Precuneus magnetic stimulation for Alzheimer's disease: a randomized, sham-controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) is emerging as a non-invasive therapeutic strategy in the battle against Alzheimer's disease. Alzheimer's disease patients primarily show alterations of the default mode network for which the precuneus is a key node. Here, we hypothesized that targeting the precuneus with TMS represents a promising strategy to slow down cognitive and functional decline in Alzheimer's disease patients. We performed a randomized, double-blind, sham-controlled, phase 2, 24-week trial to determine the safety and efficacy of precuneus stimulation in patients with mild-to-moderate Alzheimer's disease. Fifty Alzheimer's disease patients were randomly assigned in a 1:1 ratio to either receive precuneus or sham rTMS (mean age 73.7 years; 52% female). The trial included a 24-week treatment, with a 2-week intensive course in which rTMS (or sham) was applied daily five times per week, followed by a 22-week maintenance phase in which stimulation was applied once weekly. The Clinical Dementia Rating Scale-Sum of Boxes was selected as the primary outcome measure, in which post-treatment scores were compared to baseline. Secondary outcomes included score changes in the Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental State Examination and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale. Moreover, single-pulse TMS in combination with EEG was used to assess neurophysiological changes in precuneus cortical excitability and oscillatory activity. Our findings show that patients that received precuneus repetitive magnetic stimulation presented a stable performance of the Clinical Dementia Rating Scale-Sum of Boxes score, whereas patients treated with sham showed a worsening of their score. Compared with the sham stimulation, patients in the precuneus stimulation group also showed also significantly better performances for the secondary outcome measures, including the Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental State Examination and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale. Neurophysiological results showed that precuneus cortical excitability remained unchanged after 24 weeks in the precuneus stimulation group, whereas it was significantly reduced in the sham group. Finally, we found an enhancement of local gamma oscillations in the group treated with precuneus stimulation but not in patients treated with sham. We conclude that 24 weeks of precuneus rTMS may slow down cognitive and functional decline in Alzheimer's disease. Repetitive TMS targeting the default mode network could represent a novel therapeutic approach in Alzheimer's disease patients.

tDCS effects on brain network properties during physiological aging.

Brain neural networks undergo relevant changes during physiological aging, which affect cognitive and behavioral functions. Currently, non-invasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), are proposed as tools able to modulate cognitive functions in brain aging, acting on networks properties and connectivity. Segregation and integration measures are used and evaluated by means of local clustering (segregation) and path length (integration). Moreover, to assess the balancing between them, the Small World (SW) parameter is employed, evaluating functional coupling in normal brain aging and in pathological conditions including neurodegeneration. The aim of this study was to systematically investigate the tDCS-induced effects on brain network proprieties in physiological aging. In order to reach this aim, cortical activity was acquired from healthy young and elderly subjects by means of EEG recorded before, during, and after anodal, cathodal, and sham tDCS sessions. Specifically, the aim to exploring tDCS polarity-dependent changes in the age-dependent network dynamics was based on a network graph theory application on two groups divided in young and elderly subjects. Eighteen healthy young (9 females; mean age = 24.7, SD = 3.2) and fifteen elderly subjects (9 females; mean = 70.1, SD = 5.1) were enrolled. Each participant received anodal, cathodal, or sham tDCS over the left prefrontal cortex (PFC) in three separate experimental sessions performed 1 week apart. SW was computed to evaluate brain network organization. The present study demonstrates that tDCS delivered in PFC can change brain network dynamics, and tDCS-EEG coregistration data can be analyzed using graph theory to understand the induced effects of different tDCS polarities in physiological and pathological brain aging.

Evidence for interhemispheric imbalance in stroke patients as revealed by combining transcranial magnetic stimulation and electroencephalography.

