Effects on Motor Control of Personalized Neuromodulation Against Multiple Sclerosis Fatigue.

Fatigue is a hidden symptom of Multiple Sclerosis (MS) disease that nevertheless impacts severely on patients' everyday life. Evidence indicates the involvement of the sensorimotor network and its inter-nodes communication at the basis of this symptom. Two randomized controlled trials (RCTs) showed that the personalized neuromodulation called Fatigue Relief in Multiple Sclerosis (FaReMuS) efficaciously fights multiple sclerosis (MS) fatigue. By this Proof of Concept study, we tested whether FaReMuS reverts the alteration of the brain-muscular synchronization previously observed occurring with fatigue. The cortico muscular coherence (CMC) was studied in 11 patients before and after FaReMuS, a 5-day tDCS (1.5 mA, 15 min per day) anodal over the whole body's somatosensory representation (S1) via a personalized MRI-based electrode (35 cm2) against the occipital cathode (70 cm2). Before FaReMuS, the CMC was observed at a mean frequency of 31.5 ± 1.6 Hz (gamma-band) and positively correlated with the level of fatigue (p = .027). After FaReMuS, fatigue reduced in average of 28% ± 33% the baseline level, and the CMC frequency reduced to 26.6 ± 1.5 Hz (p = .022), thus forthcoming the physiological beta-band as observed in healthy people. The personalized S1 neuromodulation treatment, ameliorating the central-peripheral communication that subtends simple everyday movements, supports the appropriateness of neuromodulations aiming at increasing the parietal excitability in fighting MS fatigue. The relationship between central-peripheral features and fatigue profile strengthens a central more than peripheral origin of the symptom.

Advanced fractional radiofrequency for the rejuvenation of face, neck, and décolleté.

Recently great attention has been paid to the rejuvenation of the face, neck, and décolleté of women with advanced radial fractional radiofrequency. We aimed to clinically evaluate the results obtained with this treatment method. We treated 10 women aged 42 to 62, suffering from skin aging. After carrying out the hydration and sebometry skin tests in each patient, collecting the medical history and taking photographs of the face and décolleté in the standard projections, a questionnaire was submitted to each patient. Finally, we have submitted the patients to one session of application of radiofrequency energy, by an Italian device named "Thuzzle" (GMV, Rome, Italy). The obtained results show a high effectiveness in improving the texture and tone of skin, decreasing micro wrinkles and spot reduction. Advanced radial fractional radiofrequency treatment method shows promising results. Further studies are required to confirm the findings.

A New, High-Efficacy, Noninvasive Transcranial Electric Stimulation Tuned to Local Neurodynamics.

In this paper, we pose the following working hypothesis: in humans, transcranial electric stimulation (tES) with a time course that mimics the endogenous activity of its target is capable of altering the target's excitability. In our case, the target was the primary motor cortex (M1). We identified the endogenous neurodynamics of hand M1's subgroups of pyramidal neuronal pools in each of our subjects by applying Functional Source Separation (FSS) to their EEG recordings. We then tested whether the corticospinal excitability of the hand representation under the above described stimulation, which we named transcranial individual neurodynamics stimulation (tIDS), was higher than in the absence of stimulation (baseline). As a check, we compared tIDS with the most efficient noninvasive facilitatory corticospinal tES known so far, which is 20 Hz transcranial alternating current stimulation (tACS). The control conditions were as follows: (1) sham, (2) transcranial random noise stimulation (tRNS) in the same frequency range as tIDS (1-250 Hz), and (3) a low current tIDS (tIDSlow). Corticospinal excitability was measured with motor-evoked potentials under transcranial magnetic stimulation. The mean motor-evoked potential amplitude increase was 31% of the baseline during tIDS (p < 0.001), and it was 15% during tACS (p = 0.096). tRNS, tIDSlow, and sham induced no effects. Whereas tACS did not produce an enhancement in any subject at the individual level, tIDS was successful in producing an enhancement in 8 of the 16 subjects. The results of the present proof-of-principle study showed that proper exploitation of local neurodynamics can enhance the efficacy of personalized tES.SIGNIFICANCE STATEMENT This study demonstrated that, in humans, transcranial individual neurodynamics stimulation (tIDS), which mimics the endogenous dynamics of the target neuronal pools, effectively changes the excitability of these pools. tIDS holds promise for high-efficacy personalized neuromodulations based on individual local neurodynamics.

