Regional Precuneus Cortical Hyperexcitability in Alzheimer's Disease Patients.

OBJECTIVE: Neuronal excitation/inhibition (E/I) imbalance is a potential cause of neuronal network malfunctioning in Alzheimer's disease (AD), contributing to cognitive dysfunction. Here, we used a novel approach combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to probe cortical excitability in different brain areas known to be directly involved in AD pathology. METHODS: We performed TMS-EEG recordings targeting the left dorsolateral prefrontal cortex (l-DLPFC), the left posterior parietal cortex (l-PPC), and the precuneus (PC) in a large sample of patients with mild-to-moderate AD (n = 65) that were compared with a group of age-matched healthy controls (n = 21). RESULTS: We found that patients with AD are characterized by a regional cortical hyperexcitability in the PC and, to some extent, in the frontal lobe, as measured by TMS-evoked potentials. Notably, cortical excitability assessed over the l-PPC was comparable between the 2 groups. Furthermore, we found that the individual level of PC excitability was associated with the level of cognitive impairment, as measured with Mini-Mental State Examination, and with corticospinal fluid levels of Aß42 . INTERPRETATION: Our data provide novel evidence that precuneus cortical hyperexcitability is a key feature of synaptic dysfunction in patients with AD. The current results point to the combined approach of TMS and EEG as a novel promising technique to measure hyperexcitability in patients with AD. This index could represent a useful biomarker to stage disease severity and evaluate response to novel therapies. ANN NEUROL 2023;93:371-383.

Decreased Frontal Gamma Activity in Alzheimer Disease Patients.

OBJECTIVE: In Alzheimer disease (AD) animal models, synaptic dysfunction has recently been linked to a disorder of high-frequency neuronal activity. In patients, a clear relation between AD and oscillatory activity remains elusive. Here, we attempt to shed light on this relation by using a novel approach combining transcranial magnetic stimulation and electroencephalography (TMS-EEG) to probe oscillatory activity in specific hubs of the frontoparietal network in a sample of 60 mild-to-moderate AD patients. METHODS: Sixty mild-to-moderate AD patients and 21 age-matched healthy volunteers (HVs) underwent 3 TMS-EEG sessions to assess cortical oscillations over the left dorsolateral prefrontal cortex, the precuneus, and the left posterior parietal cortex. To investigate the relations between oscillatory activity, cortical plasticity, and cognitive decline, AD patients underwent a TMS-based neurophysiological characterization and a cognitive evaluation at baseline. The latter was repeated after 24 weeks to monitor clinical evolution. RESULTS: AD patients showed a significant reduction of frontal gamma activity as compared to age-matched HVs. In addition, AD patients with a more prominent decrease of frontal gamma activity showed a stronger impairment of long-term potentiation-like plasticity and a more pronounced cognitive decline at subsequent follow-up evaluation at 24 weeks. INTERPRETATION: Our data provide novel evidence that frontal lobe gamma activity is dampened in AD patients. The current results point to the TMS-EEG approach as a promising technique to measure individual frontal gamma activity in patients with AD. This index could represent a useful biomarker to predict disease progression and to evaluate response to novel pharmacological therapies. ANN NEUROL 2022;92:464-475.

Placebo effects and neuromodulation for depression: a meta-analysis and evaluation of shared mechanisms.

There is growing evidence that placebo effects can meaningfully modulate the brain. However, there has been little consideration of whether these changes may overlap with regions/circuits targeted by depression treatments and what the implications of this overlap would be on measuring efficacy in placebo-controlled clinical trials. In this systematic review and meta-analysis, we searched PubMed/Medline and Google Scholar for functional MRI and PET neuroimaging studies of placebo effects. Studies recruiting both healthy subjects and patient populations were included. Neuroimaging coordinates were extracted and included for Activation Likelihood Estimation (ALE) meta-analysis. We then searched for interventional studies of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) for depression and extracted target coordinates for comparative spatial analysis with the placebo effects maps. Of 1169 articles identified, 34 neuroimaging studies of placebo effects were included. There were three significant clusters of activation: left dorsolateral prefrontal cortex (DLPFC) (x = -41, y = 16, z = 34), left sub-genual anterior cingulate cortex (sgACC)/ventral striatum (x = -8, y = 18, z = -15) and the right rostral anterior cingulate cortex (rACC) (x = 4, y = 42, z = 10). There were two significant deactivation clusters: right basal ganglia (x = 20, y = 2, z = 7) and right dorsal anterior cingulate cortex (dACC) (x = 1, y = -5, z = 45). TMS and DBS targets for depression treatment overlapped with the left DLPFC cluster and sgACC cluster, respectively. Our findings identify a common set of brain regions implicated in placebo effects across healthy individuals and patient populations, and provide evidence that these regions overlap with depression treatment targets. We model the statistical impacts of this overlap and demonstrate critical implications on measurements of clinical trial efficacy for this field.