Interhemispheric interactions in stroke patients are frequently characterized by abnormalities, in terms of balance and inhibition. Previous results showed an impressive variability, mostly given to the instability of motor-evoked potentials when evoked from the affected hemisphere. We aim to find reliable interhemispheric measures in stroke patients with a not-evocable motor-evoked potential from the affected hemisphere, by combining transcranial magnetic stimulation (TMS) and electroencephalography. Ninteen stroke patients (seven females; 61.26 ± 9.8 years) were studied for 6 months after a first-ever stroke in the middle cerebral artery territory. Patients underwent four evaluations: clinical, cortical, corticospinal, and structural. To test the reliability of our measures, the evaluations were repeated after 3 weeks. To test the sensitivity, 14 age-matched healthy controls were compared to stroke patients. In stroke patients, stimulation of the affected hemisphere did not result in any inhibition onto the unaffected. The stimulation of the unaffected hemisphere revealed a preservation of the inhibition mechanism onto the affected. This resulted in a remarkable interhemispheric imbalance, whereas this mechanism was steadily symmetric in healthy controls. This result was stable when cortical evaluation was repeated after 3 weeks. Importantly, patients with a better recovery of the affected hand strength were the ones with a more stable interhemispheric balance. Finally, we found an association between microstructural integrity of callosal fibers, suppression of interhemispheric TMS-evoked activity and interhemispheric connectivity. We provide direct and sensitive cortical measures of interhemispheric imbalance in stroke patients. These measures offer a reliable means of distinguishing healthy and pathological interhemispheric dynamics.

Improving visuo-motor learning with cerebellar theta burst stimulation: Behavioral and neurophysiological evidence.

The cerebellum is strongly implicated in learning new motor skills. Theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation, can be used to influence cerebellar activity. Our aim was to explore the potential of cerebellar TBS in modulating visuo-motor adaptation, a form of motor learning, in young healthy subjects. Cerebellar TBS was applied immediately before the learning phase of a visuo-motor adaptation task (VAT), in two different experiments. Firstly, we evaluated the behavioral effects of continuous (cTBS), intermittent (iTBS) or sham TBS on the learning, re-adaptation and de-adaptation phases of VAT. Subsequently, we investigated the changes induced by iTBS or sham TBS on motor cortical activity related to each phase of VAT, as measured by concomitant TMS/EEG recordings. We found that cerebellar TBS induced a robust bidirectional modulation of the VAT performance. More specifically, cerebellar iTBS accelerated visuo-motor adaptation, by speeding up error reduction in response to a novel perturbation. This gain of function was still maintained when the novel acquired motor plan was tested during a subsequent phase of re-adaptation. On the other hand, cerebellar cTBS induced the opposite effect, slowing the rate of error reduction in both learning and re-adaptation phases. Additionally, TMS/EEG recordings showed that cerebellar iTBS induced specific changes of cortical activity in the interconnected motor networks. The improved performance was accompanied by an increase of TMS-evoked cortical activity and a generalized desynchronization of TMS-evoked cortical oscillations. Taken together, our behavioral and neurophysiological findings provide the first-time multimodal evidence of the potential efficacy of cerebellar TBS in improving motor learning, by promoting successful cerebellar-cortical reorganization.

Intermittent Cerebellar Theta Burst Stimulation Improves Visuo-motor Learning in Stroke Patients: a Pilot Study.

The cerebellum plays a critical role in promoting learning of new motor tasks, which is an essential function for motor recovery. Repetitive transcranial magnetic stimulation (rTMS) of the cerebellum can be used to enhance learning. In this study, we investigated the effects of cerebellar intermittent theta burst stimulation (c-iTBS), a high-frequency rTMS protocol, on visuo-motor learning in a sample of hemiparetic patients due to recent stroke in the territory of the contralateral middle cerebral artery. Eight stroke patients were enrolled for the purposes of the study in the chronic stage of recovery (i.e., at least 6 months after stroke). In two sessions, Patients were randomly assigned to treatment with real or sham c-iTBS applied over the cerebellar hemisphere ipsilateral to the affected body side. c-iTBS was applied immediately before the learning phase of a visuo-motor adaptation task. Real, but not sham, c-iTBS improved visuo-motor learning as revealed by an increased performance in of the learning phase of the visuo-moto adaptation task. Moreover, we also found that real but not sham c-iTBS induced a sustained improvement in the re-adaptation of the recently learned skill (i.e., when patients were re-tested after 30 min). Taken together, these data point to c-iTBS as a potential novel strategy to promote motor learning in patients with stroke.

