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.

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.

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.

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.

Algorithm for fast monoexponential fitting based on Auto-Regression on Linear Operations (ARLO) of data.

PURPOSE: To develop a fast and accurate monoexponential fitting algorithm based on Auto-Regression on Linear Operations (ARLO) of data, and to validate its accuracy and computational speed by comparing it with the conventional Levenberg-Marquardt (LM) and Log-Linear (LL) algorithms. METHODS: ARLO, LM, and LL performances for T2* mapping were evaluated in simulation and in vivo imaging of liver (n=15) and myocardial (n=1) iron overload patients and the brain (two healthy volunteers). RESULTS: In simulations, ARLO consistently delivered accuracy similar to LM and significantly superior to LL. In in vivo mapping of T2 * values, ARLO showed excellent agreement with LM, while LL showed only limited agreements with ARLO and LM. Compared with LM and LL in the liver, ARLO was 125 and 8 times faster using our Matlab implementations, and 156 and 13 times faster using our C++ implementations. In C++ implementations, ARLO reduced the online whole-brain processing time from 9 min 15 s of LM and 35 s of LL to 2.7 s, providing T2 * maps approximately in real time. CONCLUSION: Due to comparable accuracy and significantly higher speed, ARLO can be considered as a valid alternative to the conventional LM algorithm for online T2 * mapping.

Intracranial calcifications and hemorrhages: characterization with quantitative susceptibility mapping.

PURPOSE: To compare gradient-echo (GRE) phase magnetic resonance (MR) imaging and quantitative susceptibility mapping (QSM) in the detection of intracranial calcifications and hemorrhages. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board. Thirty-eight patients (24 male, 14 female; mean age, 33 years ± 16 [standard deviation]) with intracranial calcifications and/or hemorrhages diagnosed on the basis of computed tomography (CT), MR imaging (interval between examinations, 1.78 days ± 1.31), and clinical information were selected. GRE and QSM images were reconstructed from the same GRE data. Two experienced neuroradiologists independently identified the calcifications and hemorrhages on the QSM and GRE phase images in two randomized sessions. Sensitivity, specificity, and interobserver agreement were computed and compared with the McNemar test and k coefficients. Calcification loads and volumes were measured to gauge intermodality correlations with CT. RESULTS: A total of 156 lesions were detected: 62 hemorrhages, 89 calcifications, and five mixed lesions containing both hemorrhage and calcification. Most of these lesions (146 of 151 lesions, 96.7%) had a dominant sign on QSM images suggestive of a specific diagnosis of hemorrhage or calcium, whereas half of these lesions (76 of 151, 50.3%) were heterogeneous on GRE phase images and thus were difficult to characterize. Averaged over the two independent observers for detecting hemorrhages, QSM achieved a sensitivity of 89.5% and a specificity of 94.5%, which were significantly higher than those at GRE phase imaging (71% and 80%, respectively; P < .05 for both readers). In the identification of calcifications, QSM achieved a sensitivity of 80.5%, which was marginally higher than that with GRE phase imaging (71%; P = .08 and .10 for the two readers), and a specificity of 93.5%, which was significantly higher than that with GRE phase imaging (76.5%; P < .05 for both readers). QSM achieved significantly better interobserver agreements than GRE phase imaging in the differentiation of hemorrhage from calcification (κ: 0.91 vs 0.55, respectively; P < .05). CONCLUSION: QSM is superior to GRE phase imaging in the differentiation of intracranial calcifications from hemorrhages and with regard to the sensitivity and specificity of detecting hemorrhages and the specificity of detecting calcifications.

Multiple frequency functional connectivity in the hand somatosensory network: an EEG study.

