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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).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.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.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.

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.

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.

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.

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.

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.

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 18 MS 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.

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.

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 ?A/cm2 and 63 ?A/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.

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.

Background Among transcranial electric stimulation (tES) parameters, personalizing the electrode geometry might help overcome the individual variability of the induced effects. Objective/hypothesis To test the need for electrode personalization, instead of a universal electrode for everyone, to induce neuromodulation effects on the bilateral primary motor cortex (M1) devoted to upper and lower limb representation. Methods By an ad-hoc neuronavigation procedure, we shaped the personalized electrode and positioned it matching the projection on the scalp of the individual central sulcus by a 2 cm strip, with total area of 35 cm 2 . The non-personalized electrode, i.e., equal for all subjects, was a 2 cm wide strip size-matched with the personalized electrode but shaped on a standard model fitting the curve passing through C3-CZ-C4 sites of the electroencephalographic (EEG) 10-20 International System. To test neuromodulation electrode-dependent efficacy, we induced a 20 Hz sinusoidal modulated current (transcranial alternating current stimulation, tACS) because it produces online effects. We simultaneously collected left and right hand and leg motor potentials (MEP) that were evoked by a rounded transcranial magnetic stimulation (TMS) coil. Through each electrode we delivered both real and sham stimulations. Results While cortical excitability during tACS increased during both the non-personalized and the personalized electrodes for the leg, the hand representation excitability enhancement was induced selectively when using the personalized electrode. The results were consistent bilaterally. Conclusions We documented that by using a personalized electrode it is possible to induce the neuromodulation of a predetermined extended cortical target, which did not occur with a non-personalized electrode. Our findings can help in building neuromodulation methods that might compensate for individual alterations across specific brain networks.

Multiple sclerosis-related fatigue is highly common and often refractory to medical therapy. Ten fatigued multiple sclerosis patients received two blocks of 5-day anodal bilateral primary somatosensory areas transcranial direct current stimulation in a randomized, doubleblind sham-controlled, cross-over study. The real neuromodulation by a personalized electrode, shaped on the MRderived primary somatosensory cortical strip, reduced fatigue in all patients, by 26% in average ( p = 0.002), which did not change after sham ( p = 0.901). Anodal tDCS over bilateral somatosensory areas was able to relief fatigue in mildly disabled MS patients, when the fatigue related symptoms severely hamper their quality of life. These small-scale study results support the concept that interventions modifying the sensorimotor network activity balances could be a suitable non-pharmacological treatment for multiple sclerosis fatigue.