Search

Background: Dementia with Lewy bodies (DLB) is characterized by a marked shift of electroencephalographic (EEG) power and dominant rhythm, from the α toward the θ frequency range. Transcranial alternate current stimulation (tACS) is a non-invasive brain stimulation technique that allows entrainment of cerebral oscillations at desired frequencies., Objectives: Our goal is to evaluate the effects of occipital α-tACS on cognitive functions and neurophysiological measures in patients with DLB., Methods: We conducted a double-blind, randomized, sham-controlled, cross-over clinical trial in 14 participants with DLB. Participants were randomized to receive either α-tACS (60 minutes of 3 mA peak-to-peak stimulation at 12 Hz) or sham stimulation applied over the occipital cortex. Clinical evaluations were performed to assess visuospatial and executive functions, as well as verbal episodic memory. Neurophysiological assessments and EEG recordings were conducted at baseline and following both α-tACS and sham stimulations., Results: Occipital α-tACS was safe and well-tolerated. We observed a significant enhancement in visuospatial abilities and executive functions, but no improvement in verbal episodic memory. We observed an increase in short latency afferent inhibition, a neurophysiological marker indirectly and partially dependent on cholinergic transmission, coinciding with an increase in α power and a decrease in Δ power following α-tACS stimulation, effects not seen with sham stimulation., Conclusions: This study demonstrates that occipital α-tACS is safe and enhances visuospatial and executive functions in patients with DLB. Improvements in indirect markers of cholinergic transmission and EEG changes indicate significant neurophysiological engagement. These findings justify further exploration of α-tACS as a therapeutic option for DLB patients. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: In recent years, significant efforts have been directed towards the research and development of disease-modifying therapies for dementia. These drugs focus on prodromal (mild cognitive impairment, MCI) and/or early stages of Alzheimer's disease (AD). Literature evidence indicates that a considerable proportion of individuals with MCI do not progress to dementia. Identifying individuals at higher risk of developing dementia is essential for appropriate management, including the prescription of new disease-modifying therapies expected to become available in clinical practice in the near future., Methods: The ongoing INTERCEPTOR study is a multicenter, longitudinal, interventional, non-therapeutic cohort study designed to enroll 500 individuals with MCI aged 50-85 years. The primary aim is to identify a biomarker or a set of biomarkers able to accurately predict the conversion from MCI to AD dementia within 3 years of follow-up. The biomarkers investigated in this study are neuropsychological tests (mini-mental state examination (MMSE) and delayed free recall), brain glucose metabolism ([ 18 F]FDG-PET), MRI volumetry of the hippocampus, EEG brain connectivity, cerebrospinal fluid (CSF) markers (p-tau, t-tau, Aβ1-42, Aβ1-42/1-40 ratio, Aβ1-42/p-Tau ratio) and APOE genotype. The baseline visit includes a full cognitive and neuropsychological evaluation, as well as the collection of clinical and socio-demographic information. Prognostic models will be developed using Cox regression, incorporating individual characteristics and biomarkers through stepwise selection. Model performance will be evaluated in terms of discrimination and calibration and subjected to internal validation using the bootstrapping procedure. The final model will be visually represented as a nomogram., Discussion: This paper contains a detailed description of the statistical analysis plan to ensure the reproducibility and transparency of the analysis. The prognostic model developed in this study aims to identify the population with MCI at higher risk of developing AD dementia, potentially eligible for drug prescriptions. The nomogram could provide a valuable tool for clinicians for risk stratification and early treatment decisions., Trial Registration: ClinicalTrials.gov NCT03834402. Registered on February 8, 2019., (© 2024. The Author(s).)

Background: In recent years, an increasing number of studies have examined the potential efficacy of cognitive training procedures in individuals with normal ageing and mild cognitive impairment (MCI)., Objective: The aims of this study were to (i) evaluate the efficacy of the cognitive Virtual Reality Rehabilitation System (VRRS) combined with anodal transcranial direct current stimulation (tDCS) applied to the left dorsolateral prefrontal cortex compared to placebo tDCS stimulation combined with VRRS and (ii) to determine how to prolong the beneficial effects of the treatment. A total of 109 subjects with MCI were assigned to 1 of 5 study groups in a randomized controlled trial design: (a) face-to-face (FTF) VRRS during anodal tDCS followed by cognitive telerehabilitation (TR) (clinic-atDCS-VRRS+Tele@H-VRRS); (b) FTF VRRS during placebo tDCS followed by TR (clinic-ptDCS-VRRS+Tele@H-VRRS); (c) FTF VRRS followed by cognitive TR (clinic-VRRS+Tele@H-VRRS); (d) FTF VRRS followed by at-home unstructured cognitive stimulation (clinic-VRRS+@H-UCS); and (e) FTF cognitive treatment as usual (clinic-TAU)., Results: An improvement in episodic memory was observed after the end of clinic-atDCS-VRRS ( p  < 0.001). We found no enhancement in episodic memory after clinic-ptDCS-VRRS or after clinic-TAU.Moreover, the combined treatment led to prolonged beneficial effects (clinic-atDCS-VRRS+Tele@H-VRRS vs. clinic-ptDCS-VRRS+Tele@H-VRRS: p  = 0.047; clinic-atDCS-VRRS+Tele@H-VRRS vs. clinic-VRRS+Tele@H-VRRS: p  = 0.06)., Discussion: The present study provides preliminary evidence supporting the use of individualized VRRS combined with anodal tDCS and cognitive telerehabilitation for cognitive rehabilitation., Clinical Trial Registration: https://clinicaltrials.gov/study/NCT03486704?term=NCT03486704&rank=1, NCT03486704., 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 © 2024 Manenti, Baglio, Pagnoni, Gobbi, Campana, Alaimo, Rossetto, Di Tella, Pagliari, Geviti, Bonfiglio, Calabrò, Cimino, Binetti, Quartarone, Bramanti, Cappa, Rossini and Cotelli.)

Background: The identification and staging of Alzheimer's Disease (AD) represent a challenge, especially in the prodromal stage of Mild Cognitive Impairment (MCI), when cognitive changes can be subtle. Worldwide efforts were dedicated to select and harmonize available neuropsychological instruments. In Italy, the Italian Network of Neuroscience and Neuro-Rehabilitation has promoted the adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB), collecting normative data from 433 healthy controls (HC). Here, we aimed to explore the ability of I-UDSNB to differentiate between a) MCI and HC, b) AD and HC, c) MCI and AD., Methods: One hundred thirty-seven patients (65 MCI, 72 AD) diagnosed after clinical-neuropsychological assessment, and 137 HC were included. We compared the I-UDSNB scores between a) MCI and HC, b) AD and HC, c) MCI and AD, with t-tests. To identify the test(s) most capable of differentiating between groups, significant scores were entered in binary logistic and in stepwise regressions, and then in Receiver Operating Characteristic curve analyses., Results: Two episodic memory tests (Craft Story and Five Words test) differentiated MCI from HC subjects; Five Words test, Semantic Fluency (vegetables), and TMT-part B differentiated AD from, respectively, HC and MCI., Conclusions: Our findings indicate that the I-UDSNB is a suitable tool for the harmonized and concise assessment of patients with cognitive decline, showing high sensitivity and specificity for the diagnosis of MCI and AD., (© 2024. The Author(s).)

Episodic memory shows the largest degree of age-related decline. Anodal transcranial Direct Current Stimulation (tDCS) can enhance episodic memory in aging but there is also evidence of response variability even when using identical stimulation parameters. To explore which inter-individual factors (i.e. age, education, encoding performance, cognitive reserve, tDCS group and timing of tDCS application) may directly and/or indirectly modulate verbal memory recall, we used data from our previous tDCS studies that showed enhanced episodic memory recall in 80 healthy older adults. In these studies we used the same paradigm and stimulation parameters but tDCS was applied during different memory stages. Memory recall was tested 48 hours and 30 days after encoding. Univariate regression models showed that tDCS group (Anodal vs. Sham) predicted memory recall, indicating higher scores in the Anodal group than in the Sham group. Encoding performance predicted memory recall in both tDCS groups. Multiple regression models revealed that cognitive reserve, measured with a life experience questionnaire, predicted memory recall only for the Anodal group. Higher cognitive reserve was linked to better memory recall. Accounting for individual differences in cognitive reserve at baseline helps to explain tDCS responsiveness. This knowledge may contribute to optimize its use in older adults., (© 2024. The Author(s).)