OBJECTIVE: To investigate the dynamics of communication within the primary somatosensory neuronal network. METHODS: Multichannel EEG responses evoked by median nerve stimulation were recorded from six healthy participants. We investigated the directional connectivity of the evoked responses by assessing the Partial Directed Coherence (PDC) among five neuronal nodes (brainstem, thalamus and three in the primary sensorimotor cortex), which had been identified by using the Functional Source Separation (FSS) algorithm. We analyzed directional connectivity separately in the low (1-200 Hz, LF) and high (450-750 Hz, HF) frequency ranges. RESULTS: LF forward connectivity showed peaks at 16, 20, 30 and 50 ms post-stimulus. An estimate of the strength of connectivity was modulated by feedback involving cortical and subcortical nodes. In HF, forward connectivity showed peaks at 20, 30 and 50 ms, with no apparent feedback-related strength changes. CONCLUSIONS: In this first non-invasive study in humans, we documented directional connectivity across subcortical and cortical somatosensory pathway, discriminating transmission properties within LF and HF ranges. SIGNIFICANCE: The combined use of FSS and PDC in a simple protocol such as median nerve stimulation sheds light on how high and low frequency components of the somatosensory evoked response are functionally interrelated in sustaining somatosensory perception in healthy individuals. Thus, these components may potentially be explored as biomarkers of pathological conditions.

Antioxidant status and APOE genotype as susceptibility factors for neurodegeneration in Alzheimer's disease and vascular dementia.

Different factors interact to develop neurodegeneration in patients with dementia and other neurodegenerative disorders. Oxidative stress and the ε4 allele of apolipoprotein E (ApoE) are associated with significant alteration in lipid metabolism, in turn connected to a variety of neurodegenerative diseases and aging. Thus, a better understanding of the pathogenetic pathways associated with lipid dyshomeostasis may elucidate the causes of neurodegenerative processes. To address this issue, we evaluated the effects of antioxidant status and APOE genotype on neurodegeneration in patients with dementia of the Alzheimer type (AD), with vascular dementia (VaD), and in elderly healthy controls. Eighty-two AD, 42 VaD patients, and 26 healthy controls were recruited and underwent medial temporal lobe atrophy (MTA) assessment, white matter hyperintensities rating (WMH), serum total antioxidant status assaying (TAS), and APOE genotyping. A logistic regression algorithm applied to our data revealed that a 0.01 mmol/L decrease of TAS concentration increased the probability of MTA by 24% (p=0.038) and that carriers of the APOE ε4 allele showed higher WMH scores (p=0.018), confirming that small variations in antioxidant systems homeostasis are associated with relevant modifications of disease risk. Furthermore, in individuals with analogous TAS values, the presence of the ε4 allele increased the predicted probability of having MTA. These outcomes further sustain the interaction of oxidative stress and APOE genotype to neurodegeneration.

Metal-score as a potential non-invasive diagnostic test for Alzheimer's disease.

The link between biometals and Alzheimer's disease (AD) has been investigated with a focus on local metal accumulations. In this work, we have looked at systemic metal changes and computed a score (M-score) based on metal disarrangements to discriminate patients with AD from patients with vascular dementia (VaD) and from controls. We measured serum levels of iron, copper, ceruloplasmin, transferrin, and total antioxidant capacity (TAS), performed Apolipoprotein E (APOE) genotyping and calculated non-ceruloplasmin copper ('free' copper') levels, transferrin saturation, total iron binding capacity, and ceruloplasmin-transferrin ratio (Cp/Tf) in 93 patients with AD, 45 patients with VaD, and 48 controls. All subjects underwent biochemical, neuroimaging and cognitive evaluations. Significant differences were observed among the tested groups for the levels of copper, free copper, peroxides, and TAS and for the Cp/Tf with disparity in couple comparison. On this basis we created the M-score as linear combination of biometal variables and APOE genotype. Besides its ability to discriminate AD patients vs. controls (ROC AUC=90%), M-score was able to distinguish AD vs. VaD (ROC AUC=79%). Moreover, we calculated the sensitivity and the specificity for M-score and for the other significant variables: M-score reached the highest sensitivity without a relevant loss in terms of specificity. When we compared M-score with APOE genotype and Medial Temporal Atrophy score, it resulted statistically better than these diagnostic markers. In conclusion, we confirm the link between biometals and AD and suggest its potential as diagnostic tool. Further studies may elucidate its potential role as reliable diagnostic test.

Association of K832R and R952K SNPs of Wilson's disease gene with Alzheimer's disease.