Pearls and pitfalls in brain functional analysis by event-related potentials: a narrative review by the Italian Psychophysiology and Cognitive Neuroscience Society on methodological limits and clinical reliability-part I.

Event-related potentials (ERPs) are obtained from the electroencephalogram (EEG) or the magnetoencephalogram (MEG, event-related fields (ERF)), extracting the activity that is time-locked to an event. Despite the potential utility of ERP/ERF in cognitive domain, the clinical standardization of their use is presently undefined for most of procedures. The aim of the present review is to establish limits and reliability of ERP medical application, summarize main methodological issues, and present evidence of clinical application and future improvement. The present section of the review focuses on well-standardized ERP methods, including P300, Contingent Negative Variation (CNV), Mismatch Negativity (MMN), and N400, with a chapter dedicated to laser-evoked potentials (LEPs). One section is dedicated to proactive preparatory brain activity as the Bereitschaftspotential and the prefrontal negativity (BP and pN). The P300 and the MMN potentials have a limited but recognized role in the diagnosis of cognitive impairment and consciousness disorders. LEPs have a well-documented usefulness in the diagnosis of neuropathic pain, with low application in clinical assessment of psychophysiological basis of pain. The other ERP components mentioned here, though largely applied in normal and pathological cases and well standardized, are still confined to the research field. CNV, BP, and pN deserve to be largely tested in movement disorders, just to explain possible functional changes in motor preparation circuits subtending different clinical pictures and responses to treatments.

Dynamic reorganization of TMS-evoked activity in subcortical stroke patients.

Since early days after stroke, the brain undergoes a complex reorganization to allow compensatory mechanisms that promote functional recovery. However, these mechanisms are still poorly understood and there is urgent need to identify neurophysiological markers of functional recovery after stroke. Here we aimed to track longitudinally the time-course of cortical reorganization by measuring for the first time EEG cortical activity evoked by TMS pulses in patients with subcortical stroke. Thirteen patients in the sub-acute phase of ischemic subcortical stroke with motor symptoms completed the longitudinal study, being evaluated within 20 days and after 40, 60 and 180 days after stroke onset. For each time-point, EEG cortical activity evoked by single TMS pulses was assessed over the motor and parietal cortex of the affected and unaffected hemisphere. We evaluated global TMS-evoked activity and TMS-evoked oscillations in different frequency bands. These measurements were paralleled with clinical and behavioral assessment. We found that motor cortical activity measured by TMS-EEG varied across time in the affected hemisphere. An increase of TMS-evoked activity was evident at 40 days after stroke onset. Moreover, stroke patients showed a significant increase in TMS-evoked alpha oscillations, as highlighted performing analysis in the time-frequency domain. Notably, these changes indicated that crucial mechanisms of cortical reorganization occur in this short-time window. These changes coincided with the clinical improvement. TMS-evoked alpha oscillatory activity recorded at baseline was associated to better functional recovery at 40 and 60 days' follow-up evaluations, suggesting that the power of the alpha rhythm can be considered a good predictor of motor recovery. This study demonstrates that cortical activity increases dynamically in the early phases of recovery after stroke in the affected hemisphere. These findings point to TMS-evoked alpha oscillatory activity as a potential neurophysiological markers of stroke recovery and could be helpful to determine the temporal window in which neuromodulation should be potentially able to drive neuroplasticity in an effective functional direction.

Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer's disease.