Primary Progressive Aphasia (PPA) is a syndrome due to different neurodegenerative disorders selectively disrupting language functions. PPA specialist care is underdeveloped. There are very few specialists (neurologists, psychiatrists, neuropsychologists, and speech therapists) and few hospital- or community-based services dedicated to the diagnosis and continuing care of people with PPA. Currently, healthcare systems struggle to provide adequate coverage of care that is too often fragmented, uncoordinated, and unresponsive to the needs of people with PPA and their families. Recently, attention has been gained by non-invasive brain stimulation techniques that allow a personalized treatment approach, such as transcranial Direct Current Stimulation (tDCS). The MAINSTREAM trial looks forward to introducing and evaluating therapeutic innovations such as tDCS coupled with language therapy in rehabilitation settings. A Multimodal Approach for Clinical Diagnosis and Treatment of Primary Progressive Aphasia, MAINSTREAM (ID: 3430931) was registered in the clinicaltrials.gov database (identifier: NCT05730023) on 15 February 2023.

Primary progressive aphasias (PPAs) are a group of neurodegenerative diseases mainly characterized by language impairment, and with variably presence of dysexecutive syndrome, behavioural disturbances and parkinsonism. Detailed knowledge of neurotransmitters impairment and its association with clinical features hold the potential to develop new tailored therapeutic approaches. In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of magnetic resonance imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission. We included 103 PPA patients and 80 age-matched healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in PPA patients (relative to HC) are correlated with specific neurotransmitter systems. As compared to HC, voxel-based brain changes in PPA were significantly associated with spatial distribution of serotonin, dopamine, and glutamatergic pathways (p < .05, False Discovery Rate corrected-corrected). Disease severity was negatively correlated with the strength of GMV colocalization of D1 receptors (p = .035) and serotonin transporter (p = .020). Moreover, we observed a significant negative correlation between positive behavioural symptoms, as measured with Frontal Behavioural Inventory, and GMV colocalization of D1 receptors (p = .007) and serotonin transporter (p < .001). This pilot study suggests that JuSpace is a helpful tool to indirectly assess neurotransmitter deficits in neurodegenerative dementias and may provide novel insight into disease mechanisms and associated clinical features., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Alzheimer's disease (AD) and frontotemporal dementia (FTD) show network dysfunctions linked with cognitive deficits. Within this framework, network abnormalities between AD and FTD show both convergent and divergent patterns. However, these functional patterns are far from being established and their relevance to cognitive processes remains to be elucidated., Methods: We investigated the relationship between cognition and functional connectivity of major cognitive networks in these diseases. Twenty-three bvFTD (age: 71±10), 22 AD (age: 72±6), and 20 controls (age: 72±6) underwent cognitive evaluation and resting-state functional MRI. Principal component analysis was used to describe cognitive variance across participants. Brain network connectivity was estimated with connectome analysis. Connectivity matrices were created assessing correlations between parcels within each functional network. The following cognitive networks were considered: default mode (DMN), dorsal attention (DAN), ventral attention (VAN), and frontoparietal (FPN) networks. The relationship between cognition and connectivity was assessed using a bootstrapping correlation and interaction analyses., Results: Three principal cognitive components explained more than 80% of the cognitive variance: the first component (cogPC1) loaded on memory, the second component (cogPC2) loaded on emotion and language, and the third component (cogPC3) loaded on the visuo-spatial and attentional domains. Compared to HC, AD and bvFTD showed impairment in all cogPCs (p<0.002), and bvFTD scored worse than AD in cogPC2 (p=0.031). At the network level, the DMN showed a significant association in the whole group with cogPC1 and cogPC2 and the VAN with cogPC2. By contrast, DAN and FPN showed a divergent pattern between diagnosis and connectivity for cogPC2. We confirmed these results by means of a multivariate analysis (canonical correlation)., Conclusions: A low-dimensional representation can account for a large variance in cognitive scores in the continuum from normal to pathological aging. Moreover, cognitive components showed both convergent and divergent patterns with connectivity across AD and bvFTD. The convergent pattern was observed across the networks primarily involved in these diseases (i.e., the DMN and VAN), while a divergent FC-cognitive pattern was mainly observed between attention/executive networks and the language/emotion cognitive component, suggesting the co-existence of compensatory and detrimental mechanisms underlying these components., (© 2022. The Author(s).)

In the human brain, physiological aging is characterized by progressive neuronal loss, leading to disruption of synapses and to a degree of failure in neurotransmission and information flow. However, there is increasing evidence to support the notion that the aged brain has a remarkable level of resilience (i.s. ability to reorganize itself), with the aim of preserving its physiological activity. It is therefore of paramount interest to develop objective markers able to characterize the biological processes underlying brain aging in the intact human, and to distinguish them from brain degeneration associated to age-related neurological progressive diseases like Alzheimer's disease. EEG, alone and combined with transcranial magnetic stimulation (TMS-EEG), is particularly suited to this aim, due to the functional nature of the information provided, and thanks to the ease with which it can be integrated in ecological scenarios including behavioral tasks. In this review, we aimed to provide the reader with updated information about the role of modern methods of EEG and TMS-EEG analysis in the investigation of physiological brain aging and Alzheimer's disease. In particular, we focused on data about cortical connectivity obtained by using readouts such graph theory network brain organization and architecture, and transcranial evoked potentials (TEPs) during TMS-EEG. Overall, findings in the literature support an important potential contribution of such neurophysiological techniques to the understanding of the mechanisms underlying normal brain aging and the early (prodromal/pre-symptomatic) stages of dementia., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. The study aims are to discuss the implementation of tES digital trials by performing a systematic scoping review and strategic process mapping, evaluate methodological aspects of tES digital trial designs, and provide Delphi-based recommendations for implementing digital trials using tES., Methods: We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided., Results: The main strengths/opportunities of tES were: (i) non-pharmacological nature (92% of agreement), safety of these techniques (80%), affordability (88%), and potential scalability (78%). As for weaknesses/threats, we listed insufficient supervision (76%) and unclear regulatory status (69%). Many issues related to methodological biases did not reach consensus. Device appraisal showed moderate digitalization readiness, with high safety and potential for trial implementation, but low connectivity., Conclusions: Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; with no consensus about aspects regarding methodological biases., Significance: We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials., (Copyright © 2022 International Federation of Clinical Neurophysiology. All rights reserved.)