Neural correlates of N-back task performance and proposal for corresponding neuromodulation targets in psychiatric and neurodevelopmental disorders.

AIM: Working memory (WM) deficit represents the most common cognitive impairment in psychiatric and neurodevelopmental disorders, making the identification of its neural substrates a crucial step towards the conceptualization of restorative interventions. We present a meta-analysis focusing on neural activations associated with the most commonly used task to measure WM, the N-back task, in patients with schizophrenia, depressive disorder, bipolar disorder, and attention-deficit/hyperactivity disorder. Showing qualitative similarities and differences in WM processing between patients and healthy controls, we propose possible targets for cognitive enhancement approaches. METHODS: Selected studies, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, were analyzed through the activation likelihood estimate statistical framework, with subsequent generation of disorder-specific N-back activation maps. RESULTS: Despite similar WM deficits shared across all disorders, results highlighted different brain activation patterns for each disorder compared with healthy controls. In general, results showed brain activity in frontal, parietal, subcortical, and cerebellar regions; however, reduced engagement of specific nodes of the fronto-parietal network emerged in patients compared with healthy controls. In particular, neither bipolar nor depressive disorders showed detectable activations in the dorsolateral prefrontal cortices, while their parietal activation patterns were lateralized to the left and right hemispheres, respectively. On the other hand, patients with attention-deficit/hyperactivity disorder showed a lack of activation in the left parietal lobe, whereas patients with schizophrenia showed lower activity over the left prefrontal cortex. CONCLUSION: These results, together with biophysical modeling, were then used to discuss the design of future disorder-specific cognitive enhancement interventions based on noninvasive brain stimulation.

Local and Distributed fMRI Changes Induced by 40 Hz Gamma tACS of the Bilateral Dorsolateral Prefrontal Cortex: A Pilot Study.

Over the past few years, the possibility of modulating fast brain oscillatory activity in the gamma (γ) band through transcranial alternating current stimulation (tACS) has been discussed in the context of both cognitive enhancement and therapeutic scenarios. However, the effects of tACS targeting regions outside the motor cortex, as well as its spatial specificity, are still unclear. Here, we present a concurrent tACS-fMRI block design study to characterize the impact of 40 Hz tACS applied over the left and right dorsolateral prefrontal cortex (DLPFC) in healthy subjects. Results suggest an increase in blood oxygenation level-dependent (BOLD) activity in the targeted bilateral DLPFCs, as well as in surrounding brain areas affected by stimulation according to biophysical modeling, i.e., the premotor cortex and anterior cingulate cortex (ACC). However, off-target effects were also observed, primarily involving the visual cortices, with further effects on the supplementary motor areas (SMA), left subgenual cingulate, and right superior temporal gyrus. The specificity of 40 Hz tACS over bilateral DLPFC and the possibility for network-level effects should be considered in future studies, especially in the context of recently promoted gamma-induction therapeutic protocols for neurodegenerative disorders.

Overlapping and dissociable brain activations for fluid intelligence and executive functions.

Cognitive enhancement interventions aimed at boosting human fluid intelligence (gf) have targeted executive functions (EFs), such as updating, inhibition, and switching, in the context of transfer-inducing cognitive training. However, even though the link between EFs and gf has been demonstrated at the psychometric level, their neurofunctional overlap has not been quantitatively investigated. Identifying whether and how EFs and gf might share neural activation patterns could provide important insights into the overall hierarchical organization of human higher-order cognition, as well as suggest specific targets for interventions aimed at maximizing cognitive transfer. We present the results of a quantitative meta-analysis of the available fMRI and PET literature on EFs and gf in humans, showing the similarity between gf and (i) the overall global EF network, as well as (ii) specific maps for updating, switching, and inhibition. Results highlight a higher degree of similarity between gf and updating (80% overlap) compared with gf and inhibition (34%), and gf and switching (17%). Moreover, three brain regions activated for both gf and each of the three EFs also were identified, located in the left middle frontal gyrus, left inferior parietal lobule, and anterior cingulate cortex. Finally, resting-state functional connectivity analysis on two independent fMRI datasets showed the preferential behavioural correlation and anatomical overlap between updating and gf. These findings confirm a close link between gf and EFs, with implications for brain stimulation and cognitive training interventions.