Memory loss is one of the first symptoms of typical Alzheimer's disease (AD), for which there are no effective therapies available. The precuneus (PC) has been recently emphasized as a key area for the memory impairment observed in early AD, likely due to disconnection mechanisms within large-scale networks such as the default mode network (DMN). Using a multimodal approach we investigated in a two-week, randomized, sham-controlled, double-blinded trial the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the PC on cognition, as measured by the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite in 14 patients with early AD (7 females). TMS combined with electroencephalography (TMS-EEG) was used to detect changes in brain connectivity. We found that rTMS of the PC induced a selective improvement in episodic memory, but not in other cognitive domains. Analysis of TMS-EEG signal revealed an increase of neural activity in patients' PC, an enhancement of brain oscillations in the beta band and a modification of functional connections between the PC and medial frontal areas within the DMN. Our findings show that high-frequency rTMS of the PC is a promising, non-invasive treatment for memory dysfunction in patients at early stages of AD. This clinical improvement is accompanied by modulation of brain connectivity, consistently with the pathophysiological model of brain disconnection in AD.

Transcranial magnetic stimulation predicts cognitive decline in patients with Alzheimer's disease.

OBJECTIVE: To determine the ability of transcranial magnetic stimulation (TMS) in detecting synaptic impairment in patients with Alzheimer's disease (AD) and predicting cognitive decline since the early phases of the disease. METHODS: We used TMS-based parameters to evaluate long-term potentiation (LTP)-like cortical plasticity and cholinergic activity as measured by short afferent inhibition (SAI) in 60 newly diagnosed patients with AD and 30 healthy age-matched subjects (HS). Receiver operating characteristic (ROC) curves were used to assess TMS ability in discriminating patients with AD from HS. Regression analyses examined the association between TMS-based parameters and cognitive decline. Multivariable regression model revealed the best parameters able to predict disease progression. RESULTS: Area under the ROC curve was 0.90 for LTP-like cortical plasticity, indicating an excellent accuracy of this parameter in detecting AD pathology. In contrast, area under the curve was only 0.64 for SAI, indicating a poor diagnostic accuracy. Notably, LTP-like cortical plasticity was a significant predictor of disease progression (p=0.02), while no other neurophysiological, neuropsychological and demographic parameters were associated with cognitive decline. Multivariable analysis then promoted LTP-like cortical plasticity as the best significant predictor of cognitive decline (p=0.01). Finally, LTP-like cortical plasticity was found to be strongly associated with the probability of rapid cognitive decline (delta Mini-Mental State Examination score ≤-4 points at 18 months) (p=0.04); patients with AD with lower LTP-like cortical plasticity values showed faster disease progression. CONCLUSIONS: TMS-based assessment of LTP-like cortical plasticity could be a viable biomarker to assess synaptic impairment and predict subsequent cognitive decline progression in patients with ADs.

Transcranial Direct Current Stimulation in Neurodegenerative Disorders.

Cortical excitability modulation and neuroplasticity are considered essential mechanisms for improving clinical and cognitive abilities in neurodegenerative disorders (NDDs). In such context, transcranial direct current stimulation (tDCS) shows great promise for facilitating remodeling of neurosynaptic organization. The aim of this review was to provide an overview of how tDCS is currently used as a neurorehabilitation strategy in some NDDs. We describe results from studies in which tDCS was applied in mild cognitive impairment, Alzheimer's disease, and primary progressive aphasia. Currently, findings related to the ability of tDCS to restore cognitive dysfunctions and behavioral impairments in these NDDs do not seem to support the notion that tDCS shows clear therapeutic efficacy in patients with mild cognitive impairment, Alzheimer disease, and primary progressive aphasia. This is probably because tDCS research in this area is still in its early stages. Methodological concerns, such as differences in tDCS parameters (eg, intensity or duration), target sites, and study design (eg, the relationship between tDCS and the rehabilitation strategy), or the use of underpowered sample sizes may also contribute to these outcomes. Nevertheless, it is important to note that almost no studies have evaluated how the underlying neurophysiological state of patients should guide the application of tDCS. These results should not prevent the use of tDCS in these NDDs, but they should trigger a deeper evaluation of how tDCS should be used. Transcranial direct current stimulation cannot be considered a neurorehabilitation apparatus by itself but should be instead viewed as a method for weakly modulating existing brain excitability. Future studies should aim to improve our understanding of the neurophysiological mechanisms that underlie the clinical effects of tDCS with the final goal of designing and performing individualized stimulation protocols that can be tailored for each NDD patient and combined with other appropriate neurorehabilitation strategies.