Background: Non-fluent/agrammatic variant of Primary Progressive Aphasia (avPPA) is primarily characterized by language impairment due to atrophy of the inferior frontal gyrus and the insula cortex in the dominant hemisphere. The Screening for Aphasia in NeuroDegeneration (SAND) battery has been recently proposed as a screening tool for PPA, with several tasks designed to be specific for different language features. Applying multivariate approaches to neuroimaging data and verbal fluency tasks, Aachener Aphasie Test (AAT) naming subtest and SAND data may help in elucidating the neuroanatomical correlates of language deficits in avPPA., Objective: To investigate the neuroanatomical correlates of language deficits in avPPA using verbal fluency tasks, AAT naming subtest and SAND scores as proxies of brain structural imaging abnormalities., Methods: Thirty-one avPPA patients were consecutively enrolled and underwent extensive neuropsychological assessment and MRI scan. Raw scores of verbal fluency tasks, AAT naming subtest, and SAND subtests, namely living and non-living picture naming, auditory sentence comprehension, single-word comprehension, words and non-words repetition and sentence repetition, were used as proxies to explore structural (gray matter volume) neuroanatomical correlates. We assessed univariate (voxel-based morphometry, VBM) as well as multivariate (source-based morphometry, SBM) approaches. Age, gender, educational level, and disease severity were considered nuisance variables., Results: SAND picture naming (total, living and non-living scores) and AAT naming scores showed a direct correlation with the left temporal network derived from SBM. At univariate analysis, the left middle temporal gyrus was directly correlated with SAND picture naming (total and non-living scores) and AAT naming score. When words and non-words repetition (total score) was considered, a direct correlation with the left temporal network (SBM) and with the left fusiform gyrus (VBM) was also evident., Conclusion: Naming impairments that characterize avPPA are related to specific network-based involvement of the left temporal network, potentially expanding our knowledge on the neuroanatomical basis of this neurodegenerative condition., 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 Premi, Cotelli, Gobbi, Pagnoni, Binetti, Gadola, Libri, Mattioli, Pengo, Iraji, Calhoun, Alberici, Borroni and Manenti.)

Background: Neuropsychological testing plays a cardinal role in the diagnosis and monitoring of Alzheimer's disease. A major concern is represented by the heterogeneity of the neuropsychological batteries currently adopted in memory clinics and healthcare centers. The current study aimed to solve this issue., Methods: Following the initiative of the University of Washington's National Alzheimer's Coordinating Center (NACC), we presented the Italian adaptation of the Neuropsychological Test Battery of the Uniform Data Set (I-UDSNB). We collected data from 433 healthy Italian individuals and employed regression models to evaluate the impact of demographic variables on the performance, deriving the reference norms., Results: Higher education and lower age were associated with a better performance in the majority of tests, while sex affected only fluency tests and Digit Span Forward., Conclusions: The I-UDSNB offers a valuable and harmonized tool for neuropsychological testing in Italy, to be used in clinical and research settings., (© 2022. The Author(s).)

Patients suffering from major depressive disorder (MDD) experience difficulties in multiple cognitive and affective abilities. A large body of literature has argued that MDD patients show impaired executive functions (EFs) and deficits in theory of mind (ToM), the ability to infer the mental states of others. However, the relationship between ToM and EFs has been poorly investigated. The aim of this review is to provide an overview of studies that evaluated the association between ToM and EFs in patients with MDD diagnosis. A literature review was conducted to identify all published studies in which ToM and EFs measures were administered to individuals with MDD and in which the relationship between these two domains was investigated. Eleven studies were included, and for each study, we discussed the findings related to ToM, EFs, and the nature of the link between these two aspects. Most of the studies reported that patients with MDD, compared with healthy controls, showed significant impairments in both ToM and EFs abilities. Moreover, this review indicates the presence of a significant association between these two domains in MDD patients, supporting the evidences that executive functioning is important to perform ToM tasks. Although the results that emerged are interesting, the relationship between ToM and EFs in MDD needs further investigation., 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 Pagnoni, Gobbi, Alaimo, Campana, Rossi, Manenti, Balconi and Cotelli.)

Objective: This study aimed to assess whether non-invasive brain stimulation with transcranial alternating current stimulation at gamma-frequency (γ-tACS) applied over the precuneus can improve episodic memory and modulate cholinergic transmission by modulating cerebral rhythms in early Alzheimer's disease (AD)., Methods: In this randomized, double-blind, sham controlled, crossover study, 60 AD patients underwent a clinical and neurophysiological evaluation including assessment of episodic memory and cholinergic transmission pre and post 60 minutes treatment with γ-tACS targeting the precuneus or sham tACS. In a subset of 10 patients, EEG analysis and individualized modelling of electric field distribution were carried out. Predictors to γ-tACS efficacy were evaluated., Results: We observed a significant improvement in the Rey Auditory Verbal Learning (RAVL) test immediate recall (p < 0.001) and delayed recall scores (p < 0.001) after γ-tACS but not after sham tACS. Face-name associations scores improved with γ-tACS (p < 0.001) but not after sham tACS. Short latency afferent inhibition, an indirect measure of cholinergic transmission, increased only after γ-tACS (p < 0.001). ApoE genotype and baseline cognitive impairment were the best predictors of response to γ-tACS. Clinical improvement correlated with the increase in gamma frequencies in posterior regions and with the amount of predicted electric field distribution in the precuneus., Interpretation: Precuneus γ-tACS, able to increase γ-power activity on the posterior brain regions, showed a significant improvement of episodic memory performances, along with restoration of intracortical excitability measures of cholinergic transmission. Response to γ-tACS was dependent on genetic factors and disease stage. ANN NEUROL 2022;92:322-334., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The objective of the present study is to explore the brain resting state differences between Parkinson's disease (PD) patients and age- and gender-matched healthy controls (elderly) in terms of complexity of electroencephalographic (EEG) signals. One non-linear approach to determine the complexity of EEG is the entropy. In this pilot study, 28 resting state EEGs were analyzed from 13 PD patients and 15 elderly subjects, applying approximate entropy (ApEn) analysis to EEGs in ten regions of interest (ROIs), five for each brain hemisphere (frontal, central, parietal, occipital, temporal). Results showed that PD patients presented statistically higher ApEn values than elderly confirming the hypothesis that PD is characterized by a remarkable modification of brain complexity and globally modifies the underlying organization of the brain. The higher-than-normal entropy of PD patients may describe a condition of low order and consequently low information flow due to an alteration of cortical functioning and processing of information. Understanding the dynamics of brain applying ApEn could be a useful tool to help in diagnosis, follow the progression of Parkinson's disease, and set up personalized rehabilitation programs., (© 2022. The Author(s), under exclusive licence to American Aging Association.)

Brain state in the time preceding the task affects motor performance at single trial level. Aim of the study was to investigate, through a single trial analysis of the Power Spectral Density (PSD) of the cortical sources of EEG rhythms, whether there are EEG markers, which can predict trial-by-trial the subject's performance as measured by the reaction time (RT). 20 healthy adult volunteers performed a specific visuomotor task while continuously recorded with a 64 electrodes EEG. For each single trial, the PSD of the cortical sources of EEG rhythms was obtained from EEG data to cortical current density time series in 12 regions of interest at Brodmann areas level. Results showed a statistically significant increase of posterior and limbic alpha 1 and of frontal beta 2 power, and a reduction of frontal and limbic delta and of temporal alpha 1 power, during triggering stimulus presentation for better performance, namely faster responses. At single trial level, correlation analyses between RTs and significant PSD, revealed positive correlations in frontal delta, temporal alpha 1, and limbic delta bands, and negative ones in frontal beta 2, parietal alpha 1, and occipital alpha 1 bands. Furthermore, the subject's faster responses have been found as correlated with the similarity between the PSD values in parietal and occipital alpha 1. Predicting individual's performance at single trial level, might be extremely useful in the clinical context, since it could allow to launch rehabilitative therapies in the most efficient brain state, avoiding useless interventions., Competing Interests: Conflict of interestNone of the authors have potential conflicts of interest to be disclosed. Individual informed consent was obtained by subjects and the study was approved by the local Ethical Committee. Experimental procedures involved humans and were conformed to the Declaration of Helsinki and national guidelines., (© The Author(s), under exclusive licence to Springer Nature B.V. 2021.)

In recent years, applications of the network science to electrophysiological data have increased as electrophysiological techniques are not only relatively low cost, largely available on the territory and non-invasive, but also potential tools for large population screening. One of the emergent methods for the study of functional connectivity in electrophysiological recordings is graph theory: it allows to describe the brain through a mathematic model, the graph, and provides a simple representation of a complex system. As Alzheimer's and Parkinson's disease are associated with synaptic disruptions and changes in the strength of functional connectivity, they can be well described by functional connectivity analysis computed via graph theory. The aim of the present review is to provide an overview of the most recent applications of the graph theory to electrophysiological data in the two by far most frequent neurodegenerative disorders, Alzheimer's and Parkinson's diseases.

