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Purpose To investigate the diagnostic efficacy of MRI diagnostic algorithms with an ascending automatization, in distinguishing between high-grade glioma (HGG) and solitary brain metastases (SBM). Methods 36 patients with histologically proven HGG (n = 18) or SBM (n = 18), matched by size and location were enrolled from a database containing 655 patients. Four different diagnostic algorithms were performed serially to mimic the clinical setting where a radiologist would typically seek out further findings to reach a decision: pure qualitative, analytic qualitative (based on standardized evaluation of tumor features), semi-quantitative (based on perfusion and diffusion cutoffs included in the literature) and a quantitative data-driven algorithm of the perfusion and diffusion parameters. The diagnostic yields of the four algorithms were tested with ROC analysis and Kendall coefficient of concordance. Results Qualitative algorithm yielded sensitivity of 72.2%, specificity of 78.8%, and AUC of 0.75. Analytic qualitative algorithm distinguished HGG from SBM with a sensitivity of 100%, specificity of 77.7%, and an AUC of 0.889. The semi-quantitative algorithm yielded sensitivity of 94.4%, specificity of 83.3%, and AUC = 0.889. The data-driven algorithm yielded sensitivity = 94.4%, specificity = 100%, and AUC = 0.948. The concordance analysis between the four algorithms and the histologic findings showed moderate concordance for the first algorithm, (k = 0.501, P k = 0.798, P k = 0.783, P k = 0.901, p Conclusion When differentiating HGG from SBM, an analytical qualitative algorithm outperformed qualitative algorithm, and obtained similar results compared to the semi-quantitative approach. However, the use of data-driven quantitative algorithm yielded an excellent differentiation.

Premature birth affects the developmental trajectory of the brain during a period of intense maturation with possible lifelong consequences. To better understand the effect of prematurity on brain structure and function, we performed blood‐oxygen‐level dependent (BOLD) and anatomical magnetic resonance imaging (MRI) at 40 weeks of postmenstrual age on 88 newborns with variable gestational age (GA) at birth and no evident radiological alterations. We extracted measures of resting‐state functional connectivity and activity in a set of 90 cortical and subcortical brain regions through the evaluation of BOLD correlations between regions and of fractional amplitude of low‐frequency fluctuation (fALFF) within regions, respectively. Anatomical information was acquired through the assessment of regional volumes. We performed univariate analyses on each metric to examine the association with GA at birth, the spatial distribution of the effects, and the consistency across metrics. Moreover, a data‐driven multivariate analysis (i.e., Machine Learning) framework exploited the high dimensionality of the data to assess the sensitivity of each metric to the effect of premature birth. Prematurity was associated with bidirectional alterations of functional connectivity and regional volume and, to a lesser extent, of fALFF. Notably, the effects of prematurity on functional connectivity were spatially diffuse, mainly within cortical regions, whereas effects on regional volume and fALFF were more focal, involving subcortical structures. While the two analytical approaches delivered consistent results, the multivariate analysis was more sensitive in capturing the complex pattern of prematurity effects. Future studies might apply multivariate frameworks to identify premature infants at risk of a negative neurodevelopmental outcome., To better understand the effect of prematurity on brain structure and function, we evaluated BOLD and anatomical MRI metrics in a set of 90 cortical and subcortical brain regions of 88 newborns at 40 weeks of postmenstrual age, with no evident radiological alterations and variable gestational age (GA) at birth. Data‐driven multivariate analyses of these measures were in agreement with univariate findings and indicated that GA at birth was associated with bidirectional and diffuse alterations of BOLD functional connectivity and more focal alterations of regional volume and BOLD activity (assessed through the fractional amplitude of low‐frequency fluctuation, fALFF). Future studies might successfully apply multivariate frameworks to identify premature infants at risk of a negative neurodevelopmental outcome.