Assessing cortical synchronization during transcranial direct current stimulation: A graph-theoretical analysis.

Transcranial direct current stimulation (tDCS) is a neuromodulation technique that can alter cortical excitability and modulate behaviour in a polarity-dependent way. Despite the widespread use of this method in the neuroscience field, its effects on ongoing local or global (network level) neuronal activity are still not foreseeable. A way to shed light on the neuronal mechanisms underlying the cortical connectivity changes induced by tDCS is provided by the combination of tDCS with electroencephalography (EEG). In this study, twelve healthy subjects underwent online tDCS-EEG recording (i.e., simultaneous), during resting-state, using 19 EEG channels. The protocol involved anodal, cathodal and sham stimulation conditions, with the active and the reference electrodes in the left frontocentral area (FC3) and on the forehead over the right eyebrow, respectively. The data were processed using a network model, based on graph theory and the synchronization likelihood. The resulting graphs were analysed for four frequency bands (theta, alpha, beta and gamma) to evaluate the presence of tDCS-induced differences in synchronization patterns and graph theory measures. The resting state network connectivity resulted altered during tDCS, in a polarity-specific manner for theta and alpha bands. Anodal tDCS weakened synchronization with respect to the baseline over the fronto-central areas in the left hemisphere, for theta band (p<0.05). In contrast, during cathodal tDCS a significant increase in inter-hemispheric synchronization connectivity was observed over the centro-parietal, centro-occipital and parieto-occipital areas for the alpha band (p<0.05). Local graph measures showed a tDCS-induced polarity-specific differences that regarded modifications of network activities rather than specific region properties. Our results show that applying tDCS during the resting state modulates local synchronization as well as network properties in slow frequency bands, in a polarity-specific manner.

Effects of transcranial direct current stimulation on the functional coupling of the sensorimotor cortical network.

Transcranial direct current stimulation (tDCS) is well established-among the non-invasive brain stimulation techniques-as a method to modulate brain excitability. Polarity-dependent modulations of membrane potentials are detected after the application of anodal and cathodal stimulation, leading to changes in the electrical activity of the neurons. The main aim of the present study was to test the hypothesis that tDCS can affect-in a polarity-specific manner-the functional coupling of the sensorimotor areas during the eyes-open resting condition as revealed by total EEG coherence (i.e., coherence across the average of all combinations of the electrode pairs placed around the stimulation electrode). The changes in the total EEG coherence were evaluated pre-, during, and post-anodal and cathodal tDCS. While no differences were observed in the connectivity characteristics of the two pre-stimulation periods, a connectivity increase was observed in the alpha 2 band in the post-anodal tDCS with respect to pre-anodal and post-cathodal tDCS. The present study suggests that a specific approach based on the analyses of the functional coupling of EEG rhythms might enhance understanding of tDCS-induced effects on cortical connectivity. Moreover, this result suggests that anodal tDCS could possibly modify cortical connectivity more effectively with respect to cathodal tDCS.

Spike-timing-dependent plasticity in the human dorso-lateral prefrontal cortex.

Changes in the synaptic strength of neural connections are induced by repeated coupling of activity of interconnected neurons with precise timing, a phenomenon known as spike-timing-dependent plasticity (STDP). It is debated if this mechanism exists in large-scale cortical networks in humans. We combined transcranial magnetic stimulation (TMS) with concurrent electroencephalography (EEG) to directly investigate the effects of two paired associative stimulation (PAS) protocols (fronto-parietal and parieto-frontal) of pre and post-synaptic inputs within the human fronto-parietal network. We found evidence that the dorsolateral prefrontal cortex (DLPFC) has the potential to form robust STDP. Long-term potentiation/depression of TMS-evoked cortical activity is prompted after that DLPFC stimulation is followed/preceded by posterior parietal stimulation. Such bidirectional changes are paralleled by sustained increase/decrease of high-frequency oscillatory activity, likely reflecting STDP responsivity. The current findings could be important to drive plasticity of damaged cortical circuits in patients with cognitive or psychiatric disorders.

