected by participant's learning strategies. Future studies should evaluate whether other brain regions or memory-relevant networks may be involved in the modulation of object-location associations, investigating other target regions, and further exploring individualized stimulation parameters.

Brain oscillatory processes related to sequence memory in healthy older adults.

Sequence memory is subject to age-related decline, but the underlying processes are not yet fully understood. We analyzed electroencephalography (EEG) in 21 healthy older (60-80 years) and 26 young participants (20-30 years) and compared time-frequency spectra and theta-gamma phase-amplitude-coupling (PAC) during encoding of the order of visually presented items. In older adults, desynchronization in theta (4-8 Hz) and synchronization in gamma (30-45 Hz) power did not distinguish between subsequently correctly and incorrectly remembered trials, while there was a subsequent memory effect for young adults. Theta-gamma PAC was modulated by item position within a sequence for older but not young adults. Specifically, position within a sequence was coded by higher gamma amplitude for successive theta phases for later correctly remembered trials. Thus, deficient differentiation in theta desynchronization and gamma oscillations during sequence encoding in older adults may reflect neurophysiological correlates of age-related memory decline. Furthermore, our results indicate that sequences are coded by theta-gamma PAC in older adults, but that this mechanism might lose precision in aging.

Electrode positioning errors reduce current dose for focal tDCS set-ups: Evidence from individualized electric field mapping.

OBJECTIVE: Electrode positioning errors contribute to variability of transcranial direct current stimulation (tDCS) effects. We investigated the impact of electrode positioning errors on current flow for tDCS set-ups with different focality. METHODS: Deviations from planned electrode positions were determined using data acquired in an experimental study (N = 240 datasets) that administered conventional and focal tDCS during magnetic resonance imaging (MRI). Comparison of individualized electric field modeling for planned and empirically derived "actual" electrode positions was conducted to quantify the impact of positioning errors on the electric field dose in target regions for tDCS. RESULTS: Planned electrode positions resulted in higher current dose in the target regions for focal compared to conventional montages (7-12%). Deviations from planned positions significantly reduced current flow in the target regions, selectively for focal set-ups (26-30%). Dose reductions were significantly larger for focal compared to conventional set-ups (29-43%). CONCLUSIONS: Precise positioning is crucial when using focal tDCS set-ups to avoid significant reductions of current dose in the intended target regions. SIGNIFICANCE: Our results highlight the urgent need to routinely implement methods for improving electrode positioning, minimization of electrode drift, verification of electrode positions before and/or after tDCS and also to consider positioning errors when investigating dose-response relationships, especially for focal set-ups.

Neural correlates of home-based intervention effects on value-based sequential decision-making in healthy older adults.

Older adults demonstrate difficulties in sequential decision-making, which is partly attributed to under-recruitment of prefrontal networks. It is, therefore, important to understand the mechanisms that may improve this ability. This study investigated the effectiveness of an 18-sessions, home-based cognitive intervention and the neural mechanisms that underpin individual differences in intervention effects. Participants were required to learn sequential choices in a 3-stage Markov decision-making task that would yield the most rewards. Participants were assigned to better or worse responders group based on their performance at the last intervention session (T18). Better responders improved significantly starting from the fifth intervention session while worse responders did not improve across all training sessions. At post-intervention, only better responders showed condition-dependent modulation of the dorsolateral prefrontal cortex (DLPFC) as measured by fNIRS, with higher DLPFC activity in the delayed condition. Despite large individual differences, our data showed that value-based sequential-decision-making and its corresponding neural mechanisms can be remediated via home-based cognitive intervention in some older adults; moreover, individual differences in recruiting prefrontal activities after the intervention are associated with variations in intervention outcomes. Intervention-related gains were also maintained at three months after post-intervention. However, future studies should investigate the potential of combining other intervention methods such as non-invasive brain stimulation with cognitive intervention for older adults who do not respond to the intervention, thus emphasizing the importance of developing individualized intervention programs for older adults.