Personalized, bilateral whole-body somatosensory cortex stimulation to relieve fatigue in multiple sclerosis.

BACKGROUND: The patients suffering from multiple sclerosis (MS) often consider fatigue the most debilitating symptom they experience, but conventional medicine currently offers poorly efficacious therapies. OBJECTIVE: We executed a replication study of an innovative approach for relieving MS fatigue. METHODS: According to the sample size estimate, we recruited 10 fatigued MS patients who received 5-day transcranial direct current stimulation (tDCS) in a randomized, double-blind, Sham-controlled, crossover study, with modified Fatigue Impact Scale (mFIS) score reduction at the end of the treatment as primary outcome. A personalized anodal electrode, shaped on the magnetic resonance imaging (MRI)-derived individual cortical folding, targeted the bilateral whole-body primary somatosensory cortex (S1) with an occipital cathode. RESULTS: The amelioration of fatigue symptoms after Real stimulation (40% of baseline) was significantly larger than after Sham stimulation (14%, p = 0.012). Anodal whole body S1 induced a significant fatigue reduction in mildly disabled MS patients when the fatigue-related symptoms severely hampered their quality of life. CONCLUSION: This second result in an independent group of patients supports the idea that neuromodulation interventions that properly select a personalized target might be a suitable non-pharmacological treatment for MS fatigue.

Effects on Corticospinal Tract Homology of Faremus Personalized Neuromodulation Relieving Fatigue in Multiple Sclerosis: A Proof-of-Concept Study.

OBJECTIVES: Fatigue in multiple sclerosis (MS) is a frequent and invalidating symptom, which can be relieved by non-invasive neuromodulation, which presents only negligible side effects. A 5-day transcranial direct-current stimulation, 15 min per day, anodically targeting the somatosensory representation of the whole body against a larger occipital cathode was efficacious against MS fatigue (fatigue relief in multiple sclerosis, Faremus treatment). The present proof-of-concept study tested the working hypothesis that Faremus S1 neuromodulation modifies the homology of the dominant and non-dominant corticospinal (CST) circuit recruitment. METHODS: CST homology was assessed via the Fréchet distance between the morphologies of motor potentials (MEPs) evoked by transcranial magnetic stimulation in the homologous left- and right-hand muscles of 10 fatigued MS patients before and after Faremus. RESULTS: In the absence of any change in MEP features either as differences between the two body sides or as an effect of the treatment, Faremus changed in physiological direction the CST's homology. Faremus effects on homology were more evident than recruitment changes within the dominant and non-dominant sides. CONCLUSIONS: The Faremus-related CST changes extend the relevance of the balance between hemispheric homologs to the homology between body sides. With this work, we contribute to the development of new network-sensitive measures that can provide new insights into the mechanisms of neuronal functional patterning underlying relevant symptoms.

Home treatment against fatigue in multiple sclerosis by a personalized, bilateral whole-body somatosensory cortex stimulation.

BACKGROUND: Fatigue in multiple sclerosis (MS) is a highly invalidating symptom with no pharmacological efficacious therapies, which furthermore present frequent severe side effects. In two previous randomized controlled trials we observed the efficacy of a personalized neuromodulation treatment consisting of a personalized transcranial Direct Current Stimulation (tDCS) for 15 min per day for 5 days (Faremus). METHODS: By this medical-device phase II study, we aimed at assessing the feasibility, acceptance, safety and efficacy of Faremus treatment when applied at patients' home. We considered the efficacy as primary outcome assessed by a reduction of fatigue levels measured by Modified Fatigue Impact Scale (mFIS) scored before and after the treatment. Primary outcome determined the sample size estimate. Individual ad-hoc questionnaires quantified the acceptance, safety and side effects during the treatment. RESULTS: All 15 patients completed the treatment, reporting optimal acceptance and safety on using Faremus at their home without side-effects. The treatment ameliorated fatigue symptoms more than 20% of baseline in 10 out of the 15 patients and of 37% on average, with a corresponding effect size 1.21. CONCLUSIONS: Faremus personalized electroceutical intervention, a 5-days anodal tDCS over the bilateral whole-body somatosensory cortex, is well accepted and can be feasibly, safely, and efficaciously applied at patients' home, offering a comfortable treatment by reducing the need to travel when fatigue-related symptoms hamper the quality of life.

