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Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation tool that is now being widely used in neuroscientific and clinical research in humans. While initial studies focused on modulation of cortical excitability, the technique quickly progressed to studies on motor and cognitive functions in healthy humans and in patients with neurological diseases. In the present review we will first provide the reader with a brief background on the basic principles of tDCS. In the main part, we will outline recent studies with tDCS that aimed at enhancing behavioral outcome or disease-specific symptoms in patients suffering from mild cognitive impairment, Alzheimer's disease, movement disorders, and epilepsy, or persistent deficits after stroke. The review will close with a summary statement on the present use of tDCS in the treatment of neurological disorders, and an outlook to further developments in this realm. tDCS may be an ideal tool to be administered in parallel to intensive cognitive or motor training in neurological disease, but efficacy for the areas of activities and participation still needs to be established in controlled randomized trials. Its use in reducing disease-specific symptoms like dystonia or epileptic seizures is still unclear. •tDCS shown to modulate cortical excitability and plasticity.•tDCS enhances memory functions in AD.•tDCS enhances motor and language function after stroke.•Impact of tDCS on activities and participation still unclear.

Sleep-related consolidation of declarative memories, as well as associated neurophysiological events such as slow oscillatory and spindle activity, deteriorate in the course of aging. This process is accelerated in neurodegenerative disease. Transcranial slow oscillatory stimulation (so-tDCS) during sleep has been shown to enhance slow oscillatory brain activity and thereby improve memory consolidation in young subjects. Here, we investigated whether so-tDCS applied to older adults during an afternoon nap exerts similar effects. Eighteen older human subjects were assessed using visuo-spatial (picture memory, primary, and location memory) and verbal memory tasks before and after a 90-min nap either comprising weak so-tDCS at 0.75Hz over fronto-central location or sham (no) stimulation in a within-subject design. Electroencephalographic activity was recorded throughout the naps and immediate effects of stimulation on brain activity were evaluated. Here, spectral power within three frequency bands of interest were computed, i.e., slow oscillatory activity, slow spindle and fast spindle activity; in 1-min stimulation-free intervals following 5 stimulation blocks. So-tDCS significantly increased frontal slow oscillatory activity as well as fast spindle activity, and significantly improved picture memory retention after sleep. Retention in the location memory subtask and in the verbal memory task was not affected. These findings may indicate a novel strategy to counteract cognitive decline in aging in a convenient manner during brief daytime naps. •Improved picture memory performance by brain stimulation during nap in older adults.•Stimulation enhanced memory-relevant slow oscillations and fast spindle activity.•Findings may indicate novel strategy to counteract cognitive decline in aging.

Non-invasive transcranial stimulation of cerebellum and primary motor cortex (M1) has been shown to enhance motor learning. However, the mechanisms by which stimulation improves learning remain largely unknown. Here, we sought to shed light on the neural correlates of transcranial direct current stimulation (tDCS) during motor learning by simultaneously recording functional magnetic resonance imaging (fMRI). We found that right cerebellar tDCS, but not left M1 tDCS, led to enhanced sequence learning in the serial reaction time task. Performance was also improved following cerebellar tDCS compared to sham in a sequence production task, reflecting superior training effects persisting into the post-training period. These behavioral effects were accompanied by increased learning-specific activity in right M1, left cerebellum lobule VI, left inferior frontal gyrus and right inferior parietal lobule during cerebellar tDCS compared to sham. Despite the lack of group-level changes comparing left M1 tDCS to sham, activity increase in right M1, supplementary motor area, and bilateral middle frontal cortex, under M1 tDCS, was associated with better sequence performance. This suggests that lack of group effects in M1 tDCS relate to inter-individual variability in learning-related activation patterns. We further investigated how tDCS modulates effective connectivity in the cortico-striato-cerebellar learning network. Using dynamic causal modelling, we found altered connectivity patterns during both M1 and cerebellar tDCS when compared to sham. Specifically, during cerebellar tDCS, negative modulation of a connection from putamen to cerebellum was decreased for sequence learning only, effectively leading to decreased inhibition of the cerebellum. These results show specific effects of cerebellar tDCS on functional activity and connectivity in the motor learning network and may facilitate the optimization of motor rehabilitation involving cerebellar non-invasive stimulation.

Recently, transcranial alternating current stimulation (tACS) has emerged as a tool to enhance human cognitive processes. Here, we provide a brief summary of the rationale behind tACS-induced effects on task-relevant brain oscillations and associated cognitive functions and review previous studies in young subjects that have applied tACS in cognitive paradigms. Additionally, we present pilot data where we administered theta-tACS (6 Hz) over the temporoparietal cortex and a supraorbital reference for 20 min during implicit language learning in healthy young (mean/SD age: 22/2) and older (mean/SD age: 66/4) adults, in a sham-controlled crossover design. Linear mixed models revealed significantly increased retrieval accuracy following tACS-accompanied associative learning, after controlling for session order and learning success. These data provide the first implementation of tACS during cognitive performance in older adults and support recent studies suggesting that tACS in the theta frequency range may serve as a tool to enhance cognition, possibly through direct modulation of task-relevant brain oscillations. So far, studies have been heterogeneous in their designs, leaving a number of issues to be addressed in future research, including the setup of electrodes and optimal stimulation frequencies to be employed, as well as the interaction with age and underlying brain pathologies in specific patient populations.