Background: Memory impairment is among one of the greatest cognitive complaints in midlife and in old age. Considering the importance of good memory functioning in everyday life, it is crucial to study interventions that can reduce the natural decline in this cognitive function. Transcranial Magnetic Stimulation (TMS) studies have demonstrated that the lateral prefrontal cortex (PFC) plays a causal role in enhancing episodic memory recall through reconsolidation. Using a similar paradigm with transcranial direct current stimulation (tDCS) over the left lateral PFC, facilitation effects were observed in delayed memory retrieval in older adults with subjective memory complaints (SMCs) and amnestic Mild Cognitive Impairment (aMCI). However, it remains unclear which potential factors (i.e., tDCS group, cognitive reserve, education level, diagnosis and encoding performance) directly and/or indirectly modulate the tDCS-induced memory reconsolidation effects., Methods: We reanalyzed data acquired in our previous tDCS studies with 22 SMC and 18 aMCI participants from the perspective of predicting delayed memory retrieval performance. These studies included a learning session on Day 1, a reactivation by a contextual reminder followed by 15 min of tDCS session on Day 2 (24 h after Day 1), and two retrieval sessions (free recall and recognition) tested on Days 3 and 30 (48 h and 30 Days after Day 1)., Results: Univariate models showed that tDCS group (sham vs. active) significantly predicted memory recognition (but not free recall), evidenced by higher scores in the active tDCS group than in sham group, confirming our previous results. Encoding performance and diagnosis (SMC vs. aMCI) significantly predicted memory retrieval, suggesting higher performances in individuals with SMC than in those with aMCI. Regarding cognitive reserve, higher leisure time activity subscores significantly predicted better memory recognition. Finally, multiple models did not show any tDCS group × predictor interaction effects, indicating that the effects of the predictors on retrieval occurred irrespective of tDCS group., Conclusion: Our results shed light on predicting factors of episodic memory retrieval in this reconsolidation paradigm in individuals with SMC and aMCI. The findings suggest that multifactorial interventions program may be most promising to slow cognitive decline and delay the onset of 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 Cotelli, Ferrari, Gobbi, Binetti, Manenti and Sandrini.)

The default mode (DMN) and the salience (SN) networks show functional hypo-connectivity in Alzheimer's disease (AD) and the behavioral variant of frontotemporal dementia (bvFTD), respectively, along with patterns of hyper-connectivity. We tested the clinical and neurobiological effects of noninvasive stimulation over these networks in 45 patients (AD and bvFTD) who received either anodal (target network: DMN in AD, SN in bvFTD) or cathodal stimulation (target network: SN in AD, DMN in bvFTD). We evaluated changes in clinical, cognitive, functional and structural connectivity, and perfusion measures. In both patient groups, cathodal stimulation was followed by behavioral improvement, whereas anodal stimulation led to cognitive improvement. Neither functional connectivity nor perfusion showed significant effects. A significant interaction between DMN and SN functional connectivity changes and stimulation protocol was reported in AD. These results suggest a protocol-dependent response, whereby the protocols studied show divergent effects on cognitive and clinical measures, along with a divergent modulatory pattern of connectivity in AD., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Noninvasive brain stimulation techniques (NiBS) have gathered substantial interest in the study of dementia, considered their possible role in help defining diagnostic biomarkers of altered neural activity for early disease detection and monitoring of its pathophysiological course, as well as for their therapeutic potential of boosting residual cognitive functions. Nevertheless, current approaches suffer from some limitations. In this study, we review and discuss experimental NiBS applications that might help improve the efficacy of future NiBS uses in Alzheimer's Disease (AD), including perturbation-based biomarkers for early diagnosis and disease tracking, solutions to enhance synchronization of oscillatory electroencephalographic activity across brain networks, enhancement of sleep-related memory consolidation, image-guided stimulation for connectome control, protocols targeting interneuron pathology and protein clearance, and finally hybrid-brain models for in-silico modeling of AD pathology and personalized target selection. The present work aims to stress the importance of multidisciplinary, translational, model-driven interventions for precision medicine approaches in AD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is the most common neurodegenerative disorder in elderly subjects. Recent studies verified the effects of cognitive training combined with repetitive transcranial magnetic stimulation (rTMS-COG) in AD patients. Here, we analyzed neuropsychological and neurophysiological data, derived from electroencephalography (EEG), to evaluate the effects of a 6-week protocol of rTMS-COG in 72 AD. We designed a randomized, double-blind, sham-controlled trial to evaluate efficacy of rTMS on 6 brain regions obtained by an individual MRI combined with COG related to brain areas to stimulate (i.e., syntax and grammar tasks, comprehension of lexical meaning and categorization tasks, action naming, object naming, spatial memory, spatial attention). Patients underwent neuropsychological and EEG examination before (T 0 ), after treatment (T 1 ), and after 40 weeks (T 2 ), to evaluate the effects of rehabilitation therapy. "Small World" (SW) graph approach was introduced allowing us to model the architecture of brain connectivity in order to correlate it with cognitive improvements. We found that following 6 weeks of intensive daily treatment the immediate results showed an improvement in cognitive scales among AD patients. SW present no differences before and after the treatment, whereas a crucial SW modulation emerges at 40-week follow-up, emphasizing the importance of rTMS-COG rehabilitation treatment for AD. Additional results demonstrated that the delta and alpha1 SW seem to be diagnostic biomarkers of AD, whereas alpha2 SW might represent a prognostic biomarker of cognitive recovery. Derived EEG parameters can be awarded the role of diagnostic and predictive biomarkers of AD progression, and rTMS-COG can be regarded as a potentially useful treatment for AD., (© 2021. The Author(s), under exclusive licence to American Aging Association.)

Background: Physiological and pathological brain aging plays a central role in brain network modulation. The aim of the present article was to assess the stability of a proposed method for evaluation of small-world (SW) characteristics for the study of the human connectome. Subjects and Methods: Eighty subjects were recruited: 36 young healthy controls, 32 elderly healthy controls, and 12 patients affected by Alzheimer's disease (AD). Electroencephalograms (EEGs) were recorded during six separate sessions (480 recordings) at an average intersession interval of 3.8 ± 0.2 days. We applied graph theory functions to the weighted and undirected networks obtained by the lagged linear coherence estimated by exact low-resolution electromagnetic tomography (eLORETA). We explored the following frequency bands: delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), beta 2 (20-30 Hz), and gamma (30-40 Hz). Results: The proposed method for evaluation of SW characteristics exhibited good reproducibility and stability. Furthermore, results showed the pattern, Young>Elderly>AD, in low-frequency delta and theta bands and vice versa in the higher alpha band. Finally, a correlation with age was confirmed in healthy subjects, showing that the older the age, the higher the SW values for alpha 2. Discussion: Evidences from the present study confirm the stability of the SW index and suggest that the analysis of connectivity patterns evaluated from EEGs can be supported by the graph theory. The proposed method for evaluation of SW characteristics has shown good reproducibility and stability. This technique, applied to patient data, could provide more information on the pathophysiological processes underlying age-related brain disconnection, as well as on administration of rehabilitation treatments at the right time, which could allow patients to avoid unnecessary interventions. Impact statement The graph analysis tools described in this study represent an interesting approach to study the distinctive characteristics of physiological aging by focusing on functional connectivity networks. The proposed method for evaluation of small-world characteristics has shown good reproducibility and stability. This technique, applied to patient data, could provide more information on the pathophysiological processes underlying age-related brain disconnection, as well as on delivery of rehabilitation treatments at the right time, which could allow patients to avoid unnecessary interventions.