Corticomuscular Coherence Dependence on Body Side and Visual Feedback.

Physiological movement develops on the basis of sensorimotor integration through synchronisation between the copy of signals sent to the effector muscles and the incoming flow of sensory information. Our aim is to study corticomuscular coherence (CMC), the most widely used measure of synchronization between brain and muscle electrical activities, in dependence on the level of visual feedback and the executing body side. We analysed CMC in 18 healthy volunteers while performing a weak isometric handgrip of an air bulb with either the right or the left hand, in either the presence or absence of visual feedback on the exerted pressure. The absence of visual feedback decreased the CMC peak frequency from 27 Hz to 23 Hz (p < 0.001), increased the CMC peak amplitude from 0.05 to 0.07 (p = 0.005) and decreased the electroencephalographic beta band power (p = 0.005). None of these measures changed in dependence on the performing hand (p > 0.2 consistently). The lack of dependence of CMC on the controlled hand involved in the movement can be considered in agreement with small hemispheric asymmetries of hand representations in primary sensorimotor cortices. Modulation of visual information changed corticomuscular synchronizations and cortical involvement, reflecting the crucial role of gaze in human behaviour. Given the fundamental role of sensory integration in motor execution, the availability of a simple index sensitive to modulations of perceptual afferents may prove useful in determining the use or the monitoring of the effects of sensory enrichments in personalized rehabilitation.

Cortical neurodynamics changes mediate the efficacy of a personalized neuromodulation against multiple sclerosis fatigue.

The people with multiple sclerosis (MS) often report that fatigue restricts their life. Nowadays, pharmacological treatments are poorly effective accompanied by relevant side effects. A 5-day transcranial direct current stimulation (tDCS) targeting the somatosensory representation of the whole body (S1) delivered through an electrode personalized based on the brain MRI was efficacious against MS fatigue (FaReMuS treatment). This proof of principle study tested whether possible changes of the functional organization of the primary sensorimotor network induced by FaReMuS partly explained the effected fatigue amelioration. We measured the brain activity at rest through electroencephalography equipped with a Functional Source Separation algorithm and we assessed the neurodynamics state of the primary somatosensory (S1) and motor (M1) cortices via the Fractal Dimension and their functional connectivity via the Mutual Information. The dynamics of the neuronal electric activity, more distorted in S1 than M1 before treatment, as well as the network connectivity, altered maximally between left and right M1 homologs, reverted to normal after FaReMuS. The intervention-related changes explained 48% of variance of fatigue reduction in the regression model. A personalized neuromodulation tuned in on specific anatomo-functional features of the impaired regions can be effective against fatigue.

Functional Semi-Blind Source Separation Identifies Primary Motor Area Without Active Motor Execution.

High time resolution techniques are crucial for investigating the brain in action. Here, we propose a method to identify a section of the upper-limb motor area representation (FS_M1) by means of electroencephalographic (EEG) signals recorded during a completely passive condition (FS_M1bySS). We delivered a galvanic stimulation to the median nerve and we applied to EEG the semi-Blind Source Separation (s-BSS) algorithm named Functional Source Separation (FSS). In order to prove that FS_M1bySS is part of FS_M1, we also collected EEG in a motor condition, i.e. during a voluntary movement task (isometric handgrip) and in a rest condition, i.e. at rest with eyes open and closed. In motor condition, we show that the cortico-muscular coherence (CMC) of FS_M1bySS does not differ from FS_ M1 CMC (0.04 for both sources). Moreover, we show that the FS_M1bySS's ongoing whole band activity during Motor and both rest conditions displays high mutual information and time correlation with FS_M1 (above 0.900 and 0.800, respectively) whereas much smaller ones with the primary somatosensory cortex [Formula: see text] (about 0.300 and 0.500, [Formula: see text]). FS_M1bySS as a marker of the upper-limb FS_M1 representation obtainable without the execution of an active motor task is a great achievement of the FSS algorithm, relevant in most experimental, neurological and psychiatric protocols.