Improving the detection of sleep slow oscillations in electroencephalographic data.

Study objectives: We aimed to build a tool which facilitates manual labeling of sleep slow oscillations (SOs) and evaluate the performance of traditional sleep SO detection algorithms on such a manually labeled data set. We sought to develop improved methods for SO detection. Method: SOs in polysomnographic recordings acquired during nap time from ten older adults were manually labeled using a custom built graphical user interface tool. Three automatic SO detection algorithms previously used in the literature were evaluated on this data set. Additional machine learning and deep learning algorithms were trained on the manually labeled data set. Results: Our custom built tool significantly decreased the time needed for manual labeling, allowing us to manually inspect 96,277 potential SO events. The three automatic SO detection algorithms showed relatively low accuracy (max. 61.08%), but results were qualitatively similar, with SO density and amplitude increasing with sleep depth. The machine learning and deep learning algorithms showed higher accuracy (best: 99.20%) while maintaining a low prediction time. Conclusions: Accurate detection of SO events is important for investigating their role in memory consolidation. In this context, our tool and proposed methods can provide significant help in identifying these events.

Cognitive training and brain stimulation in patients with cognitive impairment: a randomized controlled trial.

BACKGROUND: Repeated sessions of training and non-invasive brain stimulation have the potential to enhance cognition in patients with cognitive impairment. We hypothesized that combining cognitive training with anodal transcranial direct current stimulation (tDCS) will lead to performance improvement in the trained task and yield transfer to non-trained tasks. METHODS: In our randomized, sham-controlled, double-blind study, 46 patients with cognitive impairment (60-80 years) were randomly assigned to one of two interventional groups. We administered a 9-session cognitive training (consisting of a letter updating and a Markov decision-making task) over 3 weeks with concurrent 1-mA anodal tDCS over the left dorsolateral prefrontal cortex (20 min in tDCS, 30 s in sham group). Primary outcome was trained task performance (letter updating task) immediately after training. Secondary outcomes included performance in tasks testing working memory (N-back task), decision-making (Wiener Matrices test) and verbal memory (verbal learning and memory test), and resting-state functional connectivity (FC). Tasks were administered at baseline, at post-assessment, and at 1- and 7-month follow-ups (FU). MRI was conducted at baseline and 7-month FU. Thirty-nine participants (85%) successfully completed the intervention. Data analyses are reported on the intention-to-treat (ITT) and the per-protocol (PP) sample. RESULTS: For the primary outcome, no difference was observed in the ITT (ß = 0.1, 95%-CI [- 1.2, 1.3, p = 0.93] or PP sample (ß = - 0.2, 95%-CI [- 1.6, 1.2], p = 0.77). However, secondary analyses in the N-back working memory task showed that, only in the PP sample, the tDCS outperformed the sham group (PP: % correct, ß = 5.0, 95%-CI [- 0.1, 10.2], p = 0.06, d-prime ß = 0.2, 95%-CI [0.0, 0.4], p = 0.02; ITT: % correct, ß = 3.0, 95%-CI [- 3.9, 9.9], p = 0.39, d-prime ß = 0.1, 95%-CI [- 0.1, 0.3], p = 0.5). Frontoparietal network FC was increased from baseline to 7-month FU in the tDCS compared to the sham group (pFDR < 0.05). Exploratory analyses showed a correlation between individual memory improvements and higher electric field magnitudes induced by tDCS (ρtDCS = 0.59, p = 0.02). Adverse events did not differ between groups, questionnaires indicated successful blinding (incidence rate ratio, 1.1, 95%-CI [0.5, 2.2]). CONCLUSIONS: In sum, cognitive training with concurrent brain stimulation, compared to cognitive training with sham stimulation, did not lead to superior performance enhancements in patients with cognitive impairment. However, we observed transferred working memory benefits in patients who underwent the full 3-week intervention. MRI data pointed toward a potential intervention-induced modulation of neural network dynamics. A link between individual performance gains and electric fields suggested dosage-dependent effects of brain stimulation. Together, our findings do not support the immediate benefit of the combined intervention on the trained function, but provide exploratory evidence for transfer effects on working memory in patients with cognitive impairment. Future research needs to explore whether individualized protocols for both training and stimulation parameters might further enhance treatment gains. TRIAL REGISTRATION: The study is registered on ClinicalTrials.gov (NCT04265378). Registered on 7 February 2020. Retrospectively registered.