Biological factors and age-dependence of primary motor cortex experimental plasticity.

To evaluate whether the age-dependence of brain plasticity correlates with the levels of proteins involved in hormone and brain functions we executed a paired associative stimulation (PAS) protocol and blood tests. We measured the PAS-induced plasticity in the primary motor cortex. Blood levels of the brain-derived neurotrophic factor (BDNF), estradiol, the insulin-like growth factor (IGF)-1, the insulin-like growth factor binding protein (IGFBP)-3, progesterone, sex hormone-binding globulin (SHBG), testosterone, and the transforming growth factor beta 1 (TGF-ß1) were determined in 15 healthy men and 20 healthy women. We observed an age-related reduction of PAS-induced plasticity in females that it is not present in males. In females, PAS-induced plasticity displayed a correlation with testosterone (p = 0.006) that became a trend after the adjustment for the age effect (p = 0.078). In males, IGF-1 showed a nominally significant correlation with the PAS-induced plasticity (p = 0.043). In conclusion, we observed that hormone blood levels (testosterone in females and IGF-1 in males) may be involved in the age-dependence of brain plasticity.

Excitability modulation of the motor system induced by transcranial direct current stimulation: a multimodal approach.

Anodal and cathodal transcranial direct current stimulations (tDCS) are both established techniques to induce cortical excitability changes. Typically, in the human motor system, such cortical modulations are inferred through changes in the amplitude of the motor evoked potentials (MEPs). However, it is now possible to directly evaluate tDCS-induced changes at the cortical level by recording the transcranial magnetic stimulation evoked potentials (TEPs) using electroencephalography (EEG). The present study investigated the modulation induced by the tDCS on the motor system. The study evaluates changes in the MEPs, in the amplitude and distribution of the TEPs, in resting state oscillatory brain activity and in behavioral performance in a simple manual response task. Both the short- and long-term tDCS effects were investigated by evaluating their time course at ~0 and 30min after tDCS. Anodal tDCS over the left primary motor cortex (M1) induced an enhancement of corticospinal excitability, whereas cathodal stimulation produced a reduction. These changes in excitability were indexed by changes in MEP amplitude. More interestingly, tDCS modulated the cortical reactivity, which is the neuronal activity evoked by TMS, in a polarity-dependent and site-specific manner. Cortical reactivity increased after anodal stimulation over the left M1, whereas it decreased with cathodal stimulation. These effects were partially present also at long term evaluation. No polarity-specific effect was found either on behavioral measures or on oscillatory brain activity. The latter showed a general increase in the power density of low frequency oscillations (theta and alpha) at both stimulation polarities. Our results suggest that tDCS is able to modulate motor cortical reactivity in a polarity-specific manner, inducing a complex pattern of direct and indirect cortical activations or inhibitions of the motor system-related network, which might be related to changes in synaptic efficacy of the motor cortex.

TMS-EEG perturbation biomarkers for Alzheimer's disease patients classification.

The combination of TMS and EEG has the potential to capture relevant features of Alzheimer's disease (AD) pathophysiology. We used a machine learning framework to explore time-domain features characterizing AD patients compared to age-matched healthy controls (HC). More than 150 time-domain features including some related to local and distributed evoked activity were extracted from TMS-EEG data and fed into a Random Forest (RF) classifier using a leave-one-subject out validation approach. The best classification accuracy, sensitivity, specificity and F1 score were of 92.95%, 96.15%, 87.94% and 92.03% respectively when using a balanced dataset of features computed globally across the brain. The feature importance and statistical analysis revealed that the maximum amplitude of the post-TMS signal, its Hjorth complexity and the amplitude of the TEP calculated in the window 45-80 ms after the TMS-pulse were the most relevant features differentiating AD patients from HC. TMS-EEG metrics can be used as a non-invasive tool to further understand the AD pathophysiology and possibly contribute to patients' classification as well as longitudinal disease tracking.