Brain Functional Connectivity Changes After Transcranial Direct Current Stimulation in Epileptic Patients.

Focal epilepsy is a network pathology, where the brain connectivity of the epileptic focus (EF) influences seizure frequency and cortical dysfunction. Growing evidence supports a clinical efficacy of cathodal transcranial direct current stimulation (ctDCS) in drug-resistant epilepsy (DRE). ctDCS effects can be merely attributed to the inhibition of cortical excitability, which is abnormally increased in epilepsy, but its effect on brain network of DRE patients has never been reported. We aimed at exploring the hypothesis that functional connectivity (FC) changes may explain part of ctDCS clinical effects in DRE patients. We assessed the ctDCS-induced changes of electroencephalography-derived brain FC of a group of six temporal lobe DRE patients receiving a seizure reduction after ctDCS. By a single-subject eLORETA analysis, we compared the FC among the EF region and other nine bilateral macro-regions, before and after Real and Sham ctDCS in a double-blind Sham-controlled crossover design. FC changed after Real ctDCS in all patients despite no appreciable changes occurred after Sham. Most of FC changes (73%) involved the EF region. The epileptic seizure reduction correlated with the increase of the EF FC, in the whole frequency band and in the theta band. This small-sample analysis clearly revealed that ctDCS induced FC changes in the brain network of temporal lobe DRE patients. Our data support the hypothesis that FC changes may contribute to explain the effects of ctDCS in epilepsy, offering a new scenario in the personalization of neuromodulation interventions in epileptic people.

MRI-Guided Regional Personalized Electrical Stimulation in Multisession and Home Treatments.

The shape and position of the electrodes is a key factor for the efficacy of transcranial electrical stimulations (tES). We have recently introduced the Regional Personalized Electrode (RePE), a tES electrode fitting the personal cortical folding, that has been able to differentiate the stimulation of close by regions, in particular the primary sensory (S1) and motor (M1) cortices, and to personalize tES onto such an extended cortical district. However, neuronavigation on individual brain was compulsory for the correct montage. Here, we aimed at developing and testing a neuronavigation-free procedure for easy and quick positioning RePE, enabling multisession RePE-tES at home. We used off-line individual MRI to shape RePE via an ad-hoc computerized procedure, while an ad-hoc developed Adjustable Helmet Frame (AHF) was used to properly position it in multisession treatments, even at home. We used neuronavigation to test the RePE shape and position obtained by the new computerized procedure and the re-positioning obtained via the AHF. Using Finite Element Method (FEM) model, we also estimated the intra-cerebral current distribution induced by transcranial direct current stimulation (tDCS) comparing RePE vs. non-RePE with fixed reference. Additionally, we tested, using FEM, various shapes, and positions of the reference electrode taking into account possible small displacements of RePE, to test feasibility of RePE-tES sessions at home. The new RePE neuronavigation-free positioning relies on brain MRI space distances, and produced a mean displacement of 3.5 ± 0.8 mm, and the re-positioning of 4.8 ± 1.1 mm. Higher electric field in S1 than in M1 was best obtained with the occipital reference electrode, a montage that proved to feature low sensitivity to typical RePE millimetric displacements. Additionally, a new tES accessory was developed to enable repositioning the electrodes over the scalp also at home, with a precision which is acceptable according to the modeling-estimated intracerebral currents. Altogether, we provide here a procedure to simplify and make easily applicable RePE-tDCS, which enables efficacious personalized treatments.