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic small-vessel disease that is characterized by a wide range of neurologic and neuropsychological impairments. Constructional impairments have been reported in some cases but have never been assessed systematically.To evaluate constructional abilities and their cognitive and neural correlates in nondemented individuals with CADASIL.Thirty individuals with CADASIL who were not affected by clinically relevant cognitive deterioration and 30 healthy controls (HC) underwent an extensive cognitive assessment and paper-and-pencil visuoconstructional tasks in order to detect constructional impairments. Performance on the visuoconstructional tasks was correlated with the cognitive assessment scores and with quantitative indices of regional gray matter atrophy (obtained via FreeSurfer image analysis) and white matter involvement.The individuals with CADASIL achieved significantly lower scores on the cognitive assessment compared with the HC. Poor visuoconstructional abilities were observed in seven (23.3%) of the individuals with CADASIL when performing the copy drawing task and in nine (30%) when performing the Rey Complex Figure Test. Logistic regression revealed that visuoconstructional impairments were significantly associated with scores on the Frontal Assessment Battery and the Attentional Matrices Test. Morphometric results revealed that scores on the visuoconstructional tasks were related to gray matter atrophy of the left frontal lobe and right parietal lobe.Impairments on visuoconstructional tasks are quite common in individuals with CADASIL, even in the lack of clinically relevant cognitive deterioration, and are critically related to frontal and parietal atrophy.

Committeri Giorgia, Danilo Bondi, Carlo Sestieri, Ginevra Di Matteo, Claudia Piervincenzi, Christian Doria, Roberto Ruffini, Antonello Baldassarre, Tiziana Pietrangelo, Rosamaria Sepe, Riccardo Navarra, Piero Chiacchiaretta, Antonio Ferretti, and Vittore Verratti. Neuropsychological and neuroimaging correlates of high-altitude hypoxia trekking during the "Gokyo Khumbu/Ama Dablam" expedition.

Decline in fluid abilities in normal aging is associated with increased white matter lesions, measured on T1-weighted images as white matter signal abnormalities (WMSAs). WMSAs are particularly evident in hypertensive older adults, suggesting vascular involvement. However, because hypertension is assessed systemically, the specific role of cerebral arterial stiffening in WMSAs has yet to be demonstrated. In 93 cognitively normal adults (aged 18-87 years), we used a novel method to measure cerebral arterial elasticity (pulse relaxation function [PReFx]) with diffuse optical tomography (pulse-DOT) and investigated its association with WMSAs, age, and cognition. PReFx was associated with WMSAs, with older adults with low PReFx showing the greatest WMSA burden. PReFx in brain regions perfused by the middle cerebral artery showed the largest associations with WMSAs and partially mediated the relationship between age and WMSAs. Finally, WMSAs partially mediated the relationship between PReFx and fluid but not crystallized abilities scores. Taken together, these findings suggest that loss of cerebral arterial elasticity is associated with cerebral white matter lesions and age-related cognitive decline. Accepted version

Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be counteracted. Intracellular calcium (Ca2+i) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a pleiotropic class of sphingolipids, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored. In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor of thede novoceramide biosynthesis, on the aging phenotype of cortical neurons cultured for 22 days, a setting employed as anin vitromodel of senescence. Our findings indicate that, compared to control cultures, 'aged' neurons display dysregulation of [Ca2+]ilevels, mitochondrial dysfunction, increased generation of reactive oxygen species (ROS), altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS positively affected the senescent phenotype, a result associated with recovery of neuronal [Ca2+]isignaling and reduction of mitochondrial dysfunction and ROS generation. The results suggest that thede novoceramide biosynthesis represents a critical intermediate in the molecular and functional cascade leading to neuronal senescence and identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease age-related neuronal dysfunctions.

Myofascial pain in the masticatory region, generally referred to as headache, is a common temporomandibular disorder (TMD) characterized by the hypersensitive regions of the contracted skeletal muscle fibers. A correct clinical treatment of myofascial pain has the potential to modify the functional activation of cerebral networks associated with pain and unconscious teeth clenching, specifically the pain network (PN) and default mode network (DMN). In this study, research is presented as a case series of five patients with myofascial pain: three were diagnosed with intra- and extra-articular disorders, and two were diagnosed with only extra-articular disorders. All five patients received gnathological therapy consisting of passive splints and biofeedback exercises for tongue–palatal vault coordination. Before and after treatment, patients underwent pain assessments (through measures of visual analog scales and muscular palpation tests), nuclear magnetic resonance of the temporomandibular joint, and functional nuclear magnetic resonance of the brain. In each patient, temporomandibular joint nuclear magnetic resonance results were similar before and after the gnathological treatment. However, the treatment resulted in a considerable reduction in pain for all patients, according to the visual analog scales and the palpation test. Furthermore, functional nuclear magnetic resonance of the brain clearly showed a homogeneous modification in cerebral networks associated with pain (i.e., PN and DMN), in all patients. In conclusion, gnathological therapy consisting of passive aligners and biofeedback exercises improved myofascial pain in all five patients. Most importantly, this study showed that all five patients had a homogeneous functional modification of pain and default mode networks. Using passive splints in combination with jaw exercises may be an effective treatment option for patients with TMD. This research could be a starting point for future investigations and for clinicians who want to approach similar situations.

