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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. more...

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. more...

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. more...

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. more...

Objective There is a long interest in using EEG measurements to inform transcranial Electrical Stimulation (tES) but adoption is lacking. 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 or assumptions. Approach The approaches are verified using a Finite Element Method (FEM) simulation of the EEG generated by a dipole, oriented either tangential or radial to the surface, and then simulating brain current flow produced by various model-free techniques including: (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 Ring. These model-free approaches are compared to a numerically optimized dose 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 Our results demonstrate how simple Ad-Hoc approaches can achieve reasonable targeting for the case of a cortical dipole with 2–8 electrodes and no need for a model of the head. Significance For its simplicity and linearity, model-free EEG guided lends itself to broad adoption and can be applied to a static (tDCS), time-variant (e.g. tACS, tRNS, tPCS), or closed-loop tES. Figure options Download full-size image Download high-quality image (1118 K) Download as PowerPoint slide Figure options Download full-size image Download high-quality image (1499 K) Download as PowerPoint slide more...

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. more...

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. more...

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. more...

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. more...

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 μ A/cm2 and 63 μ 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=.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. more...

Brodmann’s pioneering work resulted in the classification of the cortical areas based on their cyto-architecture and topology. Here, we aim at documenting that cortical areas can be also classified by neuronal activities specific to well identifiable structures and to the latter’s networking within the whole brain. We investigated this notion in the primary somatosensory area (S1) and in the primary motor area (M1) in both hemispheres. Our results show that S1 and M1 are topologically differentiated by their respective neuronal activities, which are specific, independent of hemisphere and of subject’s state (i.e., at rest, performing movements or receiving external stimulations). S1 displays higher power than M1 (p = .001) in the beta frequency band, while the opposite occurs in the gamma2 band (p = .034). We also show that the fractal dimensions (FD) emerged from our study as a strong index capable of differentiating the two brain areas in all subject’s states, with S1’s FD smaller than M1’s (p .00001). The present work intends to be a first step toward the identification and classification of brain cortical areas via the dynamics of their neuronal activity, which we believe will advance our knowledge of the brain’s intimate structural–functional unity. more...

Introduction Recently we developed a new procedure to personalize the electrode to selectively stimulate specific cortical regions by transcranial electric stimulations (tES).This study aims to assess by computational approach the distribution of the intra-cerebral electric field induced by tES through the personalized in comparison with a non-personalized electrode in human models. Methods We used two realistic human models and 40 tissue conductivities.We targeted bilateral primary motor (M1) and somatosensory cortex (S1) alternatively with the personalized and non-personalized electrode, with the reference on the occipital area. We estimated the distribution of the electric field across the brain structures. Results The personalized electrode was able to modulate more deeply and strongly the area of the central sulcus than the non-personalized one. This trend was more evident in the regions along the central sulcus more far away from Cz, where the two electrodes are less overlapped and for both targets (M1 and S1). Moreover, the personalized electrode used to target S1 more selectively modulated the postcentral gyrus, whereas the personalized electrode used to target M1 broadened its effects over both the pre and postcentral gyrus. Discussions This work strengthens the notion that tES can be focused by properly shaping and positioning the stimulating electrodes according to the target regions. more...

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. more...

Rationale: Personalizing transcranial stimulations promises to enhance beneficial effects for individual patients. Objective: To stimulate specific cortical regions by developing a procedure to bend and position custom shaped electrodes; to probe the effects on cortical excitability produced when the properly customized electrode is targeting different cortical areas. Method: An ad hoc neuronavigation procedure was developed to accurately shape and place the personalized electrodes on the basis of individual brain magnetic resonance images (MRI) on bilateral primary motor (M1) and somatosensory (S1) cortices. The transcranial alternating current stimulation (tACS) protocol published by Feurra et al. (2011b) was used to test the effects on cortical excitability of the personalized electrode when targeting S1 or M1. Results: Neuronal excitability as evaluated by tACS was different when targeting M1 or S1, with the General Estimating Equation model indicating a clear tCS Effect (p more...

The large majority (80%) of people with multiple sclerosis (MS) complain of fatigue, which is the most disabling symptom in half of them. While the few drugs used to treat MS fatigue are limitedly useful, it was recently observed the efficacy of a personalized neuromodulation treatment, supporting the concept that interventions modifying the sensorimotor network activity balances could be suitable non-pharmacological treatments for MS fatigue. Aim of the present study is to strengthen knowledge of the brain unbalances, which proper neuromodulations should target to compensate. We collected electroencephalographic (EEG) data in 18 people with mild MS, while they were in resting state with open eyes. To ensure a wide range of fatigue, we enrolled patients to have Higher- or Lower-Fatigue based on scores of the modified Fatigue Impact Scale (mFIS). We selected the graph theory small-world index, calculated on networks of cortical nodes estimated by eLORETA, to evaluate the characteristics of left and right frontal (Motor) and parieto-occipital-temporal (Sensory) brain networks separately. Fatigue symptoms increased together with the small-world index in the Sensory network of the left dominant hemisphere. This finding hones understanding of the targets of neuromodulation interventions, indicating the sensory network of the dominant left hemisphere as a specific target. more...

Recently we developed a new procedure to personalize the electrode to selectively stimulate specific cortical regions by transcranial electric stimulations (tES) [Tecchio et al.,2013] and we showed that tES via this innovative personalized electrode shaped on individual brain MRI can relieve multiple sclerosis fatigue [Tecchio et al., 2014]. This study aims to assess by computational approach the distriution of the intra-cerebral electric field induced by tES through the personalized in comparison with a non-personalized electrode in two realistic human models. more...

Objective To test the need for the electrode personalization to induce neuromodulation effects on the bilateral primary motor cortex (M1) devoted to upper and lower limb representation. Methods We shaped the personalized electrode and positioned it matching the projection on the scalp of the individual central sulcus by a 2 cm strip. The non personalized electrode,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.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 magneticstimulation (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 Personalized electrode can induce the neuromodulation of a predetermined extended cortical target, which is impossible with a non-personalized electrode. Our findings can help in building neuromodulations that compensate for alterations across specific brain networks. more...