Many clinical studies reporting accelerometry data use sum score measures such as percentage of time spent in moderate to vigorous activity which do not provide insight into differences in activity patterns over 24 hours, and thus do not adequately depict circadian activity patterns. Here, we present an improved functional data analysis approach to model activity patterns and circadian rhythms from accelerometer data. As a use case, we demonstrated its application in patients with mild cognitive impairment (MCI) and age-matched healthy older volunteers (HOV). Data of two studies were pooled for this analysis. Following baseline cognitive assessment participants were provided with accelerometers for seven consecutive days. A function on scalar regression (FoSR) approach was used to analyze 24 hours accelerometer data. Information on 48 HOV (mean age 65 SD 6 years) and 18 patients with MCI (mean age 70, SD 8 years) were available for this analysis. MCI patients displayed slightly lower activity in the morning hours (minimum relative activity at 6:05 am: -41.3%, 95% CI -64.7 to -2.5%, p = 0.031) and in the evening (minimum relative activity at 21:40 am: -48.4%, 95% CI -68.5 to 15.4%, p = 0.001) as compared to HOV after adjusting for age and sex. Using a novel approach of FoSR, we found timeframes with lower activity levels in MCI patients compared to HOV which were not evident if sum scores of amount of activity were used, possibly indicating that changes in circadian rhythmicity in neurodegenerative disease are detectable using easy-to-administer accelerometry. Effects of Brain Stimulation During Nocturnal Sleep on Memory Consolidation in Patients With Mild Cognitive Impairments, ClinicalTrial.gov identifier: NCT01782391. Effects of Brain Stimulation During a Daytime Nap on Memory Consolidation in Patients With Mild Cognitive Impairment, ClinicalTrial.gov identifier: NCT01782365.

We previously identified IgG autoantibodies targeting epitopes within brainstem proteins-disabled homolog 1 ( ), apoptosis-inducing factor 1 ( ), and surfeit locus protein 1 ( )-as markers of severe acute COVID-19. This study investigates whether the same autoantibodies contribute to the pathophysiology of Post COVID Syndrome (PCS). Using a multiplexed bead-based immunoassay, we measured IgG levels against 18 synthetic peptides derived from , , and in serum samples from 45 PCS patients and 30 post-COVID controls without long-term symptoms. We employed generalized linear mixed models (GLMM) and nonlinear principal component analysis (CATPCA) to explore associations between antibody levels and clinical variables, including functional status (PCFS), respiratory symptoms, fatigue, cognitive impairment (as assessed by the Montreal Cognitive Assessment, MoCA), and mood. Higher IgG levels against the three autoantigens significantly predicted PCS at 3 months postinfection (t=2.21, p=0.03), whereas antibodies against a control peptide (polio) showed no such association. CATPCA identified a principal component capturing respiratory symptoms and functional impairment (PCFS), which was also significantly predicted by autoantibody levels (t=2.04, p=0.04). MoCA scores did not correlate with autoantibody levels, and subjective cognitive complaints were paradoxically linked to lower antibody titers and fewer physical symptoms. The findings from the present explorative study, although largely correlative, appear to suggest a sustained autoimmune response targeting neuronal and mitochondrial proteins in PCS, particularly associated with respiratory dysfunction and reduced functional capacity. The results also highlight potential limitations of standard cognitive screening tools like the MoCA in detecting subtle deficits in PCS. The identified autoantibodies may serve as biomarkers for persistent post-COVID disability. Future research replicating present results on larger samples and specifically investigating a causal link between occurrence of the Auto-Abs and PCS is needed for shaping future immunomodulatory therapeutic strategies.

In the absence of effective therapies for dementia and its precursors, enhancing neuroplasticity by means of non-invasive brain stimulation such as anodal transcranial direct current stimulation (atDCS) might be a promising approach to counteract or delay the onset of cognitive decline, but effect sizes have been moderate so far. Previous reports indicate that increasing serotonin levels may enhance atDCS-induced neuroplasticity. However, evidence for serotonergic modulation of atDCS effects on memory is still lacking. Here, we conducted a double-blind, randomized, sham-/placebo-controlled trial to investigate the impact of a selective serotonin reuptake inhibitor (SSRI; single dose of 20 mg citalopram) and atDCS over the right temporoparietal cortex (1 mA, 20 min) on memory formation. Twenty young and 20 older subjects completed an object-location learning task in each of the four conditions: sham+placebo, sham+SSRI, atDCS+placebo, and atDCS+SSRI. Outcome measures were performance in immediate (primary outcome) and delayed cued recall. While we found an SSRI effect, but no statistically significant effect of atDCS on immediate recall scores, young and older adults benefited most from the combined application (comparisons: atDCS+SSRI>atDCS+placebo and atDCS+SSRI>sham+placebo). Thus, our data provide evidence that atDCS improves memory formation if serotonergic neurotransmission is enhanced simultaneously. Further studies are needed to assess whether these findings extend to clinical populations with memory impairment and translate into clinically relevant improvements after long-term serotonergic enhancement and repeated stimulation.