Mindfulness-based stress reduction training modulates striatal and cerebellar connectivity.

Mindfulness is a meditation practice frequently associated with changes in subjective evaluation of cognitive and sensorial experience, as well as with modifications of brain activity and morphometry. Aside from the anatomical localization of functional changes induced by mindfulness practice, little is known about changes in functional and effective functional magnetic resonance imaging (fMRI) connectivity. Here we performed a connectivity fMRI analysis in a group of healthy individuals participating in an 8-week mindfulness-based stress reduction (MBSR) training program. Data from both a "mind-wandering" and a "meditation" state were acquired before and after the MBSR course. Results highlighted decreased local connectivity after training in the right anterior putamen and insula during spontaneous mind-wandering and the right cerebellum during the meditative state. A further effective connectivity analysis revealed (a) decreased modulation by the anterior cingulate cortex over the anterior portion of the putamen, and (b) a change in left and right posterior putamen excitatory input and inhibitory output with the cerebellum, respectively. Results suggest a rearrangement of dorsal striatum functional and effective connectivity in response to mindfulness practice, with changes in cortico-subcortical-cerebellar modulatory dynamics. Findings might be relevant for the understanding of widely documented mindfulness behavioral effects, especially those related to pain perception.

Impact of network-targeted multichannel transcranial direct current stimulation on intrinsic and network-to-network functional connectivity.

Dynamics within and between functional resting-state networks have a crucial role in determining both healthy and pathological brain functioning in humans. The possibility to noninvasively interact and selectively modulate the activity of networks would open to relevant applications in neuroscience. Here we tested a novel approach for multichannel, network-targeted transcranial direct current stimulation (net-tDCS), optimized to increase excitability of the sensorimotor network (SMN) while inducing cathodal inhibitory modulation over prefrontal and parietal brain regions negatively correlated with the SMN. Using an MRI-compatible multichannel transcranial electrical stimulation (tES) device, 20 healthy participants underwent real and sham tDCS while at rest in the MRI scanner. Changes in functional connectivity (FC) during and after stimulation were evaluated, looking at the intrinsic FC of the SMN and the strength of the negative connectivity between SMN and the rest of the brain. Standard, bifocal tDCS targeting left motor cortex (electrode ~C3) and right frontopolar (~Fp2) regions was tested as a control condition in a separate sample of healthy subjects to investigate network specificity of multichannel stimulation effects. Net-tDCS induced greater FC increase over the SMN compared to bifocal tDCS, during and after stimulation. Moreover, exploratory analysis of the impact of net-tDCS on negatively correlated networks showed an increase in the negative connectivity between SMN and prefrontal/parietal areas targeted by cathodal stimulation both during and after real net-tDCS. Results suggest preliminary evidence of the possibility of manipulating distributed network connectivity patterns through net-tDCS, with potential relevance for the development of cognitive enhancement and therapeutic tES solutions.

Stimuli, presentation modality, and load-specific brain activity patterns during n-back task.

Working memory (WM) refers to a set of cognitive processes that allows for the temporary storage and manipulation of information, crucial for everyday life skills. WM deficits are present in several neurological, psychiatric, and neurodevelopmental disorders, thus making the full understanding of its neural correlates a key aspect for the implementation of cognitive training interventions. Here, we present a quantitative meta-analysis focusing on the underlying neural substrates upon which the n-back, one of the most commonly used tasks for WM assessment, is believed to rely on, as highlighted by functional magnetic resonance imaging and positron emission tomography findings. Relevant published work was scrutinized through the activation likelihood estimate (ALE) statistical framework in order to generate a set of task-specific activation maps, according to n-back difficulty. Our results confirm the known involvement of frontoparietal areas across different types of n-back tasks, as well as the recruitment of subcortical structures, cerebellum and precuneus. Specific activations maps for four stimuli types, six presentation modalities, three WM loads and their combination are provided and discussed. Moreover, functional overlap with resting-state networks highlighted a strong similarity between n-back nodes and the Dorsal Attention Network, with less overlap with other networks like Salience, Language, and Sensorimotor ones. Additionally, neural deactivations during n-back tasks and their functional connectivity profile were examined. Clinical and functional implications are discussed in the context of potential noninvasive brain stimulation and cognitive enhancement/rehabilitation programs.

Brain functional connectivity correlates of coping styles.