To investigate modifications of Magnetic Resonance Diffusion Tensor Imaging (DTI) and Diffusion Kurtosis Imaging (DKI) metrics in lateral white matter (WM) bundles of the cervical spinal cord in patients with previous stroke in the vascular territory of the middle cerebral artery (MCA). Twenty consecutive patients with a previous ischemic stroke of the MCA territory and a varying degree of upper motor impairment were enrolled. DKI was centered at the C3C4 and C5C6 intervertebral level. The fractional anisotropy (FA) values in C3C4 and C5C6 were found to be significantly lower in the lateral WM bundles contralateral to the ischemic lesion and thus, in the WM bundle including the affected corticospinal tract (CST) (p = 0.005 and p = 0.008, respectively), as well as mean kurtosis (MK) and axonal water fraction (AWF) values (p = 0.004 and p = 0.04. respectively). FA values correlated significantly with the Global Motor Index (GMI) both for C3C4 (ρ = 0.61, p = 0.004) and C5C6 (ρ = 0.69, p = 0.002). At C3C4, AWF correlated significantly with GMI (ρ = 0.54, p = 0.03). No correlations were found between lateral WM bundle volumes and GMI. A reduction of anisotropy and microstructural complexity in the affected lateral WM bundle of the cervical spinal cord was observed in patients with previous ischemic stroke involving the CST. The correlations between these metrics and motor performance were statistically significant.

Background MRI plays a crucial role to identify men with a high likelihood of clinically significant prostate cancer who require immediate biopsy. The added value of DCE MRI in combination with T2-weighted imaging and DWI is controversial (risks related to gadolinium administration, duration of MR exam, financial burden, effects on diagnostic performance). A comparison of a biparametric and a standard multiparametric MR imaging protocol, taking into account the different experience of the readers, may help to choose the best MR approach regarding diagnostic performance. Purpose To determine the added value of dynamic contrasted-enhanced imaging (DCE) over T2-weighted imaging (T2-WI) and diffusion weighted imaging (DWI) for the detection of clinically significant prostate cancer, and to evaluate how it affects the diagnostic performance of three readers with different grade of experience in prostate imaging. Materials and methods Eighty-five patients underwent prostate MR examination at 1.5 T MR scanner performed because of elevated prostate-specific antigen level and/or suspicion of prostate cancer at digital rectal examination. Two MR images sets (Set 1 = biparametric, Set 2 = multiparametric) were retrospectively and independently scored by three radiologists with 7, 3 and 1 years of experience in prostate MR imaging respectively, according to PI-RADS v2. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated by dichotomizing reader scores. Receiver operating characteristic (ROC) analysis was performed and areas under the curve (AUCs) were calculated for each reader and image set. A comparison of ROC curves was performed to test the difference between the areas under the ROC curves among the three readers. Results There was no significant difference regarding the detection of clinically significant tumor among the three readers between the two image sets. The AUC for the bi-parametric and multi-parametric MR imaging protocol was respectively 0.68–0.72 (Reader 1), 0.72–0.70 (Reader 2) and 0.60–0.54 (Reader 3). ROC curve comparison revealed no statistically significant differences for each protocol among the most experienced (Reader 1) and the other readers (Readers 2–3). Conclusion The diagnostic accuracy of a bi-parametric MR imaging protocol consisting of T2-weighted imaging and DWI is comparable with that of a standard multi-parametric imaging protocol for the detection of clinically significant prostate cancer. The experience of the reader does not significantly modify the diagnostic performance of both MR protocols.