Neuro-plasticity describes the ability of the brain in achieving novel functions, either by transforming its internal connectivity, or by changing the elements of which it is made, meaning that, only those changes, that affect both structural and functional aspects of the system, can be defined as "plastic." The concept of plasticity can be applied to molecular as well as to environmental events that can be recognized as the basic mechanism by which our brain reacts to the internal and external stimuli. When considering brain plasticity within a clinical context-that is the process linked with changes of brain functions following a lesion- the term "reorganization" is somewhat synonymous, referring to the specific types of structural/functional modifications observed as axonal sprouting, long-term synaptic potentiation/inhibition or to the plasticity related genomic responses. Furthermore, brain rewires during maturation, and aging thus maintaining a remarkable learning capacity, allowing it to acquire a wide range of skills, from motor actions to complex abstract reasoning, in a lifelong expression. In this review, the contribution on the "neuroplasticity" topic coming from advanced analysis of EEG rhythms is put forward., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Importance: Thrombosis with thrombocytopenia syndrome (TTS) has been reported after vaccination with the SARS-CoV-2 vaccines ChAdOx1 nCov-19 (Oxford-AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson)., Objective: To describe the clinical characteristics and outcome of patients with cerebral venous sinus thrombosis (CVST) after SARS-CoV-2 vaccination with and without TTS., Design, Setting, and Participants: This cohort study used data from an international registry of consecutive patients with CVST within 28 days of SARS-CoV-2 vaccination included between March 29 and June 18, 2021, from 81 hospitals in 19 countries. For reference, data from patients with CVST between 2015 and 2018 were derived from an existing international registry. Clinical characteristics and mortality rate were described for adults with (1) CVST in the setting of SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia, (2) CVST after SARS-CoV-2 vaccination not fulling criteria for TTS, and (3) CVST unrelated to SARS-CoV-2 vaccination., Exposures: Patients were classified as having TTS if they had new-onset thrombocytopenia without recent exposure to heparin, in accordance with the Brighton Collaboration interim criteria., Main Outcomes and Measures: Clinical characteristics and mortality rate., Results: Of 116 patients with postvaccination CVST, 78 (67.2%) had TTS, of whom 76 had been vaccinated with ChAdOx1 nCov-19; 38 (32.8%) had no indication of TTS. The control group included 207 patients with CVST before the COVID-19 pandemic. A total of 63 of 78 (81%), 30 of 38 (79%), and 145 of 207 (70.0%) patients, respectively, were female, and the mean (SD) age was 45 (14), 55 (20), and 42 (16) years, respectively. Concomitant thromboembolism occurred in 25 of 70 patients (36%) in the TTS group, 2 of 35 (6%) in the no TTS group, and 10 of 206 (4.9%) in the control group, and in-hospital mortality rates were 47% (36 of 76; 95% CI, 37-58), 5% (2 of 37; 95% CI, 1-18), and 3.9% (8 of 207; 95% CI, 2.0-7.4), respectively. The mortality rate was 61% (14 of 23) among patients in the TTS group diagnosed before the condition garnered attention in the scientific community and 42% (22 of 53) among patients diagnosed later., Conclusions and Relevance: In this cohort study of patients with CVST, a distinct clinical profile and high mortality rate was observed in patients meeting criteria for TTS after SARS-CoV-2 vaccination.

Parkinson's disease (PD) is the second most common neurodegenerative disease in the elderly population. Similarly to other neurodegenerative diseases, the early diagnosis of PD is quite difficult. The current pilot study aimed to explore the differences in brain connectivity between PD and NOrmal eLDerly (Nold) subjects to evaluate whether connectivity analysis may speed up and support early diagnosis. A total of 26 resting state EEGs were analyzed from 13 PD patients and 13 age-matched Nold subjects, applying to cortical reconstructions the graph theory analyses, a mathematical representation of brain architecture. Results showed that PD patients presented a more ordered structure at slow-frequency EEG rhythms (lower value of SW) than Nold subjects, particularly in the theta band, whereas in the high-frequency alpha, PD patients presented more random organization (higher SW) than Nold subjects. The current results suggest that PD could globally modulate the cortical connectivity of the brain, modifying the functional network organization and resulting in motor and non-motor signs. Future studies could validate whether such an approach, based on a low-cost and non-invasive technique, could be useful for early diagnosis, for the follow-up of PD progression, as well as for evaluating pharmacological and neurorehabilitation treatments.

Background: Primary progressive aphasia (PPA) is a neurodegenerative disorder characterized by a gradual, insidious and progressive loss of language abilities, with naming difficulties being an early and persistent impairment common to all three variants. In the absence of effective pharmacological treatments and given the progressive nature of the disorder, in the past few decades, many studies have investigated the effectiveness of language training to minimize the functional impact of word-finding difficulties in daily life., Main Body: We review language treatments most commonly used in clinical practice among patients with different variants of PPA, with a focus on the enhancement of spoken and written naming abilities. Generalization of gains to the ability to name untrained stimuli or to other language abilities and the maintenance of these results over time are also discussed. Forty-eight studies were included in this literature review, identifying four main types of language treatment: a) lexical retrieval treatment, b) phonological and/or orthographic treatment, c) semantic treatment, and d) a multimodality approach treatment. Overall, language training is able to induce immediate improvements of naming abilities in all variants of PPA. Moreover, despite the large variability among results, generalization and long-term effects can be recorded after the training. The reviewed studies also suggest that one factor that determines the choice of a particular approach is the compromised components of the lexical/semantic processing system., Conclusion: The majority of studies have demonstrated improvements of naming abilities following language treatments. Given the progressive nature of PPA, it is essential to apply language treatment in the early stages of the disease., (© 2021. The Author(s).)

Background: In recent years, emphasis has been placed on cognitive enhancement to stimulate cognitive abilities and prevent functional decline. Considering that traditional face-to-face interventions can be very expensive and are not accessible to all individuals, the need to transfer care from the clinic to the patient's home is evident. In this regard, cognitive tele-enhancement interventions have received increased attention. Aim: The aim of this review was to provide an overview of protocols that apply remotely controlled cognitive training with individualized feedback on performance by the therapist in healthy older adults or participants with subjective memory complaints. Methods: Out of 35 articles assessed for eligibility, eight studies were identified. Of the selected studies, five included cognitively healthy older adults, while three included participants with subjective memory complaints. Results: Most of the reviewed studies showed beneficial effects of cognitive tele-enhancement interventions, reporting improvements in memory, sustained attention, working memory, executive functions, and language abilities. Moreover, reductions in anxiety and depression symptomatology levels, as well as in subjective memory difficulties, were described in some of the studies. Conclusions: Cognitive tele-enhancement treatment could be a good alternative to face-to-face intervention. This literature review highlights the importance of applying preventive cognitive interventions to subjects with initial subjective memory complaints. Remote modalities seem to facilitate the application of such interventions., 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 © 2021 Alaimo, Campana, Stoppelli, Gobbi, Baglio, Rossetto, Binetti, Zanetti, Manenti and Cotelli.)

Aging is a multifactorial physiological process characterized by the accumulation of degenerative processes impacting on different brain functions, including the cognitive one. A tool largely employed in the investigation of brain networks is the electroencephalogram (EEG). Given the cerebral complexity and dynamism, many non-linear approaches have been applied to explore age-related brain electrical activity modulation detected by the EEG: one of them is the entropy, which measures the disorder of a system. The present study had the aim to investigate aging influence on brain dynamics applying Approximate Entropy (ApEn) parameter to resting state EEG data of 68 healthy adult participants, divided with respect to their age in two groups, focusing on several specialized brain regions. Results showed that elderly participants present higher ApEn values than younger participants in the central, parietal and occipital areas, confirming the hypothesis that aging is characterized by an evolution of brain dynamics. Such findings may reflect a reduced synchronization of the neural networks cyclic activity, due to the reduction of cerebral connections typically found in aging process. Understanding the dynamics of brain networks by applying the entropy parameter could be useful for developing appropriate and personalized rehabilitation programs and for future studies on neurodegenerative diseases., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The observation of neurological patients showing selective impairments for specific conceptual categories contributed in the development of semantic memory theories. Here, we studied two patients (P01, P02), affected, respectively, by the semantic variant of Primary Progressive Aphasia (sv-PPA) and Cortico-Basal Syndrome (CBS). An implicit lexical decision task, including concrete (animals, tools) and abstract (emotions, social, quantity) concepts, was administered to patients and healthy controls.P01 and P02 showed an abolished priming effect for social and quantity-related concepts, respectively. This double dissociation suggests a role of different brain areas in representing specific abstract categories, giving insights for current semantic memory theories.