Coping abilities represent the individual set of mental and behavioral strategies adopted when facing stress or traumatic experiences. Coping styles related to avoidance have been linked to a disposition to develop psychiatric disorders such as PTSD, anxiety, and major depression, whereas problem-oriented coping skills have been positively correlated with well-being and high quality of life. Even though coping styles constitute an important determinant of resilience and can impact many aspects of everyday living, no study has investigated their brain functional connectivity underpinnings in humans. Here we analyzed both psychometric scores of coping and resting-state fMRI data from 102 healthy adult participants. Controlling for personality and problem-solving abilities, we identified significant links between the propensity to adopt different coping styles and the functional connectivity profiles of regions belonging to the default mode (DMN) and anterior salience (AS) networks-namely, the anterior cingulate cortex, left frontopolar cortex, and left angular gyrus. Also, a reduced negative correlation between AS and DMN nodes explained variability in one specific coping style, related to avoiding problems while focusing on the emotional component of the stressor at hand, instead of relying on cognitive resources. These results might be integrated with current neurophysiological models of resilience and individual responses to stress, in order to understand the propensity to develop clinical conditions (e.g., PTSD) and predict the outcomes of psychotherapeutic interventions.

Modulation of Corticospinal Excitability during Action Observation in Patients with Disorders of Consciousness.

Brain imaging studies have recently provided some evidence in favor of covert cognitive processes that are ongoing in patients with disorders of consciousness (DoC) (e.g., a minimally conscious state and vegetative state/unresponsive wakefulness syndrome) when engaged in passive sensory stimulation or active tasks such as motor imagery. In this exploratory study, we used transcranial magnetic stimulation (TMS) of the motor cortex to assess modulations of corticospinal excitability induced by action observation in eleven patients with DoC. Action observation is known to facilitate corticospinal excitability in healthy subjects, unveiling how the observer's motor system maps others' actions onto her/his motor repertoire. Additional stimuli were non-biological motion and acoustic startle stimuli, considering that sudden and loud acoustic stimulation is known to lower corticospinal excitability in healthy subjects. The results indicate that some form of motor resonance is spared in a subset of patients with DoC, with some significant difference between biological and non-biological motion stimuli. However, there was no covariation between corticospinal excitability and the type of DoC diagnosis (i.e., whether diagnosed with VS/UWS or MCS). Similarly, no covariation was detected with clinical changes between admission and discharge in clinical outcome measures. Both motor resonance and the difference between the resonance with biological/non-biological motion discrimination correlated with the amplitude of the N20 somatosensory evoked potentials, following the stimulation of the median nerve at the wrist (i.e., the temporal marker signaling the activation of the contralateral primary somatosensory cortex). Moreover, the startle-evoking stimulus produced an anomalous increase in corticospinal excitability, suggesting a functional dissociation between cortical and subcortical circuits in patients with DoC. Further work is needed to better comprehend the conditions in which corticospinal facilitation occurs and whether and how they may relate to individual clinical parameters.

Macro and micro structural preservation of grey matter integrity after 24 weeks of rTMS in Alzheimer's disease patients: a pilot study.

Alzheimer's Disease (AD) is characterized by structural and functional dysfunction involving the Default Mode Network (DMN), for which the Precuneus (PC) is a key node. We proposed a randomized double-blind pilot study to determine neurobiological changes after 24 weeks of PC-rTMS in patients with mild-to-moderate AD. Sixteen patients were randomly assigned to SHAM or PC-rTMS, and received an intensive 2-weeks course with daily rTMS sessions, followed by a maintenance phase in which rTMS has been applied once a week. Before and after the treatment structural and functional MRIs were collected. Our results showed macro- and micro-structural preservation in PC-rTMS compared to SHAM-rTMS group after 24 weeks of treatment, correlated to an increase of functional connectivity (FC) within the PC in the PC-rTMS group. Even if preliminary, these results trigger the possibility of using PC-rTMS to arrest atrophy progression by manipulating distributed network connectivity patterns.

Simultaneous transcranial electrical and magnetic stimulation boost gamma oscillations in the dorsolateral prefrontal cortex.

