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Introduction: Brain-Derived Neurotrophic Factor (BDNF) and its most common polymorphism Val66Met are known to have a role in Multiple Sclerosis (MS) pathogenesis. Evidence is accumulating that there is an involvement of DNA methylation in the regulation of BDNF expression. The aim of this study was to assess in blood samples of MS patients the correlation between the methylation status of the CpG site near BDNF-Val66Met polymorphism and the severity of the disease. Methods: We recruited 209 MS patients that were genotyped for the BDNF Val66Met polymorphism. For each patient we quantitatively measured the methylation level of cytosine included in the exonic CpG site that can be created or abolished by the Val66Met BDNF polymorphism. Furthermore, we analyzed the clinical history of each patient and determined the time elapsed since the onset of the disease and an EDSS score of 6.0. Results: The genetic analysis identified 122 (58.4%) subjects carrying the Val/Val genotype, 81 (38.8%) with Val/Met genotype, and 6 (2.8%) carrying the Met/Met genotype. When the endpoint of an EDSS score of 6 was taken into account by means of a survival analysis, 52 failures (i.e., reaching an EDSS score of 6) were reported. When the sample was stratified according to the percentage of the BDNF methylation, subjects falling below the median (median methylation = 81%) were at higher risk of failure (IRD = 0.016; 95%CI = 0.0050–0.0279; p = 0.004). Conclusions: In patients with a high disease progression the hypomethylation of the BDNF gene could increase the secretion of the protective neurotrophin, so epigenetic modifications could be the organism response to limit a brain functional reserve loss. Our study suggests that the percentage of methylation of the BDNF gene could be used as a prognostic factor for disease progression toward a high disability in MS patient. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Previous studies with Transcranial Magnetic Stimulation (TMS) have focused on the cortical representation of limited group of muscles. No attempts have been carried out so far to get simultaneous recordings from hand, forearm and arm with TMS in order to disentangle a 'functional' map providing information on the rules orchestrating muscle coupling and overlap. The aim of the present study is to disentangle functional associations between 12 upper limb muscles using two measures: cortical overlapping and cortical covariation of each pair of muscles. Interhemispheric differences and the influence of posture were evaluated as well. Methodology/Principal Findings: TMS mapping studies of 12 muscles belonging to hand, forearm and arm were performed. Findings demonstrate significant differences between the 66 pairs of muscles in terms of cortical overlapping: extremely high for hand-forearm muscles and very low for arm vs hand/forearm muscles. When right and left hemispheres were compared, overlapping between all possible pairs of muscles in the left hemisphere (62.5%) was significantly higher than in the right one (53.5% ). The arm/hand posture influenced both measures of cortical association, the effect of Position being significant [p = .021] on overlapping, resulting in 59.5% with prone vs 53.2% with supine hand, but only for pairs of muscles belonging to hand and forearm, while no changes occurred in the overlapping of proximal muscles with those of more distal districts. Conclusions/Significance: Larger overlapping in the left hemisphere could be related to its lifetime higher training of all twelve muscles studied with respect to the right hemisphere, resulting in larger intra-cortical connectivity within primary motor cortex. Altogether, findings with prone hand might be ascribed to mechanisms facilitating coupling of muscles for object grasping and lifting -with more proximal involvement for joint stabilization- compared to supine hand facilitating actions like catching. TMS multiple-muscle mapping studies permit a better understanding of motor control and 'plastic' reorganization of motor system. [ABSTRACT FROM AUTHOR]