Copper homeostasis appears abnormal in Alzheimer's disease (AD) patients. The aim of this study was to assess whether loci of susceptibility for AD lie in the Wilson's disease (WD) ATP7B gene. We studied single nucleotide polymorphisms (SNPs) K832R (c.2495 A>G, rs1061472) and R952K (c. 2855 G>A, rs732774) of the WD gene in 251 AD patients and 201 healthy controls. We also evaluated their relation with apolipoprotein E (ApoE) ε4 allele frequency. R allele in K832R [adjusted Odds Ratio (OR) = 1.71 (1.12-2.60); p = 0.012] and the K allele in R952K [adjusted OR = 1.82 (1.19-2.80); p = 0.006] ATP7B SNPs were associated with an increased risk of developing AD, as well as the haplotype R832/K952, containing the 2 risk alleles (X2 = 4.85; p = 0.028). Conversely, the K832/R952 haplotype appeared to confer protection against the disease (X2 = 7.21; p = 0.007). No difference in the frequency of the ATP7B alleles between carriers and non-carriers of the ApoE ε4 variant was revealed. The linkage disequilibrium (LD) analysis revealed an association between K832R and R952K substitutions in both AD patients (D' = 0.79) and controls (D' = 0.81). A high LD between K832R and R952K was also confirmed in all HapMap populations. Our investigation demonstrated the presence of loci of susceptibility for AD in the WD ATP7B gene, supporting a role of copper dysfunction in contributing or accelerating neurodegenerative processes leading to AD.

Effects of hemochromatosis and transferrin gene mutations on iron dyshomeostasis, liver dysfunction and on the risk of Alzheimer's disease.

It is now accepted that transition metals, such as iron and copper, are involved in the pathogenesis of the Alzheimer's disease (AD) through their participation in toxic oxidative phenomena. In this context, hemochromatosis (Hfe) and transferrin (Tf) genes are of particular importance, since they play a key role in iron homeostasis. Also, signs of liver distress which accompany metal dysmetabolisms have been shown to be linked to AD. In order to investigate whether and how all these factors are interconnected, in this study we have explored the relationship of the gene variants of Hfe H63D and C282Y and of Tf C2 with serum markers of iron status (iron, ferritin, TF, TF-saturation, ceruloplasmin -CP-, CP and TF serum concentrations (CP/TF) ratio), and of liver function (albumin, transaminases, prothrombin time-prothrombin time (PT)) in a sample of 160 AD patients and 79 healthy elderly controls. Albumin resulted in lower, PT longer and AST/ALT higher ratios in AD patients than in controls, indicating a distress of the liver. Also TF was lower and ferritin higher in AD. Multiple logistic regression backward analyses, performed to evaluate the effects of our biochemical variables upon the probability of developing AD, revealed that a one-unit TF serum-decrease increases the probability of AD by 80%, a one-unit albumin serum-decrease reduces this probability by 20%, and a one-unit increase of AST/ALT ratio generates a 4-fold probability increase. Patients who were carriers of the H63D mutation showed higher levels of iron, lower levels of TF and CP and higher CP/TF ratios, a panel resembling hemochromatosis. This picture was found neither in H63D non-carrier patients, nor in healthy controls. Our results suggest the existence of a link between Hfe mutations and iron abnormalities that increases the probability of developing AD when accompanied by a distress of the liver.

Glutamate-mediated primary somatosensory cortex excitability correlated with circulating copper and ceruloplasmin.

Objective. To verify whether markers of metal homeostasis are related to a magnetoencephalographic index representative of glutamate-mediated excitability of the primary somatosensory cortex. The index is identified as the source strength of the earliest component (M20) of the somatosensory magnetic fields (SEFs) evoked by right median nerve stimulation at wrist. Method. Thirty healthy right-handed subjects (51 ± 22 years) were enrolled in the study. A source reconstruction algorithm was applied to assess the amount of synchronously activated neurons subtending the M20 and the following SEF component (M30), which is generated by two independent contributions of gabaergic and glutamatergic transmission. Serum copper, ceruloplasmin, iron, transferrin, transferrin saturation, and zinc levels were measured. Results. Total copper and ceruloplasmin negatively correlated with the M20 source strength. Conclusion. This pilot study suggests that higher level of body copper reserve, as marked by ceruloplasmin variations, parallels lower cortical glutamatergic responsiveness.