Gliomas disturb brain functions, contributing to abnormal neuronal activity and connectivity changes that can be effectively investigated using magnetoencephalography (MEG). In this work, we used MEG to evaluate frequency-specific alterations of brain activity and functional connectivity in glioma patients. Two consecutive 5-min sessions of eyes-closed resting-state brain activity were recorded from ten glioma patients and ten age-matched healthy subjects. Modulations of power and functional connectivity, within the patient group and between patients and the healthy control group, were assessed in terms of the Neural Activity Index and the Multivariate Interaction Measure, respectively. These quantities were calculated in individualized frequency bands (delta, theta, lower alpha, upper alpha and beta) to account for changes in spectral peaks in patients. We report a decrease in power in tumor and peri-tumor regions in the upper-alpha and beta bands with respect to the rest of the brain, paired to a decrease in lower and upper-alpha band functional connectivity of the tumor and peri-tumor regions. In comparison with healthy subjects, we observe a global enhancement in power in lower-alpha in patients. Overall, our study shows that glioma infiltration can widely influence brain local and long-range synchrony in an individualized frequency-specific manner.

The aim of this prospective study was to determine the feasibility in terms of repeatability and reproducibility of diffusional kurtosis imaging (DKI) for microstructural assessment of the normal cervical spinal cord (cSC) using a phase-sensitive inversion recovery (PSIR) sequence as the anatomical reference for accurately defining white-matter (WM) and gray-matter (GM) regions of interests (ROIs). Thirteen young healthy subjects were enrolled to undergo DKI and PSIR sequences in the cSC. The repeatability and reproducibility of kurtosis metrics and fractional anisotropy (FA) were calculated in GM, WM, and cerebral-spinal-fluid (CSF) ROIs drawn by two independent readers on PSIR images of three different levels (C1–C4). The presence of statistically significant differences in DKI metrics for levels, ROIs (GM, WM, and CSF) repeatability, reproducibility, and inter-reader agreement was evaluated. Intra-class correlation coefficients between the two readers ranged from good to excellent (0.75 to 0.90). The inferior level consistently had the highest concordance. The lower values of scan–rescan variability for all DKI parameters were found for the inferior level. Statistically significant differences in kurtosis values were not found in the lateral white-matter bundles of the spinal cord. The integration of DKI and PSIR sequences in a clinical MR acquisition to explore the regional microstructure of the cSC in healthy subjects is feasible, and the results obtainable are reproducible. Further investigation will be required to verify the possibility to translate this method to a clinical setting to study patients with SC involvement especially in the absence of MRI abnormalities on standard sequences.

Left ventricular assist device (LVAD) is considered a standard care for patients with advanced heart failure. The aim of this work was to study in vitro the effects of direct exposure of the Jarvik 2000 LVAD to 10-MV photon beams. Jarvik 2000 pump was immersed in a siliconized box filled with deionized water. A 30 × 30 × 15 cm RW3 slabs were added forth and back to the box. A treatment plan consisting of a single direct 10 × 10 cm2 field size beam was used to deliver 1000 MU at the center of the pump. During irradiation, the external Flow Maker controller and the lithium battery were positioned away from the beam. Pump parameter data (included voltage, current and frequency) were measured, recorded and analyzed for changes in pump function among baseline, pre-irradiation, during irradiation, post-irradiation and after 6 months. The whole session lasted 6 months. The Mann–Whitney U test was used to compare the repeated measurements. X-ray radiation attenuation was also studied. The parameters investigated remained stable over the 6 months; that is, no pump stops, alarms, events, operational changes or abnormalities during the discharge rate of the connected power sources, were encountered, confirmed by the Mann–Whitney U test applied to all sessions (p > 0.1). The measured X-ray attenuation differed from the calculated one by TPS by 34%. The Jarvik 2000 resulted stable under direct X-ray beam of 10-MV energy. Its strong attenuation, however, can affect dose deposition in the pump in TPS, and it must be taken into account.

Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be counteracted. Intracellular calcium (Ca2+i) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a pleiotropic class of sphingolipids, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored. In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor of thede novoceramide biosynthesis, on the aging phenotype of cortical neurons cultured for 22 days, a setting employed as anin vitromodel of senescence. Our findings indicate that, compared to control cultures, ‘aged’ neurons display dysregulation of [Ca2+]ilevels, mitochondrial dysfunction, increased generation of reactive oxygen species (ROS), altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS positively affected the senescent phenotype, a result associated with recovery of neuronal [Ca2+]isignaling and reduction of mitochondrial dysfunction and ROS generation. The results suggest that thede novoceramide biosynthesis represents a critical intermediate in the molecular and functional cascade leading to neuronal senescence and identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease age-related neuronal dysfunctions.

Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be delayed, counteracted, if not completely interrupted. Aging is the primary risk factor for the onset and development of neurodegenerative conditions like Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis. Intracellular calcium (Ca2+i) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a class of sphingolipids involved in a wide array of biological functions, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored.In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor ofde novoceramide biosynthesis, on the aging phenotype of cortical neurons that have been maintained in culture for 22 days, a setting employed as anin vitromodel of cellular senescence. Our findings indicate that ‘aged’ neurons display, when compared to control cultures, overt dysregulation of cytosolic and subcellular [Ca2+]ilevels, mitochondrial dysfunction, increased reactive oxygen species generation, altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS (30 µM) positively affected the senescent phenotype, a result accompanied by recovery of neuronal [Ca2+]isignaling, and reduction of mitochondrial dysfunction and reactive oxygen species generation.The results suggest that thede novoceramide biosynthesis may represent a critical intermediate in the molecular and functional cascade leading to neuronal senescence. Our findings also identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease age-related neuronal dysfunctions.

Purpose Abnormal brain perfusion is a critical mechanism in neonatal brain injury. The aim of the present study was to compare Cerebral Blood Flow (CBF) evaluated with ASL MRI in three groups of neonates: preterms without brain lesions on MRI (PN), preterms with periventricular white matter lesions (PNp) and term neonates with normal MRI (TN). The correlation between CBF and clinical outcome was explored. Materials and methods The institutional review board approved this prospective study and waived informed consent. The perfusion ASL data from 49 consecutive preterm neonates (PN) studied at term-equivalent age and 15 TN were evaluated. Statistically significant differences in gray matter CBF were evaluated by using a linear mixed-model analysis and Mann-Whitney U test. Logistic regression analysis was used to assess the relation between CBF and neuromotor outcome at 12 months. Results Comparison of means indicated that the CBF of the whole brain were significantly higher in PN compared to TN (P = 0.011). This difference remained significant when considering the frontal (P = 0.038), parietal (P = 0.002), temporal (P = 0.030), occipital (P = 0.041) and cerebellar (P = 0.010) gray matter. In the PN group, lower CBF in basal ganglia was associated with a worse neuromotor outcome (P = 0.012). Conclusions ASL MRI demonstrated differences in brain perfusion of the basal ganglia between PN and TN. In PN, a positive correlation between CBF and neuromotor outcome was demonstrated in this area., Highlights • Different ASL cerebral perfusion between preterm and term neonates • Global reduction of CBF values in preterm neonates with white matter lesions • ASL identifies preterm neonates at higher risk for sub-optimal neuromotor development. • Worst 12-months neuromotor outcome in preterm neonates with lower CBF of basal ganglia

Application parameters of transcranial direct current stimulation (tDCS) for therapeutic purposes are relatively restricted. The aim of this study was to assess safety and effects on motor cortex excitability of an intensive anodal-tDCS protocol.In 26 healthy subjects, five 15-minute anodal-tDCS sessions were delivered, at increasing time intervals, over 24hours. Safety was defined as absence of serious adverse events including brain tissue alterations on magnetic resonance imaging. Effect on motor cortex excitability was evaluated by motor evoked potential (MEP) amplitude, measured eight times.No serious adverse events occurred. Mild adverse events, such as reversible scalp erythema or transient metallic taste, were observed in 27% of subjects. MEP amplitudes did not change in any of the recording periods. When inter-individual variability was taken into account and threshold values defined, 50% of subjects were classified as responders, 15% were inverse responders, and 35% non-responders. In the responders, normalized MEP was increased by 57% 1hour after the first anodal-tDCS and increased by 50% three hours after two stimulations delivered 1hour apart. Intra-individual, inter-sessional consistency of MEP response over four measurements was 61-77%.Five anodal-tDCS delivered in 24hours are safe and well tolerated, expanding the safety standard of tDCS. However, only half of subjects respond to anodal-tDCS with a robust and durable MEP augmentation. On the other hand, the response to a single anodal-tDCS predicts fairly well the response to other sessions in the same subject.These findings should be considered in clinical trials utilizing repeated anodal-tDCS.

