Neurosciences

Driving is a complex behavior involving multiple cognitive domains. To identify neural correlates of driving performance, [ 15 O]H 2 O positron emission tomography was performed using a simulated driving task. Compared with the resting condition, simulated driving increased regional cerebral blood Xow (rCBF) in the cerebellum, occipital, and parietal cortices. Correlations between rCBF and measurements of driving performance were evaluated during simulated driving. Interestingly, rCBF in the thalamus, midbrain, and cerebellum were positively correlated with time required to complete the course and rCBF in the posterior cingulate gyrus was positively correlated with number of crashes during the task. These brain regions may thus play roles in the maintenance of driving performance.

Kyoto Prd. Univ. Mcd~cine. K;imig> o-ku. Kyrltr) 60_-1 OX41 'K 'ori) Inst Tcc11 I tic' veto 605-X5X5. IDi\,. C,WJIII\C NCLII~WI.. Kvc,tci I'~I\,.. S<I~~P 'u. K~"Iu 606 Xi0 I. k 'Shlmad/u t;o.. Nakagyo-ku. ~yoto 6031X5 I 1. "Dept. NWWI-g.. a bl/lcq~ C~,llcgc' 01-1cnr~<l Mdicine. HI>~,~I. (12')~(1300 Ncul.al respr~nscs prdLlccd Ln the left occipit;ll cortex by prcacnt;lti<ln 01 Lhrcc ~ypcs 01 \.i+ual SIIIIIUI~ (\Lthtcdcd Anglo'. I S\i6 i including stationary sinusoidal gratings i SSGs). stationary and lllovII1, (1 I-;indom-doLs (SRD\ and 51RDx) wcrc ~r~11cd using 3D III~I~IXtomcter-spatial filtersystcm. SSGs prodL~ced sin@-pcakcd m~~~~ct~~enchephalo~r~~~ns (MEGx) whosc'currcnt-s\clurccs MLW loc'~ll/~~d 111 the lower balk ofthc left calcarine subs hy the convcntion;ll CIIITC'III-~O~~TC~'~LI~CC analysis (g~~~dn~s~ ~)l'l'it > 9X'/: 1. Accord~nfly. the sp:~ti;d I'ilters rcvcalcd single-peaked rcsponscs distrihutcd in ;I cortical reg1011 ;NOLIII~ the calc~u~~~~e \LIICLIS probably corrcspondi y 10 V I SRD\ and MRDs produced muI&pc&ed ME&. for which the ~Llr~mt-s~L~r~c anulyais less rcliahly loc;lli/ed the CLII~~CII~-S~~LII'C'C (poodles 01 t'i t < 95 'Z ). The spatial filters dcmonstratcd that responses to SRDs distii hurcd III ;L wider-COIIIUI ;II'C;I includm, I' \; I. all ill'c';l \LIITilllllcllIlf VI corresponding to V2/3 than that l'or SSGs. while those to MRDs dlstrihuted III ;I CVCII hrcdcrcort~cal a~-ca mcluding V I aml L'21.7 AS well as the one antero-inferior to V2/3. The results wcrc Illrthel-confirmed hy mapping the cortical xcxs x~~v;Lted by the th1.w I\ ps of visual stimuli using the functional MRI. In summary. SSGs sclcctivcly activated VI. SRDs ;tctivatcd V I and VY3. ;IIKI MRD\ ;,I; 01 VI V213 and VS. Thcsc findings open ;I way for functional mapplnf ol'visrial colllcal ;Irus using lhc l!ircc lypcs 01 \.ixuiil stimnll.

BackgroundLittle is known about how conspiracy beliefs and health responses are interrelated over time during the course of the coronavirus disease 2019 (Covid-19) pandemic. This longitudinal study tested two contrasting, but not mutually exclusive, hypotheses through cross-lagged modeling. First, based on the consequential nature of conspiracy beliefs, we hypothesize that conspiracy beliefs predict an increase in detrimental health responses over time. Second, as people may rationalize their behavior through conspiracy beliefs, we hypothesize that detrimental health responses predict increased conspiracy beliefs over time.MethodsWe measured conspiracy beliefs and several health-related responses (i.e. physical distancing, support for lockdown policy, and the perception of the coronavirus as dangerous) at three phases of the pandemic in the Netherlands (N = 4913): During the first lockdown (Wave 1: April 2020), after the first lockdown (Wave 2: June 2020), and during the second lock...