Language abilities are known to deteriorate in aging, possibly related to decreased functional and structural connectivity within specialized brain networks. Here, we investigated syntactic ability in healthy young and older adults using a comprehensive assessment of behavioral performance, task-independent functional (FC) and structural brain connectivity (SC). Seed-based FC originating from left pars opercularis (part of Broca's area) known to support syntactic processes was assessed using resting-state functional magnetic resonance imaging, and SC using fractional anisotropy from diffusion weighted imaging, in the dorsally located superior longitudinal and the ventrally located uncinate fasciculi (SLF, UF) and forceps minor. Young compared to older adults exhibited superior syntactic performance and stronger FC within the mainly left-lateralized syntax network, which was beneficial for performance. In contrast, in older adults, FC within the mainly left-lateralized syntax network was reduced and did not correlate with performance; inter-hemispheric FC to right inferior frontal and angular gyri was detrimental for performance. In both groups, performance was positively correlated with inter-hemispheric SC. For intra-hemispheric SC, performance correlated with structural integrity of SLF in young adults and with integrity of UF in older adults. Our data show that reduced syntactic ability in older adults is associated with decreased FC within dedicated syntax networks. Moreover, young adults showed an association of syntactic ability with structural integrity of the dorsal tract, while older adults rely more on ventral fibers. In sum, our study provided novel insight into the relationship between connectivity and syntactic performance in young and older adults. In addition to elucidating age-related changes in syntax networks and their behavioral relevance, our results contribute to a better understanding of age-related changes in functional and structural brain organization in general, an important prerequisite for developing novel strategies to counteract age-related cognitive decline. •Syntax networks differ between older and young adults.•Functional connectivity within syntax networks correlates with performance.•Inter- and intra-hemispheric structural connectivity is associated with performance.•Young adults rely on dorsal, older adults on ventral language pathways.

The relationship between brain structure, cortical physiology, and learning ability in older adults is of particular interest in understanding mechanisms of age-related cognitive decline. Only a few studies addressed this issue so far, yielding mixed results. Here, we used comprehensive multiple regression analyses to investigate associations between brain structure on the one hand, i.e., cortical thickness (CT), fractional anisotropy (FA) of the pyramidal tract and individual coil-to-cortex distance, and cortical physiology on the other hand, i.e. motor cortex excitability and long-term potentiation (LTP)-like cortical plasticity, in healthy older adults (mean age 64years, 14 women). Additional exploratory analyses assessed correlations between cortical physiology and learning ability in the verbal domain. In the regression models, we found that cortical excitability could be best predicted by CT of the hand knob of the primary motor cortex (CT-M1HAND) and individual coil-to-cortex distance, while LTP-like cortical plasticity was predicted by CT-M1HAND and FA of the pyramidal tract. Exploratory analyses revealed a significant inverse correlation between cortical excitability and learning ability. In conclusion, higher cortical excitability was associated with lower CT and lower learning ability in a cohort of healthy older adults, in line with previous reports of increased cortical excitability in patients with cortical atrophy and cognitive deficits due to Alzheimer's Disease. Cortical excitability may thus be a parameter to identify individuals at risk for cognitive decline and gray matter atrophy, a hypothesis to be explored in future longitudinal studies. •Associations between brain structure (MRI) and cortical physiology (TMS).•Higher cortical excitability was associated with lower CT in healthy older adults.•Cortical LTP-like plasticity was dependent on structural integrity of the pyramidal tract.•Subjects with higher cortical excitability revealed lower learning ability.•TMS may help to identify patients at risk for developing dementia.

Patients with unilateral occlusive processes of the internal carotid artery (ICA) show subtle cognitive deficits. Decline in cerebral autoregulation and in functional and structural integrity of brain networks have previously been reported in the affected hemisphere (AH). However, the association between cerebral autoregulation, brain networks, and cognition remains to be elucidated. Fourteen neurologically asymptomatic patients (65±11 years) with either ICA occlusion or high-grade ICA stenosis and 11 age-matched healthy controls (HC) (67±6 years) received neuropsychologic testing, transcranial Doppler sonography to assess cerebral autoregulation using vasomotor reactivity (VMR), and magnetic resonance imaging to probe white matter microstructure and resting-state functional connectivity (RSFC). Patients performed worse on memory and executive tasks when compared with controls. Vasomotor reactivity, white matter microstructure, and RSFC were lower in the AH of the patients when compared with the unaffected hemisphere and with controls. Lower VMR of the AH was associated with several ipsilateral clusters of lower white matter microstructure and lower bilateral RSFC in patients. No correlations were found between VMR and cognitive scores. In sum, impaired cerebral autoregulation was associated with reduced structural and functional connectivity in cerebral networks, indicating possible mechanisms by which severe unilateral occlusive processes of the ICA lead to cognitive decline.