Summary Background and objective Application parameters of transcranial direct current stimulation (tDCS) for therapeutic purposes are relatively restricted. The aim of this study was to assess safety and effects on motor cortex excitability of an intensive anodal-tDCS protocol. Methods In 26 healthy subjects, five 15-minute anodal-tDCS sessions were delivered, at increasing time intervals, over 24 hours. Safety was defined as absence of serious adverse events including brain tissue alterations on magnetic resonance imaging. Effect on motor cortex excitability was evaluated by motor evoked potential (MEP) amplitude, measured eight times. Results No serious adverse events occurred. Mild adverse events, such as reversible scalp erythema or transient metallic taste, were observed in 27% of subjects. MEP amplitudes did not change in any of the recording periods. When inter-individual variability was taken into account and threshold values defined, 50% of subjects were classified as responders, 15% were inverse responders, and 35% non-responders. In the responders, normalized MEP was increased by 57% 1 hour after the first anodal-tDCS and increased by 50% three hours after two stimulations delivered 1 hour apart. Intra-individual, inter-sessional consistency of MEP response over four measurements was 61–77%. Discussion Five anodal-tDCS delivered in 24 hours are safe and well tolerated, expanding the safety standard of tDCS. However, only half of subjects respond to anodal-tDCS with a robust and durable MEP augmentation. On the other hand, the response to a single anodal-tDCS predicts fairly well the response to other sessions in the same subject. Conclusions These findings should be considered in clinical trials utilizing repeated anodal-tDCS.

Rational Emotive Education (REE) is a psychological educational program offering a preventative psycho-educational curriculum to children in order to teach them emotional literacy skills. REE helps children by teaching them to challenge irrational thinking, to minimize their reactions to disappointment and frustrations, to cope more effectively with problems, and to more fully accept themselves. The efficacy of REE training for children and teachers was examined in a sample of 211 third grade students from nine different classes and 26 teachers. Each class was randomly assigned to one of three different groups, two experimental groups and a control group, each receiving different training. First objective of our study was to evaluate the efficacy of a REE training based on storytelling in changing children’s irrational beliefs. Second objective of our study was to observe the efficacy of a teachers’ training similar to that applied in REBT-focused school consultation groups in enhancing their self-efficacy. Results show an improved tendency in children to think rationally and an enhanced perception of self-efficacy in teachers for those groups that underwent the training compared to the control group. Our results suggest that REBT based trainings for children and teachers should be integrated into the classroom curriculum in order to prevent mental health problems and encourage positive social and emotional well-being.

To compare the features of capsulotomy obtained during femtosecond laser-assisted cataract surgery with those of continuous curvilinear capsulorhexis (CCC) obtained using a standard manual technique.Ophthalmology Clinic, Department of Medicine and Science of Ageing, University G. D'Annunzio Chieti-Pescara, Chieti, Italy.Prospective randomized clinical study.Candidates for cataract extraction were randomized into 1 of 3 groups as follows: Lensx femtosecond laser-assisted cataract surgery capsulotomy (laser group 1), Lensar femtosecond laser-assisted cataract surgery capsulotomy (laser group 2), and manual CCC (manual group).Each group comprised 30 eyes (30 patients). The capsulotomies in laser group 1 and laser group 2 showed significantly better circularity than the manual CCCs at 7 days (P.001). There was a significant correlation between the intended versus achieved capsulotomy size in the 2 laser groups. Both laser groups had better intraocular lens (IOL) centration than the manual group at all timepoints (P.001). Between-group differences in uncorrected and corrected distance visual acuities were not statistically significant. The residual spherical equivalent and mean absolute error were statistically significantly smaller in the 2 laser groups than in the manual group (P=.038) and increased significantly over time in all the groups (P.001).Femtosecond laser capsulotomies showed better circularity with more predictable size than manual CCCs. In addition, IOL centration was better immediately after surgery and over time with better refractive results in the 2 laser groups.

A magnetic resonance (MR) diffusion tensor imaging (DTI) study was performed in a newborn with bilateral subependymal heterotopia (SE). White matter fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) were compared to values obtained in four newborns with moderate perinatal asphyxia and normal MRI findings. The reduction of FA and increase of AD and RD in the newborn with SE were the in vivo late expression of alterations in the intermediate zone, with an underlying arrest of neuronal migration.