Neuronal electrical ongoing activity as a signature of cortical areas.

Brodmann's pioneering work resulted in the classification of cortical areas based on their cytoarchitecture and topology. Here, we aim at documenting that diverse cortical areas also display different neuronal electric activities. We investigated this notion in the hand-controlling sections of the primary somatosensory (S1) and motor (M1) areas, in both hemispheres. We identified S1 and M1 in 20 healthy volunteers by applying functional source separation (FSS) to their recorded electroencephalograms (EEG). Our results show that S1 and M1 can be clearly differentiated by their neuroelectric activities in both hemispheres and independently of the subject's state (i.e., at rest or performing movements or receiving external stimulations). In particular, S1 displayed higher relative power than M1 in the alpha and low beta frequency ranges (8-25 Hz, p < .003), whereas the opposite occurred in the high gamma band (52-90 Hz, p = .006). In addition, S1's activity had a smaller Higuchi's fractal dimensions (HFD) than M1's (p < .00001) in all subjects, permitting a reliable classification of the two areas. Moreover, HFD of M1's activity resulted correlated with the hand's fine motor control, as expressed by the 9-hole peg test scores. The present work is a first step toward the identification and classification of brain cortical areas based on neuronal dynamics rather than on cytoarchitectural features. We deem this step to be an improvement of our knowledge of the brain's structural-functional unity.

Simple index of functional connectivity at rest in Multiple Sclerosis fatigue.

OBJECTIVE: To investigate the EEG-derived functional connectivity at rest (FCR) patterns of fatigued Multiple Sclerosis (MS) patients in order to find good parameters for a future EEG-Neurofeedback intervention to reduce their fatigue symptoms. METHODS: We evaluated FCR between hemispheric homologous areas, via spectral coherence between pairs of corresponding left and right bipolar derivations, in the Theta, Alpha and Beta bands. We estimated FCR in 18MS patients with different levels of fatigue and minimal clinical severity and in 11 age and gender matched healthy controls. We used correlation analysis to assess the relationship between the fatigue scores and the FCR values differing between fatigued MS patients and controls. RESULTS: Among FCR values differing between fatigued MS patients and controls, fatigue symptoms increased with higher Beta temporo-parietal FCR (p=0.00004). Also, positive correlations were found between the fatigue levels and the fronto-frontal FCR in Beta and Theta bands (p=0.0002 and p=0.001 respectively). CONCLUSION: We propose that a future EEG-Neurofeedback system against MS fatigue would train patients to decrease voluntarily the beta coherence between the homologous temporo-parietal areas. SIGNIFICANCE: We extracted a feature for building an EEG-Neurofeedback system against fatigue in MS.

A Computational Model of the Electric Field Distribution due to Regional Personalized or Nonpersonalized Electrodes to Select Transcranial Electric Stimulation Target.

OBJECTIVE: A procedure to personalize the electrode to stimulate specific cortical regions by transcranial electric stimulations has been recently proposed. This study aims to assess the distribution of the electric field (E) induced by tES via the personalized (RePE) and the nonpersonalized (ReNPE) electrode. METHODS: We used two anatomical models on which we shaped and placed the RePE, based on brain anatomy, and the ReNPE to target the bilateral primary motor (M1) or somatosensory cortex (S1) with the reference on the occipital area in both cases. The effect of shifts of the ReNPE position has been also evaluated. RESULTS: The RePE induced higher E peak and median values than the ReNPE along the bilateral primary motor sensory cortices, up to their lateral regions, on a great percentage of volume of these cortices along all their extent. The shift of the ReNPE electrode toward the inion still induced higher E peak and median values than the ReNPE not shifted, but less than the RePE, mainly in the central region and, in a lower percentage of volume, in the lateral regions of these cortices. CONCLUSION: The E distributions induced for both targets (M1 and S1) by the RePE are different from the ones due to the ReNPE, along the whole extent of the bilateral primary sensorimotor cortices. The shift in the ReNPE positioning can modify the E distributions mainly in the more central region of these cortices. SIGNIFICANCE: These results strengthen the suitability of personalized electrodes in targeting extended cortical regions.

