Carlo Cottone

Regional personalized electrodes to select transcranial current stimulation target

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 < 0.001), and post hoc comparisons showing solely M1 20 Hz tACS to reduce M1 excitability with respect to baseline and other tACS conditions. Conclusions: The present work indicates that specific cortical regions can be targeted by tCS properly shaping and positioning the stimulating electrode. Significance: Through multimodal brain investigations continuous efforts in understanding the neuronal changes related to specific neurological or psychiatric diseases become more relevant as our ability to build the compensating interventions improves. An important step forward on this path is the ability to target the specific cortical area of interest, as shown in the present pilot work.

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.

Brain Plasticity Effects of Neuromodulation Against Multiple Sclerosis Fatigue

Rationale We recently reported on the efficacy of a personalized transcranial direct current stimulation (tDCS) treatment in reducing multiple sclerosis (MS) fatigue. The result supports the notion that interventions targeted at modifying abnormal excitability within the sensorimotor network could represent valid non-pharmacological treatments. Objective The present work aimed at assessing whether the mentioned intervention also induces changes in the excitability of sensorimotor cortical areas. Method Two separate groups of fatigued MS patients were given a 5-day tDCS treatments targeting, respectively, the whole body somatosensory areas (S1wb) and the hand sensorimotor areas (SM1hand). The study had a double blind, sham-controlled, randomized, cross-over (Real vs. Sham) design. Before and after each treatment, we measured fatigue levels (by the modified fatigue impact scale, mFIS), motor evoked potentials (MEPs) in response to transcranial magnetic stimulation and somatosensory evoked potentials (SEPs) in response to median nerve stimulation. We took MEPs and SEPs as measures of the excitability of the primary motor area (M1) and the primary somatosensory area (S1), respectively. Results The Real S1wb treatment produced a 27% reduction of the mFIS baseline level, while the SM1hand treatment showed no difference between Real and Sham stimulations. M1 excitability increased on average 6% of the baseline in the S1wb group and 40% in the SM1hand group. Observed SEP changes were not significant and we found no association between M1 excitability changes and mFIS decrease. Conclusion The tDCS treatment was more effective against MS fatigue when the electrode was focused on the bilateral whole body somatosensory area. Changes in S1 and M1 excitability did not correlate with symptoms amelioration. Significance The neuromodulation treatment that proved effective against MS fatigue induced only minor variations of the motor cortex excitability, not enough to explain the beneficial effects of the intervention.

Personalizing the Electrode to Neuromodulate an Extended Cortical Region

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.

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.

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.

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.

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.

Transcranial Direct Current Stimulation: Personalizing the neuromodulation

The beneficial effects of transcranial direct current stimulation (tDCS) has been demonstrated, but the neuroscientific community is working to increase its efficiency. A promising line of advancement may be reducing the inter-individual variability of the response through the personalization of the stimulation, adapted to fit the structural and functional features of individual subjects. In this paper, we approach the personalization of stimulation parameters using modeling, a powerful tool to test montages enabling the optimization of brains targeting.

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.