Glaucoma is a multifactorial disease that is the leading cause of irreversible blindness. Recent data documented that glaucoma is not limited to the retinal ganglion cells but that it also extends to the posterior visual pathway. The diagnosis is based on the presence of signs of glaucomatous optic neuropathy and consistent functional visual field alterations. Unfortunately these functional alterations often become evident when a significant amount of the nerve fibers that compose the optic nerve has been irreversibly lost. Advanced morphological and functional magnetic resonance (MR) techniques (morphometry, diffusion tensor imaging, arterial spin labeling, and functional connectivity) may provide a means for observing modifications induced by this fiber loss, within the optic nerve and the visual cortex, in an earlier stage. The aim of this systematic review was to determine if the use of these advanced MR techniques could offer the possibility of diagnosing glaucoma at an earlier stage than that currently possible.

To assess safety and effects of five C-tDCS (charge density 342,857 C/m 2 ) delivered at increasing time intervals in 25 h. Safety was defined as absence of serious adverse events and by magnetic resonance imaging and spectroscopy. Effects on motor cortex excitability were evaluated by motor evoked potential (MEP) amplitudes. Inter-individual MEP variability was calculated by the SEM at baseline and subjects were classified on the basis of the ratio between normalized MEPs after the first stimulation compared to baseline. Thirty-two healthy subjects were enrolled. No serious adverse events occurred. Magnetic resonance imaging and spectroscopy did not show structural and biochemical alterations. Only 56% of subjects responded to cathodal-tDCS with the expected reduction of MEP amplitude, 25% were non-responders and 19% opposite responders. In responders, MEP suppression was 32% one hour after the first cathodal-tDC, 21% three hours after the second, no longer present four hours after the third and 12 h after the fourth cathodal-tDCS. Loss of effect was due to the increasing interval between C-tDCS and not to intervening homeostatic plasticity. Five C-tDCS in 25 h are safe. Interindividual variability on motor cortex excitability and effect duration limited to three hours should be considered in planning therapeutic trials utilizing repeated C-tDCS.

Altered neuronal excitability is emerging as an important feature in Alzheimer’s disease (AD). Kv2.1 potassium channels are important modulators of neuronal excitability and synaptic activity. We investigated Kv2.1 currents and its relation to the intrinsic synaptic activity of hippocampal neurons from 3xTg-AD (triple transgenic mouse model of Alzheimer's disease) mice, a widely employed preclinical AD model. Synaptic activity was also investigated by analyzing spontaneous [Ca2+]i spikes. Compared with wild-type (Non-Tg (non-transgenic mouse model)) cultures, 3xTg-AD neurons showed enhanced spike frequency and decreased intensity. Compared with Non-Tg cultures, 3xTg-AD hippocampal neurons revealed reduced Kv2.1-dependent Ik current densities as well as normalized conductances. 3xTg-AD cultures also exhibited an overall decrease in the number of functional Kv2.1 channels. Immunofluorescence assay revealed an increase in Kv2.1 channel oligomerization, a condition associated with blockade of channel function. In Non-Tg neurons, pharmacological blockade of Kv2.1 channels reproduced the altered pattern found in the 3xTg-AD cultures. Moreover, compared with untreated sister cultures, pharmacological inhibition of Kv2.1 in 3xTg-AD neurons did not produce any significant modification in Ik current densities. Reactive oxygen species (ROS) promote Kv2.1 oligomerization, thereby acting as negative modulator of the channel activity. Glutamate receptor activation produced higher ROS levels in hippocampal 3xTg-AD cultures compared with Non-Tg neurons. Antioxidant treatment with N-Acetyl-Cysteine was found to rescue Kv2.1-dependent currents and decreased spontaneous hyperexcitability in 3xTg-AD neurons. Analogous results regarding spontaneous synaptic activity were observed in neuronal cultures treated with the antioxidant 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). Our study indicates that AD-related mutations may promote enhanced ROS generation, oxidative-dependent oligomerization, and loss of function of Kv2.1 channels. These processes can be part on the increased neuronal excitability of these neurons. These steps may set a deleterious vicious circle that eventually helps to promote excitotoxic damage found in the AD brain.