Objective: To assess whether exposure to non-invasive brain stimulation with transcranial alternating current stimulation at γ frequency (γ-tACS) applied over Pz (an area overlying the medial parietal cortex and the precuneus) can improve memory and modulate cholinergic transmission in mild cognitive impairment due to Alzheimer's disease (MCI-AD)., Methods: In this randomized, double-blind, sham controlled, crossover pilot study, participants were assigned to a single 60 min treatment with exposure to γ-tACS over Pz or sham tACS. Each subject underwent a clinical evaluation including assessment of episodic memory pre- and post-γ-tACS or sham stimulation. Indirect measures of cholinergic transmission evaluated using transcranial magnetic stimulation (TMS) pre- and post-γ-tACS or sham tACS were evaluated., Results: Twenty MCI-AD participants completed the study. No tACS-related side effects were observed, and the intervention was well tolerated in all participants. We observed a significant improvement at the Rey auditory verbal learning (RAVL) test total recall (5.7 [95% CI, 4.0 to 7.4], p < 0.001) and long delayed recall scores (1.3 [95% CI, 0.4 to 2.1], p = 0.007) after γ-tACS but not after sham tACS. Face-name associations scores improved during γ-tACS (4.3 [95% CI, 2.8 to 5.8], p < 0.001) but not after sham tACS. Short latency afferent inhibition, an indirect measure of cholinergic transmission evaluated with TMS, increased only after γ-tACS (0.31 [95% CI, 0.24 to 0.38], p < 0.001) but not after sham tACS., Conclusions: exposure to γ-tACS over Pz showed a significant improvement of memory performances, along with restoration of intracortical connectivity measures of cholinergic neurotransmission, compared to sham tACS., Competing Interests: Declaration of competing interest Alberto Benussi, MD was partially supported by the Airalzh-AGYR2020; and is listed as an inventor on issued and pending patents on the use of non-invasive brain stimulation for the differential diagnosis of dementia and to increase cognitive functions in patients with neurodegenerative disorders. Maria Sofia Cotelli, MD received financial support by the Italian Ministry of Health (Ricerca Corrente). Emiliano Santarnecchi, PsyD, PhD: is consultant for Neuroelectrics and Neurocare Group Italy. Alvaro Pascual-Leone, MD, PhD is a co-founder of Linus Health and TI Solutions AG; serves on the scientific advisory boards for Starlab Neuroscience, Neuroelectrics, Magstim Inc., Nexstim, Cognito, and MedRhythms; and is listed as an inventor on several issued and pending patents on the real-time integration of noninvasive brain stimulation with electroencephalography and magnetic resonance imaging. Dr. Pascual-Leone was partly supported by the National Institutes of Health (R01MH100186, R21AG051846, R01MH111875, R01MH115949, R01 MH117063, R24AG06142, and P01 AG031720), the National Science Foundation, DARPA, and the Barcelona Brain Health Initiative (La Caixa and Institute Guttmann). Barbara Borroni, MD, is listed as an inventor on issued and pending patents on the use of non-invasive brain stimulation for the differential diagnosis of dementia and to increase cognitive functions in patients with neurodegenerative disorders. Valentina Cantoni, MS, Maria Cotelli, PhD, Chiara Brattini, MS, Abhishek Datta, PhD, Chris Thomas, BS, report no disclosures., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective. In modern neuroscience, the underlying mechanisms of the elaboration and reaction to different kinds of stimuli of the brain hemispheres remain still very challenging to understand, together with the possibility to anticipate certain behaviors to improve the performance. Approach. The purpose of the present study was to investigate the brain rhythms characteristics of electroencephalographic (EEG) recordings and in particular, their interhemispheric differences in resting state condition before a visuo-motor task in a population of healthy adults. During the task, subjects were asked to react to a sequence of visual cues as quick as possible. The reaction times (RTs) to the task were measured, collected and correlated with the EEG signals recorded in a resting state condition immediately preceding the task. The EEG data were analyzed in the space of cortical sources of EEG rhythms by the computation of the global spectra power density (GSPD) in the left and in the right hemisphere, and of an index of brain laterality ( L ). Main results. The results showed a negative correlation between the RTs and the GSPD in the central areas in the left and in the right hemisphere in both eyes open (EO) and eyes closed (EC) conditions. A close to significant and negative correlation was found in the parietal areas. Furthermore, RTs negatively correlated with L in the central areas in EC condition. The results showed a negative correlation between the RTs and the GSPD in the central areas in the left and in the right hemisphere in both EO and EC conditions. Significance. The correlations between the brain activity before a task and the RTs to the task can represent an interesting tool for exploring the brain state characterization for the upcoming tasks performance., (© 2021 IOP Publishing Ltd.)

Aim of the study was to evaluate the influence of the EEG channels number on the brain networks' analysis, to establish whether and how much higher density EEG actually contributes to add supplementary information to brain networks analyses. 59 electrodes EEGs were recorded in 20 healthy subjects in eyes open and closed condition. For each condition, we analyzed the recording dataset of 59 channels, and three sub-datasets obtained by the selection of 44, 30, 19 channels from the 59 ones. Then we computed the EEG sources of current density and evaluated the SW index in the four EEGs data montages. Results showed that in the eyes open condition the number of recording channels influences more the SW index modulation respect that in the eyes closed condition. Conversely, in the eyes closed condition the brain activity is less affected by specific brain regions' activations and the signal's generators produced not significant variations on EEG data and consequently the small world network measure is not affected by the recording channels number. We can conclude that in the eyes closed condition, the 19 EEG channels is an acceptable montage to study brain networks' modulations, to both detect the higher and the lower brain waves' frequencies., (Copyright © 2020. Published by Elsevier Inc.)

Background: Most common progressive brain diseases in the elderly are Alzheimer's disease (AD) and vascular dementia (VaD). They present with relatively similar clinical symptoms of cognitive decline, but the underlying pathophysiological mechanisms are different., Objective: The aim is to explore the brain connectivity differences between AD and VaD patients compared to mild cognitive impairment (MCI) and normal elderly (Nold) subjects applying graph theory, in particular the Small World (SW) analysis., Methods: 274 resting state EEGs were analyzed in 100 AD, 80 MCI, 40 VaD, and 54 Nold subjects. Graph theory analyses were applied to undirected and weighted networks obtained by lagged linear coherence evaluated by eLORETA tool., Results: VaD and AD patients presented more ordered low frequency structure (lower value of SW) than Nold and MCI subjects, and more random organization (higher value of SW) in low and high frequency alpha rhythms. Differences between patients have been found in high frequency alpha rhythms in VaD (higher value of SW) with respect to AD, and in theta band with a trend which is more similar to MCI and Nold than to AD. MCI subjects presented a network organization which is intermediate, in low frequency bands, between Nold and patients., Conclusion: Graph theory applied to EEG data has proved very useful in identifying differences in brain network patterns in subjects with dementia, proving to be a valid tool for differential diagnosis. Future studies will aim to validate this method to diagnose especially in the early stages of the disease and at single subject level.