Electroencephalography-Derived Sensory and Motor Network Topology in Multiple Sclerosis Fatigue.

People with multiple sclerosis (MS) frequently complain of excessive fatigue, which is the most disabling symptom for half of them. While the few drugs used to treat MS fatigue are of limited utility, we recently observed the efficacy of a personalized neuromodulation treatment. Here, we aim at strengthening knowledge of the brain network changes that occur when MS fatigue increases, using graph theory. We collected electroencephalographic (EEG; 23 or 64 channels) data in resting state with eyes open in 27 relapsing-remitting (RR) patients with mild MS (EDSS ≤2), suffering a wide range of fatigue as scored by the modified Fatigue Impact Scale (mFIS) (2-69, within a total range 0-84). To estimate graph theory small-world index (SW), we calculated the lagged linear coherence between EEG cortical eLORETA sources, in the standard frequency bands delta (2-4 Hz), theta (4-8 Hz), alpha1 (8-10.5 Hz), alpha2 (10.5-13 Hz), beta1 (13-20 Hz), beta2 (20-30 Hz), and gamma (30-45 Hz). We calculated the SW of these undirected and weighted networks separately in the four left and right frontal (motor) and parieto-occipito-temporal (sensory) brain networks. A correlative analysis demonstrated increased fatigue symptoms along with the SW specifically in the Sensory network of the left dominant hemisphere in the beta1 band (Pearson's r = 0.404, P = .020). Our study indicates a specific involvement of the dominant-hemisphere sensory network in MS fatigue. It suggests that compensatory neuromodulation interventions could enhance efficacy in relieving this debilitating symptom by targeting this area.

A simple method for EEG guided transcranial electrical stimulation without models.

OBJECTIVE: There is longstanding interest in using EEG measurements to inform transcranial Electrical Stimulation (tES) but adoption is lacking because users need a simple and adaptable recipe. The conventional approach is to use anatomical head-models for both source localization (the EEG inverse problem) and current flow modeling (the tES forward model), but this approach is computationally demanding, requires an anatomical MRI, and strict assumptions about the target brain regions. We evaluate techniques whereby tES dose is derived from EEG without the need for an anatomical head model, target assumptions, difficult case-by-case conjecture, or many stimulation electrodes. APPROACH: We developed a simple two-step approach to EEG-guided tES that based on the topography of the EEG: (1) selects locations to be used for stimulation; (2) determines current applied to each electrode. Each step is performed based solely on the EEG with no need for head models or source localization. Cortical dipoles represent idealized brain targets. EEG-guided tES strategies are verified using a finite element method simulation of the EEG generated by a dipole, oriented either tangential or radial to the scalp surface, and then simulating the tES-generated electric field produced by each model-free technique. These model-free approaches are compared to a 'gold standard' numerically optimized dose of tES that assumes perfect understanding of the dipole location and head anatomy. We vary the number of electrodes from a few to over three hundred, with focality or intensity as optimization criterion. MAIN RESULTS: Model-free approaches evaluated include (1) voltage-to-voltage, (2) voltage-to-current; (3) Laplacian; and two Ad-Hoc techniques (4) dipole sink-to-sink; and (5) sink to concentric. Our results demonstrate that simple ad hoc approaches can achieve reasonable targeting for the case of a cortical dipole, remarkably with only 2-8 electrodes and no need for a model of the head. SIGNIFICANCE: Our approach is verified directly only for a theoretically localized source, but may be potentially applied to an arbitrary EEG topography. For its simplicity and linearity, our recipe for model-free EEG guided tES lends itself to broad adoption and can be applied to static (tDCS), time-variant (e.g., tACS, tRNS, tPCS), or closed-loop tES.

Electroencephalographic Fractal Dimension in Healthy Ageing and Alzheimer's Disease.