[Transcranial direct current stimulation to enhance training effectiveness in chronic poststroke aphasia-A challenge for recruiting participants]. / Transkranielle Gleichstromstimulation zur Verbesserung der Trainingseffektivität bei chronischer Aphasie nach Schlaganfall ­ wie gelingt die Studienrekrutierung Betroffener?

INTRODUCTION/BACKGROUND: DC_TRAIN_APHASIA is an ongoing multicenter, randomized controlled trial, conducted since November 2019 under the lead of the University Medicine Greifswald (ClinicalTrials.gov Identifier: NCT03930121). The study seeks to determine whether adjuvant transcranial direct current stimulation (tDCS) can increase the effectiveness of a 3­week treatment with intensive speech-language therapy in chronic post-stroke aphasia. MATERIAL AND METHOD: Until the end of 2024, a total of 130 patients are to be included in Germany. Recruitment has been a challenge throughout the study and substantial efforts went into devising innovative recruiting approaches. Standard recruitment strategies were used, such as directly approaching people with aphasia in clinical settings, inpatient and outpatient language rehabilitation facilities, and patient support and advocacy groups, alongside more innovative techniques including radio commercials, dissemination of study information via national television and social media platforms. PROVISIONAL RESULTS: Up until now, 110 patients have been included into the study. The largest short-term response was achieved via television and radio. The largest long-term response was obtained through recruitment via logopaedic and neurological facilities, patient support groups, and social media. Participants served as "testimonials", expressing that they were satisfied with the therapy and the tDCS application. DISCUSSION: The multicenter study DC_TRAIN_APHASIA aims to provide evidence on tDCS as an adjuvant application to increase the effect size of intensive speech-language therapy in chronic post-stroke aphasia. The present review may guide future studies in recruiting samples that involve people with impaired communicative abilities.

Association of spermidine blood levels with microstructure of sleep-implications from a population-based study.

Deteriorations in slow wave sleep (SWS) have been linked to brain aging and Alzheimer's disease (AD), possibly due to its key role in clearance of amyloid-beta and tau (Aß/tau), two pathogenic hallmarks of AD. Spermidine administration has been shown to improve sleep quality in animal models. So far, the association between spermidine levels in humans and parameters of SWS physiology are unknown but may be valuable for therapeutic strategies. Data from 216 participants (age range 50-81 years) of the population-based Study of Health in Pomerania TREND were included in our analysis. We investigated associations between spermidine plasma levels, key parameters of sleep macroarchitecture and microarchitecture that were previously associated with AD pathology, and brain health measured via a marker of structural brain atrophy (AD score). Higher spermidine levels were significantly associated with lower coupling between slow oscillations and spindle activity. No association was evident for SWS, slow oscillatory, and spindle activity throughout non-rapid eye movement sleep. Furthermore, elevated spermidine blood levels were significantly associated with a higher AD score, while sleep markers revealed no association with AD score. The association between higher spermidine levels and brain health was not mediated by coupling between slow oscillations and spindle activity. We report that higher spermidine blood levels are associated not only with deteriorated brain health but also with less advantageous markers of sleep quality in older adults. Future studies need to evaluate whether sleep, spermidine, and Aß/tau deposition are interrelated and whether sleep may play a mediating role.

Nationwide Retrospective Analysis of Combinations of Advanced Therapies in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications. METHODS: Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT. RESULTS: A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [p < 0.001], of MDS-UPDRS Part IV 6.0 points [p < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [p < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS. DISCUSSION: Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting.