Neural oscillations in the gamma frequency band have been identified as a fundament for synaptic plasticity dynamics and their alterations are central in various psychiatric and neurological conditions. Transcranial magnetic stimulation (TMS) and alternating electrical stimulation (tACS) may have a strong therapeutic potential by promoting gamma oscillations expression and plasticity. Here we applied intermittent theta-burst stimulation (iTBS), an established TMS protocol known to induce LTP-like cortical plasticity, simultaneously with transcranial alternating current stimulation (tACS) at either theta (θtACS) or gamma (γtACS) frequency on the dorsolateral prefrontal cortex (DLPFC). We used TMS in combination with electroencephalography (EEG) to evaluate changes in cortical activity on both left/right DLPFC and over the vertex. We found that simultaneous iTBS with γtACS but not with θtACS resulted in an enhancement of spectral gamma power, a trend in shift of individual peak frequency towards faster oscillations and an increase of local connectivity in the gamma band. Furthermore, the response to the neuromodulatory protocol, in terms of gamma oscillations and connectivity, were directly correlated with the initial level of cortical excitability. These results were specific to the DLPFC and confined locally to the site of stimulation, not being detectable in the contralateral DLPFC. We argue that the results described here could promote a new and effective method able to induce long-lasting changes in brain plasticity useful to be clinically applied to several psychiatric and neurological conditions.

Brain Functional Correlates of Episodic Memory Using an Ecological Free Recall Task.

Episodic Memory (EM) allows us to revive a past event through mental time-travel. The neural correlates of memories recollection have been identified in hippocampal regions and multiple neocortical areas, but few neuroimaging studies have used an ecological task such as a free recall of a structured story. Using an ecological fMRI-free recall (FR) task, we aimed to investigate the relevant recruitment of the brain networks associated with the story recollection process and its performance. Fourteen healthy participants listened to a brief story and were tested for Immediate-Recall (IR), a task that is widely used in a neuropsychological evaluation. Then, the subjects underwent an fMRI session, where they had to perform a free recall (FR) of the story subvocally. Finally, the participants were tested for Delayed-Recall (DR). IR and DR scores were significantly (r = 0.942; p < 0.001) correlated. FR enhanced the activity of the Language, the Left Executive Control, the Default Mode and the Precuneus brain networks, with the strongest BOLD signal localized in the left Angular Gyrus (AG) (p < 0.05; FWE-corrected). Furthermore, the story recall performance covaried with specific network activation patterns and the recruitment of the left anterior/posterior AG correlated, respectively, with higher/lower performance scores (p > 0.05). FR seems to be a promising task to investigate ecologically the neural correlates of EM. Moreover, the recruitment of the anterior AG might be a marker for an optimal functioning of the recall process. Preliminary outcomes lay the foundation for the investigation of the brain networks in the healthy and pathological elderly population during FR.

Feasibility of TMS in patients with new generation cochlear implants.

OBJECTIVE: The presence of a cochlear implant is being considered an absolute contraindication for experiments and/or treatments. We aimed to verify TMS (Transcranial Magnetic Stimulation) compatibility of a new generation of cochlear implants. METHODS: In a series of experiments, we test if MED-EL cochlear implants -compatible with stable fields of magnetic resonance imaging scanning- are fully resistant even to rapidly varying magnetic fields as those generated by single pulses and low and high-frequency trains of repetitive TMS (rTMS) applied with a figure of eight coil and different magnetic stimulators. RESULTS: With a TMS intensity equal or below 2.2 Tesla (T) the cochlear implant and all its electronic components remain fully functional, even when the combination of frequency, intensity and number of pulses exceeds the currently available safety guidelines. Induced forces on the implant are negligible. With higher magnetic fields (i.e., 3.2 T), one device was corrupted. CONCLUSIONS: Results exclude the risk of electronic damaging, demagnetizing or displacements of the studied cochlear implants when exposed to magnetic fields of up to 2.2 T delivered through a focal coil. SIGNIFICANCE: They open the way to use focal rTMS protocols with the aim of promoting neural plasticity in auditory networks, possibly helping the post-implant recovery of speech perception performance.

Functional connectivity changes and symptoms improvement after personalized, double-daily dosing, repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: A pilot study.