BackgroundConspiracy beliefs are associated with detrimental health attitudes during the coronavirus disease 2019 (Covid-19) pandemic. Most prior research on these issues was cross-sectional, however, and restricted to attitudes or behavioral intentions. The current research was designed to examine to what extent conspiracy beliefs predict health behavior and well-being over a longer period of time.MethodsIn this preregistered multi-wave study on a large Dutch research panel (weighted to provide nationally representative population estimates), we examined if conspiracy beliefs early in the pandemic (April 2020) would predict a range of concrete health and well-being outcomes eight months later (December 2020; N = 5745).ResultsThe results revealed that Covid-19 conspiracy beliefs prospectively predicted a decreased likelihood of getting tested for corona; if tested, an increased likelihood of the test coming out positive; and, an increased likelihood of having violated corona regulat...

Dopamine is often used to treat hypotension in preterm infants; these infants are at risk of developing brain injury due to impaired autoregulation and cerebral hypoperfusion. However the effects of dopamine on the immature brain under conditions of cerebral hypoxia are not known. We hypothesized that pretreatment with dopamine would protect the immature brain from injury caused by cerebral hypoxia. Preterm fetal sheep were used to determine the effects of intravenous dopamine on hypoxia-induced brain injury. In 16 pregnant sheep at 90 days of gestation (0.6 of term, term = 147 days) catheters were implanted aseptically into the fetal carotid artery and jugular vein; an inflatable occluder was placed loosely around the umbilical cord for later induction of fetal hypoxemia. At 5 days after surgery, dopamine (10 lg/kg/min, n = 7 fetuses) or saline (n = 9 fetuses) was infused for 74 h. Two hours after commencing the dopamine/saline infusion, we induced umbilical cord occlusion (UCO) for up to 25 min to produce fetal asphyxia. Fetuses were allowed to recover, and brains were collected 72 h later for assessment of neuropathology. Unoperated twin fetuses were used as age-matched non-UCO controls (n = 8). In UCO + saline fetuses, microglial and apoptotic cell density in the subcortical and periventricular white matter, caudate nucleus and hippocampus was greater than that in age-matched controls; oxidative stress was elevated in the subcortical and periventricular white matter and caudate nucleus compared to that in agematched controls. In UCO + dopamine fetuses microglial density and oxidative stress in the cerebral white matter and caudate nucleus were not different to that of agematched controls. Apoptotic cell death was decreased in the cerebral white matter of UCO + dopamine brains, relative to UCO + saline brains. We conclude that pretreatment with dopamine does not exacerbate hypoxiainduced injury in the immature brain and may be neuroprotective because it led to decreased apoptosis, oxidative stress and neuroinflammation in the cerebral white matter and decreased neuroinflammation in the caudate nucleus.

Multiple sclerosis (MS) is an inflammatory demyelinating disease classically associated with axonal damage and loss; more recently, however, synaptic changes have been recognized as additional contributing factors. An anatomical area commonly affected in MS is the visual pathway; yet, changes other than those associated with inflammatory demyelination of the optic nerve, i.e., optic neuritis, have not been described in detail. Adult mice were subjected to a diet containing cuprizone to mimic certain aspects of inflammatory demyelination as seen in MS. Demyelination and inflammation were assessed by real-time polymerase chain reaction and immunohistochemistry. Synaptic changes associated with inflammatory demyelination in the dorsal lateral geniculate nucleus (dLGN) were determined by immunohistochemistry, Western blot analysis, and electrophysiological field potential recordings. In the cuprizone model, demyelination was observed in retinorecipient regions of the subcortical visual ...

Neuroprotective strategies for stroke remain inadequate. Nanoliposomes comprised of phos-phatidylcholine, cholesterol and monosialogangliosides (NL) induced an antioxidant protective response in endothelial cells exposed to amyloid insults. We tested the hypotheses that NL will preserve SH-SY5Y neuroblastoma cell viability following hypoxic injury and will reduce injury in mice following middle cerebral artery occlusion (MCAO). Neuroblastoma were exposed to 20-hour physoxic (5% oxygen) or hypoxic (1% oxygen) condition without or with NL (100 or 300 µg/mL). Viability was measured using calcein-AM fluorescence and SH-SY5Y gene expression of antioxidant proteins heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1) and superoxide dismutase 1 (SOD1) were measured by quantitative polymerase chain reaction. C57BL/6J mice were treated with saline (N=8) or NL (10000 ug/mL, N=7) while undergoing 60-minute MCAO followed by reperfusion. Day 2 post-injury neurologic impairment score a...