Brain activity is complex; a reflection of its structural and functional organization. Among other measures of complexity, the fractal dimension is emerging as being sensitive to neuronal damage secondary to neurological and psychiatric diseases. Here, we calculated Higuchi's fractal dimension (HFD) in resting-state eyes-closed electroencephalography (EEG) recordings from 41 healthy controls (age: 20-89 years) and 67 Alzheimer's Disease (AD) patients (age: 50-88 years), to investigate whether HFD is sensitive to brain activity changes typical in healthy aging and in AD. Additionally, we considered whether AD-accelerating effects of the copper fraction not bound to ceruloplasmin (also called "free" copper) are reflected in HFD fluctuations. The HFD measure showed an inverted U-shaped relationship with age in healthy people (R2 = .575, p < .001). Onset of HFD decline appeared around the age of 60, and was most evident in central-parietal regions. In this region, HFD decreased with aging stronger in the right than in the left hemisphere (p = .006). AD patients demonstrated reduced HFD compared to age- and education-matched healthy controls, especially in temporal-occipital regions. This was associated with decreasing cognitive status as assessed by mini-mental state examination, and with higher levels of non-ceruloplasmin copper. Taken together, our findings show that resting-state EEG complexity increases from youth to maturity and declines in healthy, aging individuals. In AD, brain activity complexity is further reduced in correlation with cognitive impairment. In addition, elevated levels of non-ceruloplasmin copper appear to accelerate the reduction of neural activity complexity. Overall, HDF appears to be a proper indicator for monitoring EEG-derived brain activity complexity in healthy and pathological aging.

Use of Computational Modeling to Inform tDCS Electrode Montages for the Promotion of Language Recovery in Post-stroke Aphasia.

BACKGROUND: Although pilot trials of transcranial direct current stimulation (tDCS) in aphasia are encouraging, protocol optimization is needed. Notably, it has not yet been clarified which of the varied electrode montages investigated is the most effective in enhancing language recovery. OBJECTIVE: To consider and contrast the predicted brain current flow patterns (electric field distribution) produced by varied 1×1 tDCS (1 anode, 1 cathode, 5 × 7 cm pad electrodes) montages used in aphasia clinical trials. METHODS: A finite element model of the head of a single left frontal stroke patient was developed in order to study the pattern of the cortical EF magnitude and inward/outward radial EF under five different electrode montages: Anodal-tDCS (A-tDCS) over the left Wernicke's area (Montage A) and over the left Broca's area (Montage B); Cathodal tDCS (C-tDCS) over the right homologue of Wernicke's area (Montage C), and of Broca's area (Montage D), where for all montages A-D the "return" electrode was placed over the supraorbital contralateral forehead; bilateral stimulation with A-tDCS over the left Broca's and CtDCS over the right Broca's homologue (Montage E). RESULTS: In all cases, the "return" electrode over the contralesional supraorbital forehead was not inert and influenced the current path through the entire brain. Montage B, although similar to montage D in focusing the current in the perilesional area, exerted the greatest effect over the left perilesional cortex, which was even stronger in montage E. CONCLUSIONS: The position and influence of both electrodes must be considered in the design and interpretation of tDCS clinical trials for aphasia.

Cortical inhibition and excitation by bilateral transcranial alternating current stimulation.

PURPOSE: Transcranial electric stimulations (tES) with amplitude-modulated currents are promising tools to enhance neuromodulation effects. It is essential to select the correct cortical targets and inhibitory/excitatory protocols to reverse changes in specific networks. We aimed at assessing the dependence of cortical excitability changes on the current amplitude of 20 Hz transcranial alternating current stimulation (tACS) over the bilateral primary motor cortex. METHODS: We chose two amplitude ranges of the stimulations, around 25 µA/cm2 and 63 µA/cm2 from peak to peak, with three values (at steps of about 2.5%) around each, to generate, respectively, inhibitory and excitatory effects of the primary motor cortex. We checked such changes online through transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs). RESULTS: Cortical excitability changes depended upon current density (p = 0.001). Low current densities decreased MEP amplitudes (inhibition) while high current densities increased them (excitation). CONCLUSIONS: tACS targeting bilateral homologous cortical areas can induce online inhibition or excitation as a function of the current density.