Transcranial electric stimulation as a neural interface to gain insight on human brain functions: current knowledge and future perspective.

The use of brain stimulation approaches in social and affective science has greatly increased over the last two decades. The interest in social factors has grown along with technological advances in brain research. Transcranial electric stimulation (tES) is a research tool that allows scientists to establish contributory causality between brain functioning and social behaviour, therefore deepening our understanding of the social mind. Preliminary evidence is also starting to demonstrate that tES, either alone or in combination with pharmacological or behavioural interventions, can alleviate the symptomatology of individuals with affective or social cognition disorders. This review offers an overview of the application of tES in the field of social and affective neuroscience. We discuss the issues and challenges related to this application and suggest an avenue for future basic and translational research.

Age-related Changes in Cortical Excitability Linked to Decreased Attentional and Inhibitory Control.

Understanding age-related changes in cortical excitability and their relation to cognitive functions will help to improve interventions based on non-invasive brain stimulation that aim to support cognitive function in older adults. Here, we investigate the relationship between cortical excitability, executive function, and underlying neural activity in samples of healthy young and older adults. These participants performed a Simon task during electroencephalogram (EEG) recording. During the task, participants had to respond to the colour of a lateralized stimulus while ignoring its spatial location. We studied event-related brain potential correlates of attentional and inhibitory control [i.e., the posterior contralateral negativity (N2pc) and central contralateral negativity (N2cc), respectively] related to the Simon task performance. We also used transcranial magnetic stimulation (TMS) EEG coregistration. In detail, we applied single-pulse TMS during EEG recording in order to analyse global mean field power (GMFP) and TMS-evoked potentials (TEPs) as correlates of cortical excitability. We found lower GMFP amplitude within 101-200 ms in older compared to young adults. Moreover, older adults showed smaller N45 amplitude and slower P180 latency. These findings suggest cortical excitability alterations related to ageing. Older adults also exhibited longer reaction times and N2pc and N2cc latencies, indicating that it took them longer to allocate attention to the target stimulus and inhibit the tendency to respond to the attended location. Finally, in older adults, cortical excitability alterations correlated with longer reaction times and N2pc latencies. These results suggest that age-related alterations in cortical excitability represent a dysfunctional change associated with physiological ageing.

Human Brain Networks in Physiological and Pathological Aging: Reproducibility of Electroencephalogram Graph Theoretical Analysis in Cortical Connectivity.

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.

Brain Networks Modulation in Young and Old Subjects During Transcranial Direct Current Stimulation Applied on Prefrontal and Parietal Cortex.

Evidence indicates that the transcranial direct current stimulation (tDCS) has the potential to transiently modulate cognitive function, including age-related changes in brain performance. Only a small number of studies have explored the interaction between the stimulation sites on the scalp, task performance, and brain network connectivity within the frame of physiological aging. We aimed to evaluate the spread of brain activation in both young and older adults in response to anodal tDCS applied to two different scalp stimulation sites: Prefrontal cortex (PFC) and posterior parietal cortex (PPC). EEG data were recorded during tDCS stimulation and evaluated using the Small World (SW) index as a graph theory metric. Before and after tDCS, participants performed a behavioral task; a performance accuracy index was computed and correlated with the SW index. Results showed that the SW index increased during tDCS of the PPC compared to the PFC at higher EEG frequencies only in young participants. tDCS at the PPC site did not exert significant effects on the performance, while tDCS at the PFC site appeared to influence task reaction times in the same direction in both young and older participants. In conclusion, studies using tDCS to modulate functional connectivity and influence behavior can help identify suitable protocols for the aging brain.