BACKGROUND: intrusive thoughts and compulsive behaviors that characterize obsessive compulsive disorder (OCD) are associated to aberrant resting state functional connectivity (rsFC) patterns within the cortico-striatal-thalamo-cortical (CSTC) circuits. A high percentage of OCD patients do not respond to conventional pharmacological treatments or psychotherapy. In these patients, inhibitory repetitive transcranial magnetic stimulation (rTMS) of the Supplementary Motor Area (SMA) resulted in a significant clinical benefit. METHODS: In the current study, we applied a novel protocol of 1-week MRI-guided individualized double-daily sessions of rTMS treatment (1-Hz; 110% of resting Motor Threshold/7200 pulses/day), to bilateral SMA in 9 OCD patients. We tested its (i) feasibility-safety, (ii) clinical efficacy and (iii) rsFC related changes. RESULTS: Patients reported no side effects during and after rTMS. Personalized rTMS treatment led to a significant improvement of OCD symptoms (average 25%; p = .005) and persistence of benefit up to 3-month follow-up. rsFC analysis revealed a significant reduction of connectivity patterns between bilateral SMA and subcortical regions, specifically in the basal ganglia and thalamus. Additional analysis showed that OCD symptoms severity correlates with a higher connectivity pattern between bilateral SMA and subcortical regions. CONCLUSIONS: rTMS double-daily sessions are safe, feasible and effective in OCD. The clinical outcomes, that are consistent with those found in our previous RCT, are linked to a decreased connectivity between SMA and subcortical brain areas implicated in control over obsessions and maladaptive compulsive behavior.

Network Mapping of Connectivity Alterations in Disorder of Consciousness: Towards Targeted Neuromodulation.

Disorder of consciousness (DoC) refers to a group of clinical conditions that may emerge after brain injury, characterized by a varying decrease in the level of consciousness that can last from days to years. An understanding of its neural correlates is crucial for the conceptualization and application of effective therapeutic interventions. Here we propose a quantitative meta-analysis of the neural substrate of DoC emerging from functional magnetic resonance (fMRI) and positron emission tomography (PET) studies. We also map the relevant networks of resulting areas to highlight similarities with Resting State Networks (RSNs) and hypothesize potential therapeutic solutions leveraging network-targeted noninvasive brain stimulation. Available literature was reviewed and analyzed through the activation likelihood estimate (ALE) statistical framework to describe resting-state or task-dependent brain activation patterns in DoC patients. Results show that task-related activity is limited to temporal regions resembling the auditory cortex, whereas resting-state fMRI data reveal a diffuse decreased activation affecting two subgroups of cortical (angular gyrus, middle frontal gyrus) and subcortical (thalamus, cingulate cortex, caudate nucleus) regions. Clustering of their cortical functional connectivity projections identify two main altered functional networks, related to decreased activity of (i) the default mode and frontoparietal networks, as well as (ii) the anterior salience and visual/auditory networks. Based on the strength and topography of their connectivity profile, biophysical modeling of potential brain stimulation solutions suggests the first network as the most feasible target for tES, tDCS neuromodulation in DoC patients.

A novel tDCS sham approach based on model-driven controlled shunting.

BACKGROUND: Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique able to transiently modulate brain activity, is surging as one of the most promising therapeutic solutions in many neurological and psychiatric disorders. However, profound limitations exist in current placebo (sham) protocols that limit single- and double-blinding, especially in non-naïve subjects. OBJECTIVE: To ensure better blinding and strengthen reliability of tDCS studies and trials, we tested a new optimization algorithm aimed at creating an "active" sham tDCS condition (ActiSham hereafter) capable of inducing the same scalp sensations perceived during real stimulation while preventing currents from reaching the cortex and cause changes in brain excitability. METHODS: A novel model-based multielectrode technique - optimizing the location and currents of a set of small electrodes placed on the scalp - was used to control the relative amount of current delivered transcranially in real and placebo multichannel tDCS conditions. The presence, intensity and localization of scalp sensations during tDCS was evaluated by means of a specifically designed questionnaire administered to the participants. We compared blinding ratings by directly addressing subjects' ability to discriminate across conditions for both traditional (Bifocal-tDCS and Sham, using sponge electrodes) and our novel multifocal approach (both real Multifocal-tDCS and ActiSham). Changes in corticospinal excitability were monitored based on Motor Evoked Potentials (MEPs) recorded via concurrent Transcranial Magnetic Stimulation (TMS) and electromyography (EMG). RESULTS: Participants perceived Multifocal-tDCS and ActiSham similarly in terms of both localization and intensity of scalp sensations, whereas traditional Bifocal stimulation was rated as more painful and annoying compared to its Sham counterpart. Additionally, differences in scalp localization were reported for active/sham Bifocal-tDCS, with Sham tDCS inducing more widespread itching and burning sensations. As for MEPs amplitude, a main effect of stimulation was found when comparing Bifocal-Sham and ActiSham (F(1,13) = 6.67, p = .023), with higher MEPs amplitudes after the application of Bifocal-Sham. CONCLUSIONS: Compared to traditional Bifocal-tDCS, ActiSham offers better participants' blinding by inducing very similar scalp sensations to those of real Multifocal tDCS both in terms of intensity and localization, while not affecting corticospinal excitability.