Coronavirus disease 2019 (COVID-19) infection has the potential for targeting the central nervous system, and several neurological symptoms have been reported in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We describe a 48-year-old Caucasian woman with SARS-CoV-2 infection followed by the onset of word finding difficulties, effortful speech along with prosody distortion, in the context of spared semantic and syntactic abilities. The clinical picture, perceived as foreign accent syndrome (FAS), was not associated with structural and functional imaging changes or neurophysiological assessment abnormalities. We suggest that FAS, herein perceived as a regional accent syndrome, should be considered a possible additional neurological manifestation of SARS-CoV-2.

Age at symptom onset (AAO) underlies different Alzheimer's disease (AD) clinical variants: late-onset AD (LOAD) is characterized by memory deficits, while early-onset AD (EOAD) presents predominantly with non-memory symptoms. The involvement of different neural networks may explain these distinct clinical phenotypes. In this study, we tested the hypothesis of an early and selective involvement of neural networks based on AAO in AD. Twenty memory clinic patients with prodromal AD (i.e., mild cognitive impairment with an AD-like cerebrospinal fluid profile) and 30 healthy controls underwent a cognitive evaluation and a resting state functional MRI exam. Independent component analysis was performed to assess functional connectivity (FC) in the following networks: default mode, frontoparietal, limbic, visual, and sensorimotor. Patients were stratified into late-onset (pLOAD) and early-onset (pEOAD) prodromal AD according to the AAO and controls were stratified into younger and older groups accordingly. Decreased FC within the default mode and the limbic networks was observed in pLOAD, while pEOAD showed lower FC in the frontoparietal and visual networks. The sensorimotor network did not show differences between groups. A significant association was found between memory and limbic network FC in pLOAD, and between executive functions and frontoparietal network FC in pEOAD, although the latter association did not survive multiple comparison correction. Our findings indicate that aberrant connectivity in memory networks is associated with pLOAD, while networks underlying executive and visuo-spatial functions are affected in pEOAD. These findings are in line with the hypothesis that the pathophysiological mechanisms underlying EOAD and LOAD are distinct.

Background: In recent years, the potential usefulness of cognitive training procedures in normal aging and mild cognitive impairment (MCI) have received increased attention., Objective: The main aim of this study was to evaluate the efficacy of the face-to-face cognitive virtual reality rehabilitation system (VRRS) and to compare it to that of face-to-face cognitive treatment as usual for individuals with MCI. Moreover, we assessed the possibility of prolonging the effects of treatment with a telerehabilitation system., Methods: A total of 49 subjects with MCI were assigned to 1 of 3 study groups in a randomized controlled trial design: (a) those who received face-to-face cognitive VRRS (12 sessions of individualized cognitive rehabilitation over 4 weeks) followed by telerehabilitation (36 sessions of home-based cognitive VRRS training, three sessions for week); (b) those who received face-to-face cognitive VRRS followed by at-home unstructured cognitive stimulation (36 sessions of home-based unstructured cognitive stimulation, three sessions for week); and (c) those who received face-to-face cognitive treatment as usual (12 sessions of face-to-face cognitive treatment as usual)., Results: An improvement in memory, language and visuo-constructional abilities was observed after the end of face-to-face VRRS treatment compared to face-to-face treatment as usual. The application of home-based cognitive VRRS telerehabilitation seems to induce more maintenance of the obtained gains than home-based unstructured stimulation., Discussion: The present study provides preliminary evidence in support of individualized VRRS treatment and telerehabilitation delivery for cognitive rehabilitation and should pave the way for future studies aiming at identifying optimal cognitive treatment protocols in subjects with MCI., Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03486704., (Copyright © 2020 Manenti, Gobbi, Baglio, Macis, Ferrari, Pagnoni, Rossetto, Di Tella, Alemanno, Cimino, Binetti, Iannaccone, Bramanti, Cappa and Cotelli.)

Human brain, a dynamic complex system, can be studied with different approaches, including linear and nonlinear ones. One of the nonlinear approaches widely used in electroencephalographic (EEG) analyses is the entropy, the measurement of disorder in a system. The present study investigates brain networks applying approximate entropy (ApEn) measure for assessing the hemispheric EEG differences; reproducibility and stability of ApEn data across separate recording sessions were evaluated. Twenty healthy adult volunteers were submitted to eyes-closed resting EEG recordings, for 80 recordings. Significant differences in the occipital region, with higher values of entropy in the left hemisphere than in the right one, show that the hemispheres become active with different intensities according to the performed function. Besides, the present methodology proved to be reproducible and stable, when carried out on relatively brief EEG epochs but also at a 1-week distance in a group of 36 subjects. Nonlinear approaches represent an interesting probe to study the dynamics of brain networks. ApEn technique might provide more insight into the pathophysiological processes underlying age-related brain disconnection as well as for monitoring the impact of pharmacological and rehabilitation treatments.