Background: Sleep electroencephalogram (EEG) brain oscillations in the low-frequency range show local signs of homeostatic regulation after learning. Such increases and decreases of slow wave activity are limited to the cortical regions involved in specific task performance during wakefulness. Here, we test the hypothesis that reorganization of motor cortex produced by long-term potentiation (LTP) affects EEG activity of this brain area during subsequent sleep. Methodology/Principal Findings: By pairing median nerve stimulation with transcranial magnetic stimulation over the contralateral motor cortex, one can potentiate the motor output, which is presumed to reflect plasticity of the neural circuitry. This paired associative stimulation increases M1 cortical excitability at interstimulus intervals of 25 ms. We compared the scalp distribution of sleep EEG power following paired associative stimulation at 25 ms to that following a control paradigm with 50 ms intervals. It is shown that the experimental manipulation by paired associative stimulation at 25 ms induces a 48% increase in amplitude of motor evoked potentials. This LTP-like potentiation, induced during waking, affects delta and theta EEG power in both REM and non-REM sleep, measured during the following night. Slow-wave activity increases in some frontal and prefrontal derivations and decreases at sites neighboring and contralateral to the stimulated motor cortex. The magnitude of increased amplitudes of motor evoked potentials by the paired associative stimulation at 25 ms predicts enhancements of slow-wave activity in prefrontal regions. Conclusions/Significance: An LTP-like paradigm, presumably inducing increased synaptic strength, leads to changes in local sleep regulation, as indexed by EEG slow-wave activity. Enhancement and depression of slow-wave activity are interpreted in terms of a simultaneous activation of both excitatory and inhibitory circuits consequent to the paired associative stimulation at 25 ms. [ABSTRACT FROM AUTHOR]

Background: Converging evidence indicates that action observation and action-related sounds activate cross-modally the human motor system. Since olfaction, the most ancestral sense, may have behavioural consequences on human activities, we causally investigated by transcranial magnetic stimulation (TMS) whether food odour could additionally facilitate the human motor system during the observation of grasping objects with alimentary valence, and the degree of specificity of these effects. Methodology/Principal Findings: In a repeated-measure block design, carried out on 24 healthy individuals participating to three different experiments, we show that sniffing alimentary odorants immediately increases the motor potentials evoked in hand muscles by TMS of the motor cortex. This effect was odorant-specific and was absent when subjects were presented with odorants including a potentially noxious trigeminal component. The smell-induced corticospinal facilitation of hand muscles during observation of grasping was an additive effect which superimposed to that induced by the mere observation of grasping actions for food or non-food objects. The odour-induced motor facilitation took place only in case of congruence between the sniffed odour and the observed grasped food, and specifically involved the muscle acting as prime mover for hand/fingers shaping in the observed action. Conclusions/Significance: Complex olfactory cross-modal effects on the human corticospinal system are physiologically demonstrable. They are odorant-specific and, depending on the experimental context, muscle- and action-specific as well. This finding implies potential new diagnostic and rehabilitative applications. [ABSTRACT FROM AUTHOR]

Background: Sleep electroencephalogram (EEG) brain oscillations in the low-frequency range show local signs of homeostatic regulation after learning. Such increases and decreases of slow wave activity are limited to the cortical regions involved in specific task performance during wakefulness. Here, we test the hypothesis that reorganization of motor cortex produced by long-term potentiation (LTP) affects EEG activity of this brain area during subsequent sleep., Methodology/principal Findings: By pairing median nerve stimulation with transcranial magnetic stimulation over the contralateral motor cortex, one can potentiate the motor output, which is presumed to reflect plasticity of the neural circuitry. This paired associative stimulation increases M1 cortical excitability at interstimulus intervals of 25 ms. We compared the scalp distribution of sleep EEG power following paired associative stimulation at 25 ms to that following a control paradigm with 50 ms intervals. It is shown that the experimental manipulation by paired associative stimulation at 25 ms induces a 48% increase in amplitude of motor evoked potentials. This LTP-like potentiation, induced during waking, affects delta and theta EEG power in both REM and non-REM sleep, measured during the following night. Slow-wave activity increases in some frontal and prefrontal derivations and decreases at sites neighboring and contralateral to the stimulated motor cortex. The magnitude of increased amplitudes of motor evoked potentials by the paired associative stimulation at 25 ms predicts enhancements of slow-wave activity in prefrontal regions., Conclusions/significance: An LTP-like paradigm, presumably inducing increased synaptic strength, leads to changes in local sleep regulation, as indexed by EEG slow-wave activity. Enhancement and depression of slow-wave activity are interpreted in terms of a simultaneous activation of both excitatory and inhibitory circuits consequent to the paired associative stimulation at 25 ms.