Purpose We evaluated in a clinical setting the INTERPRET decision-support system (DSS), a software generated to aid in MRS analysis to achieve a specific diagnosis for brain lesions. Methods The material consisted of 100 examinations of focal intracranial lesions with confirmed diagnoses. MRS was obtained at 1.5 T using TE 20-30 ms. Data were processed with the LCModel for conventional analysis. The INTERPRET DSS 3.1. was used to obtain specific diagnoses. MRI and MRS were reviewed by one interpreter. DSS analysis was made by another interpreter, in 80 cases by two interpreters. The diagnoses were compared with the definitive diagnoses. For comparisons between DSS, conventional MRS analysis, and MRI, the diagnoses were categorised: high-grade tumour, low-grade tumour, non-neoplastic lesion. Results Interobserver agreement in choosing the diagnosis from the INTERPRET database was 75%. The diagnosis was correct in 38/100 cases, incorrect in 57 cases. No good match was found in 5/100 cases. The diagnostic category was correct with DSS/ conventional MRS/MRI in 67/58/52 cases, indeterminate in 5/8/20 cases, incorrect in 28/34/28 cases. Results with DSS were not significantly better than with conventional MRS analysis. All definitive diagnoses did not exist in the INTERPRET database. In the 61 adult patients with the diagnosis included in the database, DSS/conventional MRS/MRI yielded a correct diagnosis category in 48/32/29 cases (DSS vs conventional MRS: p = 0.002, DSS vs MRI: p = 0.0004). Conclusion Use of the INTERPRET DSS did not improve MRS categorisation of the lesions in the unselected clinical cases. In adult patients with lesions existing in the INTERPRET database, DSS improved the results, which indicates the potential of this software with an extended database.

Prediction of response to prophylactic treatment of bipolar disorder (BPD) and other forms of manicdepressive illness (MDI) remains challenging. A clinically plausible hypothesis is that a greater number of prior episodes of illness, or longer temporal delay (latency) of long-term, prophylactic treatment may lead to inferior treatment responses. At the extreme, illness history can affect treatment

Objectives: To further test the hypothesis that past illness episodes and delay of long‐term treatment do not limit maintenance treatment response among patients with manic‐depressive illnesses (MDI).Methods:  In a sample of 764 MDI patients in Cagliari and Berlin, 77% of whom had bipolar disorder (BPD), we: (i) correlated treatment latency or pretreatment episode counts versus hospitalized morbidity during treatment; (ii) correlated treatment duration versus pretreatment morbidity; (iii) correlated treatment latency versus pretreatment or treated morbidity; (iv) modeled factors associated with longer treatment latency; (v) compared treatment latencies at extremes of treatment outcomes, and (vi) compared pretreatment morbidity within 2 years of the longest versus shortest treatment latency quartiles.Results:  Pretreatment morbidity was strongly correlated with shorter treatment latency, but morbidity during treatment was unrelated to treatment latency, pretreatment episode counts, s...

The intracranial distribution of [ 14 C]sucrose, an extracellular marker infused for 30 s into one lateral ventricle, was determined by autoradiography of frozen-dried brain sections. Within 3.5 min [ 14 C]sucrose appeared in: (i) the third ventricle, including optic, infundibular and mammillary recesses; (ii) the aqueduct of Sylvius; (iii) the velum interpositum, a part of the subarachnoid space that runs along the roof of the third ventricle and contains many blood vessels; (iv) the mesencephalic and fourth ventricles; and (v) the superior medullary velum, a highly vascular extension of the subarachnoid space that terminates at the walls of the mesencephalic and fourth ventricles. Within 5 min, radioactivity was present in the interpeduncular, ambient and quadrigeminal cisterns, which encircle the midbrain. By 10 min, approximately 11% of the radioactivity had passed into the subarachnoid space via a previously undescribed flow pathway that included the velum interpositum and superior medullary velum. At many places along the ventricular system, [ 14 C]sucrose appeared to move from cerebrospinal fluid into the adjacent tissue by simple diffusion, as reported previously (Blasberg R. G. et al. (1974)

Nicotine (1.75 mg/kg s.c.) was administered to rats to raise local CBF (lCBF) in various parts of the brain, test the capillary recruitment hypothesis, and determine the effects of this increase in lCBF on local solute uptake by brain. lCBF as well as the local influx rate constants ( K1) and permeability-surface area ( PS) products of [14C]antipyrine and [14C]-3- O-methyl-d-glucose (30MG) were estimated by quantitative autoradiography in 44 brain areas. For this testing, the finding of significantly increased PS products supports the capillary recruitment hypothesis. In 17 of 44 areas, nicotine treatment increased lCBF by 30–150%, K1 of antipyrine by 7–40%, K1 of 30MG by 5–27%, PS product of antipyrine by 0–20% (mean 7%), and PS product of 30MG by 0–23% (mean 8%). Nicotine had no effect on blood flow or influx in the remaining 27 areas. The increases in lCBF and K1 of antipyrine were significant, whereas those in K1 of 30MG and in PS for both antipyrine and 30MG were not statistica...