Copper in Alzheimer's disease: a meta-analysis of serum,plasma, and cerebrospinal fluid studies.

There is an ongoing debate on the involvement of systemic copper (Cu) dysfunctions in Alzheimer's disease (AD), and clinical studies comparing Cu levels in serum, plasma, and cerebrospinal fluid (CSF) of AD patients with those of healthy controls have delivered non-univocal and often conflicting results. In an attempt to evaluate whether Cu should be considered a potential marker of AD, we applied meta-analysis to a selection of 26 studies published in the literature. Meta-analysis is a quantitative method that combines the results of independent reports to distinguish between small effects and no effects, random variations, variations in sample used, or in different analytical approaches. The subjects' sample obtained by merging studies was a pooled total of 761 AD subjects and 664 controls for serum Cu studies, 205 AD subjects and 167 controls for plasma Cu, and of 116 AD subjects and 129 controls for CSF Cu. Our meta-analysis of serum data showed that AD patients have higher levels of serum Cu than healthy controls. Plasma data did not allow conclusions, due to their high heterogeneity, but the meta-analysis of the combined serum and plasma studies confirmed higher Cu levels in AD. The analysis of CSF data, instead, revealed no difference between AD patients and controls.

Oxidative stress and brain glutamate-mediated excitability in depressed patients.

BACKGROUND: Several neuropsychiatric pathologies have been recently linked to oxidative stress. In this study, we investigated the relationship between depression, markers of oxidative stress and neurotransmission, as expressed by sensory cortex excitability. METHODS: Serum levels of oxidative stress markers and somatosensory magnetic fields, evoked by external galvanic stimulation, were measured in 13 depressed patients and 13 controls. RESULTS: Depressives had higher levels of total and free copper than controls and lower levels of transferrin. They also showed lower sensory cortex excitability, which correlated with copper levels in controls, but not in patients. Transferrin correlated with sensory cortex excitability in both patients and controls, although in opposite ways. Copper level results associated with the patients' clinical status. LIMITATIONS: Small sample size and possible sampling bias in patient selection. CONCLUSIONS: Pro-oxidant agents appear to affect neuronal excitability and clinical state of depressed patients, as free copper excess alters their cortical glutamatergic neurotransmission.

Is cognitive function linked to serum free copper levels? A cohort study in a normal population.

OBJECTIVE: Much research on copper-dependent neurodegeneration has focused on the study of total copper levels in the organism. However, recent evidence suggests that the portion of copper that does not bind to ceruloplasmin and is loosely transported by micronutrients (free copper) may play a more significant role than copper as a whole. In this paper, we measured markers of copper metabolism in the sera of a group of cognitively normal women to test whether abnormal amounts of free copper have detectable effects on the mental state of clinically normal people. METHODS: We measured serum levels of free and ceruloplasmin-bound copper in 64 women whose normal mental state had been assessed via a battery of neuropsychological tests representing the major cognitive domains. RESULTS: Results show a significant inverse correlation of the serum levels of free copper with both Mini-Mental State Examination (MMSE) and attention-related neuropsychological tests scores. Bound copper, instead, did not correlate with either MMSE scores or any cognitive domain. CONCLUSIONS: Free copper appears to be a player in cognitive decline. SIGNIFICANCE: This evidence suggests the need for a shift of focus from total to free copper levels in the study of mental decline and sustains the notion that free copper may be a risk factor in the development of impaired cognition.

Ceruloplasmin/Transferrin ratio changes in Alzheimer's disease.

The link between iron and Alzheimer's disease (AD) has been mainly investigated with a focus on the local accumulation of this metal in specific areas of the brain that are critical for AD. In the present study, we have instead looked at systemic variations of markers of iron metabolism. We measured serum levels of iron, ceruloplasmin, and transferrin and calculated the transferrin saturation and the ceruloplasmin to transferrin ratio (Cp/Tf). Cp/Tf and transferrin saturation increased in AD patients. Cp/Tf ratios also correlated positively with peroxide levels and negatively with serum iron concentrations. Elevated values of ceruloplasmin, peroxides, and Cp/Tf inversely correlated with MMSE scores. Isolated medial temporal lobe atrophy positively correlated with Cp/Tf and negatively with serum iron. All these findings indicate that the local iron accumulation found in brain areas critical for AD should be viewed in the frame of iron systemic alterations.