In the present study, we aim at investigating whether education modulates dynamical properties of time-varying whole-brain network connectivity (the chronnectome) in frontotemporal dementia (FTD) at a given level of symptom severity. Dynamic connectivity parameters were evaluated in 128 patients with FTD using independent component analysis, sliding-time window correlation, and k-means approach to resting state-magnetic resonance imaging data. We evaluated the relationship between education, a proxy measure of cognitive reserve, and 4 indexes of metastate dynamic connectivity: (1) the number of distinct metastates a patient passes through, (2) the number of switches from one metastate to another, (3) the span of the realized metastates, and (4) the total distance traveled in the state space. We found a significant inverse correlation between years of education and the 4 indexes of metastate dynamic fluidity (all p-values ≤ 0.03, false discovery rate-corrected). This study suggests that patients with FTD with higher education but comparable clinical severity show more global functional brain impairment, suggesting that patients with higher cognitive reserve can cope with more global brain fluidity reduction., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Episodic memory is impaired in amnestic mild cognitive impairment (aMCI), which is posited as a potential prodromal form of Alzheimer's disease. Reactivated existing memories become sensitive to modification during reconsolidation. There is evidence that the lateral prefrontal cortex (PFC) plays causal role in episodic memory reconsolidation. Transcranial direct current stimulation (tDCS) applied to the PFC after a contextual reminder enhanced episodic memory performance up to 1 month, conceivably through reconsolidation, in older adults with subjective memory complaints, a condition that may represent a "pre-mild cognitive impairment" stage. The aim of this pilot study was to test the effect of PFC-tDCS (anode over left lateral PFC, cathode over right supraorbital area) after a contextual reminder on episodic memory in older adults with aMCI., Method: Older adults with aMCI learned a list of words. Twenty-four hours later, tDCS (Active or Sham) was applied after a contextual reminder. Memory retrieval (free recall and recognition) was tested 48 hrs and 1 month after the learning session., Results: Active tDCS enhanced recognition memory relative to Sham stimulation., Discussion: Modulating reconsolidation with PFC-tDCS might be a novel intervention to enhance episodic memories in aMCI., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Memory for personally-relevant past events (episodic memory) is critical for activities of daily living. Decline in this type of declarative long-term memory is a common characteristic of healthy ageing, a process accelerated in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Transcranial electrical stimulation (tES) has been used as a strategy to ameliorate episodic memory. Here, we critically review studies investigating whether tES may improve episodic memory in physiological and pathological ageing. Most of the studies suggest that tES over the prefrontal or temporoparietal cortices can have a positive effect on episodic memory, but the transfer to improvement of execution of daily living activities is still unknown. Further work is needed to better understand the mechanisms underlying the effects of stimulation, combine tES with neuroimaging and optimizing the dosing of stimulation. Future studies should also investigate the optimal timing of stimulation and the combination with medications to induce long-lasting beneficial effects in pathological ageing. More open science efforts should be done to improve rigor and reliability of tES in ageing research., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In Severe Mental Disorders (SMDs) the most important cognitive deficits involve the Executive Functions (EFs). In this study we examined the association between EFs and aggressive behaviour in outpatients with SMDs. We included a total of 247 outpatients divided into two groups: 'cases', patients with a history of violence (N=126) and 'non-violent' (N=121). We compared their EFs score and then categorized the participants into four groups (Pathological Non-Violent comparison group; Non-Pathological Non-Violent comparison group; Pathological Violent cases and Non-Pathological Violent cases), based on the scores of a subtest assessing processing speed (i.e., Symbol-coding task) of the Brief Assessment of Cognition in Schizophrenia (BACS). We followed the 4 groups during a 1-year follow-up (FU) monitoring violent behaviour with the Modified Overt Aggression Scale (MOAS). According to the classification based on the BACS-Symbol Coding Task we found no statistically significant differences between subgroups in MOAS scores. We only found that the trend curve for PV was almost consistently over the other group curves in the MOAS 'aggression against people'. Our results suggested a worse performance in the violent compared to non-violent group in EFs. Despite this evidence, the score on the processing speed task was not associated with aggressive behaviour during FU., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Frontotemporal dementia (FTD) is a progressive disease for which no curative treatment is currently available. We aimed to determine whether transcranial direct current stimulation (tDCS) can modulate intracortical connectivity and improve cognition in symptomatic FTD patients and presymptomatic FTD subjects., Methods: We performed a double-blind, randomized, sham-controlled trial with anodal tDCS or sham stimulation over the left prefrontal cortex in 70 participants (15 presymptomatic and 55 symptomatic FTD)., Results: We observed a significant increase of intracortical connectivity (short interval intracortical inhibition and facilitation) and improvement in clinical scores and behavioral disturbances in both symptomatic FTD patients and presymptomatic carriers after real tDCS but not after sham stimulation., Discussion: A 2-weeks' treatment with anodal left prefrontal tDCS improves symptoms and restores intracortical inhibitory and excitatory circuits in both symptomatic FTD patients and presymptomatic carriers. tDCS might represent a promising future therapeutic and rehabilitative approach in patients with FTD., Competing Interests: A. Benussi, V. Dell'Era, M. Cosseddu,V. Cantoni, M.S. Cotelli, M. Cotelli, R. Manenti, L. Benussi, C. Brattini, A. Alberici, B. Borroni, report no disclosures relevant to the manuscript., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Neurodegenerative processes of various types of dementia start years before symptoms, but the presence of a "neural reserve", which continuously feeds and supports neuroplastic mechanisms, helps the aging brain to preserve most of its functions within the "normality" frame. Mild cognitive impairment (MCI) is an intermediate stage between dementia and normal brain aging. About 50% of MCI subjects are already in a stage that is prodromal-to-dementia and during the following 3 to 5 years will develop clinically evident symptoms, while the other 50% remains at MCI or returns to normal. If the risk factors favoring degenerative mechanisms are modified during early stages (i.e., in the prodromal), the degenerative process and the loss of abilities in daily living activities will be delayed. It is therefore extremely important to have biomarkers able to identify-in association with neuropsychological tests-prodromal-to-dementia MCI subjects as early as possible. MCI is a large (i.e., several million in EU) and substantially healthy population; therefore, biomarkers should be financially affordable, largely available and non-invasive, but still accurate in their diagnostic prediction. Neurodegeneration initially affects synaptic transmission and brain connectivity; methods exploring them would represent a 1st line screening. Neurophysiological techniques able to evaluate mechanisms of synaptic function and brain connectivity are attracting general interest and are described here. Results are quite encouraging and suggest that by the application of artificial intelligence (i.e., learning-machine), neurophysiological techniques represent valid biomarkers for screening campaigns of the MCI population., Competing Interests: Appendix A

Transcranial Direct Current Stimulation (tDCS) has become an increasingly promising tool for understanding the relationship between brain and behavior. The purpose of this study was to investigate whether the magnitude of sex- and age-related tDCS effects previously found in the medial prefrontal cortex (mPFC) during a Theory of Mind (ToM) task correlates with social cognition performance; in particular, we explored whether different patterns of activity would be detected in high- and low-performing participants. For this, young and elderly, male and female participants were categorized as a low- or high-performer according to their score on the Reading the Mind in the Eyes task. Furthermore, we explored whether sex- and age-related effects associated with active tDCS on the mPFC were related to cognitive functioning. We observed the following results: (i) elderly participants experience a significant decline in ToM performance compared to young participants; (ii) low-performing elderly females report slowing of reaction time when anodal tDCS is applied over the mPFC during a ToM task; and (iii) low-performing elderly females are characterized by lower scores in executive control functions, verbal fluency and verbal short-term memory. The relationship between tDCS results and cognitive functioning is discussed in light of the neuroscientific literature on sex- and age-related differences.

Moving from the hypothesis that aging processes modulate brain connectivity networks, 170 healthy elderly volunteers were submitted to EEG recordings in order to define age-related normative limits. Graph theory functions were applied to exact low-resolution electromagnetic tomography on cortical sources in order to evaluate the small-world parameter as a representative model of network architecture. The analyses were carried out in the whole brain-as well as for the left and the right hemispheres separately-and in three specific resting state subnetworks defined as follows: attentional network (AN), frontal network (FN), and default mode network (DMN) in the EEG frequency bands (delta, theta, alpha 1, alpha 2, beta 1, beta 2, gamma). To evaluate the stability of the investigated parameters, a subgroup of 32 subjects underwent three separate EEG recording sessions in identical environmental conditions after a few days interval. Results showed that the whole right/left hemispheric evaluation did not present side differences, but when individual subnetworks were considered, AN and DMN presented in general higher SW in low (delta and/or theta) and high (gamma) frequency bands in the left hemisphere, while for FN, the alpha 1 band was lower in the left with respect to the right hemisphere. It was also evident the test-retest reliability and reproducibility of the present methodology when carried out in clinically stable subjects.Evidences from the present study suggest that graph theory represents a reliable method to address brain connectivity patterns from EEG data and is particularly suitable to study the physiological impact of aging on brain functional connectivity networks.

Aim of this study was to explore the EEG functional connectivity in amnesic mild cognitive impairments (MCI) subjects with multidomain impairment in order to characterize the Default Mode Network (DMN) in converted MCI (cMCI), which converted to Alzheimer's disease (AD), compared to stable MCI (sMCI) subjects. A total of 59 MCI subjects were recruited and divided -after appropriate follow-up- into cMCI or sMCI. They were further divided in MCI with linguistic domain (LD) impairment and in MCI with executive domain (ED) impairment. Small World (SW) index was measured as index of balance between integration and segregation brain processes. SW, computed restricting to nodes of DMN regions for all frequency bands, evaluated how they differ between MCI subgroups assessed through clinical and neuropsychological four-years follow-up. In addition, SW evaluated how this pattern differs between MCI with LD and MCI with ED. Results showed that SW index significantly decreased in gamma band in cMCI compared to sMCI. In cMCI with LD impairment, the SW index significantly decreased in delta band, while in cMCI with ED impairment the SW index decreased in delta and gamma bands and increased in alpha1 band. We propose that the DMN functional alterations in cognitive impairment could reflect an abnormal flow of brain information processing during resting state possibly associated to a status of pre-dementia.

The aim of this systematic review and meta-analysis is to examine the efficacy of language training, alone or in combination with non-invasive brain stimulation techniques, designed to improve oral and written naming abilities in Primary Progressive Aphasia (PPA), and to investigate whether gains can be maintained over time and generalize to untrained items. An electronic database search was conducted up to 31 st of May 2019. Forty-three articles on language training alone and seven articles on the combined treatment fitted the inclusion criteria for the systematic review. Results indicated that language training, alone or in combination with transcranial direct current stimulation (tDCS), improves oral naming accuracy for trained items in patients with PPA, with a long-term maintenance of the gain over time. Only language training combined with tDCS improves oral naming accuracy for untrained items. Considering written naming abilities, language training combined with tDCS improves performance for both trained and untrained items, immediately after training and at follow-up., (Copyright © 2019 Elsevier Ltd. All rights reserved.)