Protocol for an economic evaluation of a tele-neurologic intervention alongside a stepped wedge randomised controlled trial (NeTKoH).

BACKGROUND: A significant and growing portion of the global burden of diseases is caused by neurological disorders. Tele-neurology has the potential to improve access to health care services and the quality of care, particularly in rural and underserved areas. The economic evaluation of the stepped wedge randomised controlled trial NeTKoH aims to ascertain the cost-effectiveness and cost-utility regarding the effects of a tele-neurologic intervention in primary care in a rural area in Germany. METHODS: This protocol outlines the methods used when conducting the trial-based economic evaluation of NeTKoH. The outcomes used in our economic analysis are all prespecified endpoints of the NeTKoH trial. Outcomes considered for the cost-utility and cost-effectiveness analyses will be quality-adjusted life years (QALYs) derived from the EQ-5D-5L, proportion of neurologic problems being solved at the GP's office (primary outcome), hospital length-of-stay and number of hospital stays. Costs will be prospectively collected during the trial by the participating statutory health insurances, and will be analysed from a statutory health insurance perspective within the German health care system. This economic evaluation will be reported complying with the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. DISCUSSION: This within-trial economic evaluation relaying the costs and outcomes of an interdisciplinary tele-consulting intervention will provide high-quality evidence for cost-effectiveness and policy implications of a tele-neurological programme, including the potential for application in other rural areas in Germany or other jurisdictions with a comparable health system. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00024492), date registered: September 28, 2021.

Effect evaluation of a tele-neurologic intervention in primary care in a rural area in Germany-the NeTKoH study protocol of a stepped-wedge cluster randomized trial.

BACKGROUND: Neurological disorders account for a large and increasing proportion of the global burden of disease. Therefore, it is important to strengthen the management of neurologic care, particularly in rural areas. The use of tele-neurology in primary care in rural areas is internationally considered to have the potential to increase access to health care services and improve the quality of care in these underserved areas. NeTKoH aims to address the existing knowledge gap regarding the effects of a tele-neurologic intervention in primary care under real-world conditions in a rural area in Germany. METHODS: NeTKoH is a cluster-randomized controlled trial with a stepped-wedge design involving 33 outpatient general practitioner's (GP) offices (clusters) in a rural area in Northeast Germany. During 11 predetermined steps, all clusters are randomized before they cross over into groups from the control to the intervention arm. The targeted sample size is 1,089 patients with neurologic symptoms that are continuously being recruited. In the intervention arm, tele-neurologic consultations will be provided via a face-to-face video conferencing system with a neurologic expert at a university hospital. The control arm will receive usual care. The primary outcome is the proportion of neurologic problems being solved at the GP's office. Secondary outcomes will comprise hospital stays and days, time until neurologic specialist appointments and diagnostics, patients' health status and quality of life, outpatient and inpatient referrals. A concurrent observational study, together with a process, implementation, and health economic evaluation, will also be conducted. DISCUSSION: Using a stepped-wedge cluster design in a real-life situation can help with logistic challenges and enhance the motivation of the participating GPs, as all, at some point, will be in the intervention phase. With the additional implementation evaluation pertaining to external validity, an observational study, and a health economic evaluation, NeTKoH will be able to provide an extensive evaluation for health policy decision-makers regarding the uptake into standard care. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00024492). Date registered: September 28, 2021. Date and protocol version: June 2023, version 1.

Interrelations and functional roles of key oscillatory activities during daytime sleep in older adults.