Acute Effects of Modafinil on Brain Resting State Networks in Young Healthy Subjects Roberto Esposito 1,2. , Franco Cilli 2. , Valentina Pieramico 2 , Antonio Ferretti 1 , Antonella Macchia 3 , Marco Tommasi 3 , Aristide Saggino 3 , Domenico Ciavardelli 2,4 , Antonietta Manna 1 , Riccardo Navarra 1 , Filippo Cieri 1 , Liborio Stuppia 3 , Armando Tartaro 1 , Stefano L. Sensi 1,2,5,6 * 1 Department of Neuroscience and Imaging, University ‘‘G. d’Annunzio’’ Chieti-Pescara, Italy, 2 Molecular Neurology Unit, Center of Excellence on Aging, University ‘‘G. d’Annunzio’’ Chieti-Pescara, Italy, 3 Department of Psychological sciences, University ‘‘G. d’Annunzio’’ Chieti-Pescara, Italy, 4 School of Engineering, Architecture, and Motor Science, Kore University of Enna, Enna, Italy, 5 Departments of Neurology and Pharmacology, University of California-Irvine, Irvine, California, United States of America, 6 Institute for Mind Impairments and Neurological Disorders, University of California-Irvine, Irvine, California, United States of America Abstract Background: There is growing debate on the use of drugs that promote cognitive enhancement. Amphetamine-like drugs have been employed as cognitive enhancers, but they show important side effects and induce addiction. In this study, we investigated the use of modafinil which appears to have less side effects compared to other amphetamine-like drugs. We analyzed effects on cognitive performances and brain resting state network activity of 26 healthy young subjects. Methodology: A single dose (100 mg) of modafinil was administered in a double-blind and placebo-controlled study. Both groups were tested for neuropsychological performances with the Raven’s Advanced Progressive Matrices II set (APM) before and three hours after administration of drug or placebo. Resting state functional magnetic resonance (rs-FMRI) was also used, before and after three hours, to investigate changes in the activity of resting state brain networks. Diffusion Tensor Imaging (DTI) was employed to evaluate differences in structural connectivity between the two groups. Protocol ID: Modrest_2011; NCT01684306; http://clinicaltrials.gov/ct2/show/NCT01684306. Principal Findings: Results indicate that a single dose of modafinil improves cognitive performance as assessed by APM. Rs- fMRI showed that the drug produces a statistically significant increased activation of Frontal Parietal Control (FPC; p,0.04) and Dorsal Attention (DAN; p,0.04) networks. No modifications in structural connectivity were observed. Conclusions and Significance: Overall, our findings support the notion that modafinil has cognitive enhancing properties and provide functional connectivity data to support these effects. Trial Registration: ClinicalTrials.gov NCT01684306 http://clinicaltrials.gov/ct2/show/NCT01684306. Citation: Esposito R, Cilli F, Pieramico V, Ferretti A, Macchia A, et al. (2013) Acute Effects of Modafinil on Brain Resting State Networks in Young Healthy Subjects. PLoS ONE 8(7): e69224. doi:10.1371/journal.pone.0069224 Editor: Ben J. Harrison, The University of Melbourne, Australia Received December 1, 2012; Accepted June 5, 2013; Published July 25, 2013 Copyright: s 2013 Esposito et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: SLS is supported by funds from the Italian Department of Education [Fondo per gli Investimenti della Ricerca di Base (FIRB) 2003; Programmi di Ricerca di Rilevante Interesse nazionale (PRIN) 2008]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: SLS is a PLOS ONE Editorial Board member. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. * E-mail: ssensi@uci.edu . These authors contributed equally to this work. norepinephrine [1]. Finally, recent studies have shown that modafinil can also block the dopamine transporter (DAT1), thereby increasing brain dopamine levels [10]. The employment of psychostimulants to promote cognitive enhancement has been recently widely debated [11]. Among the drugs that have gathered some interest as cognitive enhancers, modafinil has emerged as a potential pharmacological aid to enhance performance in domains like attention and memory [12– 14]. However, to date, the potential of this drug as modulator of fluid intelligence (Gf) is still unknown. In this study, we aimed at filling this knowledge gap and evaluated effects of a single dose of Introduction Modafinil (Provigil), a drug on the market since 1997, is employed for the treatment of narcolepsy and other sleep disorders [1], [2]. In recent years, modafinil has also been used off-label to treat cognitive dysfunction in psychiatric disorders such as schizophrenia and the Attention Deficit/Hyperactivity Disorder (ADHD) [3–5]. Modafinil is involved in the modulation of orexin, a hypotha- lamic neuropeptide [6] that regulates wakefulness. Several studies have also indicated that the drug interferes with the activity of additional neurotransmitters like hypocretin, histamine [7], gamma-aminobutyric acid (GABA) [8], glutamate [9], and PLOS ONE | www.plosone.org July 2013 | Volume 8 | Issue 7 | e69224