Agents complexing copper as a therapeutic strategy for the treatment of Alzheimer's disease.

The notion that a copper dysfunction is implicated in Alzheimer's disease (AD) is based on a number of observations from in vitro and clinical studies, as well as animal models. However, there is still significant controversy over whether it is an excess or a deficiency of copper to be involved in the pathogenesis of AD. Numerous studies support the hypothesis that an excess of copper contributes to AD, but experimental evidence in transgenic mouse models seems to suggest the contrary, and at least one clinical study shows that cognitive decline correlates positively with low copper levels. We have recently reported on a deregulation of the ceruloplasmin-copper relationship, specific to AD patients, consisting of an elevation of the copper pool not bound to ceruloplasmin, i.e. 'free' copper. This phenomenon could provide an explanation of the contrasting results obtained in clinical studies. Several clinical trials have been attempted in search of an anti-metal effect counteracting AD progression. Some of them have delivered encouraging results indicating that "metal protein attenuating compounds" can indeed alter positively the progression of the disease. This review summarizes these clinical studies and provides an overview of those in progress and in preparation.

An observational study on the influence of the APOE-epsilon4 allele on the correlation between 'free' copper toxicosis and EEG activity in Alzheimer disease.

Since many years the apolipoprotein E epsilon4 allele (APOE-epsilon4) is known to be associated with Alzheimer disease (AD) but the mechanisms of these associations remained unclear. In the last years, the potential pathogenetic role of 'free' copper (i.e. non-ceruloplasmin bound copper) has been evidenced in AD. Recently, elevated 'free' copper was found to be correlated with slowing of cortical electroencephalographic (EEG) rhythms. The present work aimed to check the hypothesis that the strength of the correlations between free-copper and alterations of cortical rhythms might be different in carriers and non-carriers of the APOE-epsilon4 allele. Fifty-four AD patients and 20 healthy controls were included in the study. In all of them 1) APOE genotyping was performed; 2) total serum copper and ceruloplasmin was determined in order to calculate the serum 'free' copper; and 3) resting eyes-closed EEG rhythms were recorded and spectral brain activity was estimated via LORETA. A 'two correlation coefficients comparison' test was used to test the strength of the correlation in APOE-epsilon4 carriers and non-carriers. 'Free' copper levels were higher in patients than in controls and correlated positively with parietal-temporal delta and negatively with parieto-temporal alpha-1 activities. The correlation between 'free' copper and temporal alpha-1 activity was stronger in APOE-epsilon4 carriers than in non-carriers. Peroxide levels correlated with higher temporal delta in the AD group. APOE-epsilon4 appears to modulate the effect of copper on the altered AD brain activities, suggesting that modulation of oxidative stress related to copper dysfunction may be one of the mechanisms that make APOE-epsilon4 a risk factor for AD.

High-gamma band activity of primary hand cortical areas: a sensorimotor feedback efficiency index.

Sensory feedback in motor control is widely recognized to be the key link between the activity of the primary motor cortex to the motor behavior. Through an ad-hoc developed procedure for source extraction (functional source separation), the primary sensory and motor cortex activities (FS(S1) and FS(M1)) were obtained from magnetoencephalographic recordings during a sensorimotor task sequence, and sensorimotor interaction was assessed. Source activity spectral powers were evaluated in the alpha (8-13 Hz), beta (14-32 Hz), gamma1 (33-60 Hz) and gamma2 (61-90 Hz) frequency bands. FS(S1) and FS(M1)had different spectral properties, with FS(S1) prevailing in alpha and FS(M1) in gamma band. Both FS(S1) and FS(M1) were reactive in the different sensorimotor tasks with respect to rest in all frequency bands, except for gamma2. During an isometric contraction, we searched for an index dependent on the performance level and with low variability in the healthy population. We found these properties satisfied within a relationship between FS(S1) and FS(M1) in the gamma2 band. This sensorimotor feedback efficiency index quantitatively estimates the continuous functional balance between primary sensory and motor areas devoted to hand control and seems promising for future developments, as it is easily assessable in patients.