Certain neurophysiological characteristics of sleep, in particular slow oscillations (SOs), sleep spindles, and their temporal coupling, have been well characterised and associated with human memory abilities. Delta waves, which are somewhat higher in frequency and lower in amplitude compared to SOs, and their interaction with spindles have only recently been found to play a critical role in memory processing of rodents, through a competitive interaction between SO-spindle and delta-spindle coupling. However, human studies that comprehensively address delta wave interactions with spindles and SOs, as well as their functional role for memory are still lacking. Electroencephalographic data were acquired across three naps of 33 healthy older human participants (17 female) to investigate delta-spindle coupling and the interplay between delta- and SO-related activity. Additionally, we determined intra-individual stability of coupling measures and their potential link to the ability to form novel memories in a verbal memory task. Our results revealed weaker delta-spindle compared to SO-spindle coupling. Contrary to our initial hypothesis, we found no evidence for an opposing dependency between SO- and delta-related activities during non-rapid eye movement sleep. Moreover, the ratio between SO- and delta-nested spindles rather than SO-spindle and delta-spindle coupling measures by themselves predicted the ability to form novel memories best. In conclusion, our results do not confirm previous findings in rodents on competitive interactions between delta activity and SO-spindle coupling in older adults. However, they support the hypothesis that SO, delta wave, and spindle activity should be jointly considered when aiming to link sleep physiology and memory formation.

Microstructural and functional plasticity following repeated brain stimulation during cognitive training in older adults.

The combination of repeated behavioral training with transcranial direct current stimulation (tDCS) holds promise to exert beneficial effects on brain function beyond the trained task. However, little is known about the underlying mechanisms. We performed a monocenter, single-blind randomized, placebo-controlled trial comparing cognitive training to concurrent anodal tDCS (target intervention) with cognitive training to concurrent sham tDCS (control intervention), registered at ClinicalTrial.gov (Identifier NCT03838211). The primary outcome (performance in trained task) and secondary behavioral outcomes (performance on transfer tasks) were reported elsewhere. Here, underlying mechanisms were addressed by pre-specified analyses of multimodal magnetic resonance imaging before and after a three-week executive function training with prefrontal anodal tDCS in 48 older adults. Results demonstrate that training combined with active tDCS modulated prefrontal white matter microstructure which predicted individual transfer task performance gain. Training-plus-tDCS also resulted in microstructural grey matter alterations at the stimulation site, and increased prefrontal functional connectivity. We provide insight into the mechanisms underlying neuromodulatory interventions, suggesting tDCS-induced changes in fiber organization and myelin formation, glia-related and synaptic processes in the target region, and synchronization within targeted functional networks. These findings advance the mechanistic understanding of neural tDCS effects, thereby contributing to more targeted neural network modulation in future experimental and translation tDCS applications.

Functional Connectivity and Microstructural Network Correlates of Interindividual Variability in Distinct Executive Functions of Healthy Older Adults.

Executive functions, essential for daily life, are known to be impaired in older age. Some executive functions, including working memory updating and value-based decision-making, are specifically sensitive to age-related deterioration. While their neural correlates in young adults are well-described, a comprehensive delineation of the underlying brain substrates in older populations, relevant to identify targets for modulation against cognitive decline, is missing. Here, we assessed letter updating and Markov decision-making task performance to operationalize these trainable functions in 48 older adults. Resting-state functional magnetic resonance imaging was acquired to quantify functional connectivity (FC) in task-relevant frontoparietal and default mode networks. Microstructure in white matter pathways mediating executive functions was assessed with diffusion tensor imaging and quantified by tract-based fractional anisotropy (FA). Superior letter updating performance correlated with higher FC between dorsolateral prefrontal cortex and left frontoparietal and hippocampal areas, while superior Markov decision-making performance correlated with decreased FC between basal ganglia and right angular gyrus. Furthermore, better working memory updating performance was related to higher FA in the cingulum bundle and the superior longitudinal fasciculus. Stepwise linear regression showed that cingulum bundle FA added significant incremental contribution to the variance explained by fronto-angular FC alone. Our findings provide a characterization of distinct functional and structural connectivity correlates associated with performance of specific executive functions. Thereby, this study contributes to the understanding of the neural correlates of updating and decision-making functions in older adults, paving the way for targeted modulation of specific networks by modulatory techniques such as behavioral interventions and non-invasive brain stimulation.