A more complete understanding of how fear extinction alters neuronal activity and connectivity within fear circuits may aid in the development of strategies to treat human fear disorders. Using a c-fos-based transgenic mouse, we found that contextual fear extinction silenced basal amygdala (BA) excitatory neurons that had been previously activated during fear conditioning. We hypothesized that the silencing of BA fear neurons was caused by an action of extinction on BA inhibitory synapses. In support of this hypothesis, we found extinction-induced target-specific remodeling of BA perisomatic inhibitory synapses originating from parvalbumin and cholecystokinin-positive interneurons. Interestingly, the predicted changes in the balance of perisomatic inhibition matched the silent and active states of the target BA fear neurons. These observations suggest that target-specific changes in perisomatic inhibitory synapses represent a mechanism through which experience can sculpt the activation patterns within a neural circuit.

For malignant gliomas, progress in molecular diagnostics such as genomewide sequencing led to identification of subgroup-defining genetic alterations representing promising immunotherapeutic targets especially for personalized vaccination strategies. One example for an oncogenic mutation occurring in about one half of all pediatric brain stem gliomas and occasionally in adult gliomas is a point mutation in the histon-3.3 gene (H3F3A) causing an amino acid exchange from lysine to methionine at position 27 (K27M). Here, we analyzed the immunogenicity of H3.3 K27M and its relevance for a mutation-specific vaccination approach. Vaccination of major histocompatibility complex (MHC)-humanized (A2DR1) mice with a H3.3 K27M-covering 10-mer peptide led to a CD8driven mutation-specific immune response. Using a human leukocyte antigen (HLA) class-I epitope prediction tool, a mutation-containing 10mer peptide sequence with a strong binding affinity compared to the corresponding wild type sequence was identified. In silico, functional presentation of the crucial epitope was predicted for the class-I haplotypes A2. Importantly, peptide vaccination of A2DR1-mice effectively inhibited growth of H3.3 K27Moverexpressing flank tumors. In summary, we demonstrated that a H3.3 K27M-specific and effective antitumor immune response can be induced by a peptide vaccine. Thus, our data provide evidence for a further clinical development of this personalized immunotherapeutic approach. OS2.

High grade gliomas are associated with poor prognosis and high mortality. Conventional treatments and management of high grade gliomas have shown little improvement in 5-year overall survival. This phase I trial evaluated the safety, immunogenicity, and potential synergy of surgical resection with Gliadel Wafer implantation, followed by autologous tumor lysate-pulsed dendritic cell (DC) vaccine in patients with malignant glioma. Primary end points of this study were safety and surrogate markers of immunogenicity, overall survival, and progression free survival. Following surgical resection, Gliadel Wafers were placed along the resection cavity. Patients subsequently received intradermal injections of autologous tumor lysate-pulsed DC vaccines 3 times at 2 week intervals. Treatment response was evaluated clinically and through MRI at regular intervals. Twenty-eight patients received Gliadel Wafers and DC vaccination: 11 newly diagnosed (8 glioblastoma [GBM], 2 anaplastic astrocytoma [AA], and 1 anaplastic oligodendroglioma [AO]) and 17 recurrent (15 GBMs, 1 AA, and 1 AO) high grade gliomas. Immunogenicity data was collected for 20 of the 28 patients. Five of 20 patients showed elevated IFN-c responses following vaccination. Median progression-free survival and overall survival for all GBM patients in the trial from the start of vaccination were 3.6 months and 16.9 months respectively. Comparisons between vaccine responders and non-vaccine responders were not statistically significant. Adjuvant autologous dendritic cells pulsed with tumor-lysate following resection and Gliadel Wafer placement is safe, elicits modest immunogenicity and shows similar clinical outcomes in patients who had DC vaccination in previous studies.

The incidence of autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD), which frequently co-occur, are both rising. The causes of ASD and ADHD remain elusive, even as both appear to involve perturbation of the gut-brain-immune axis. CD103 is an integrin and E-cadherin receptor most prominently expressed on CD8 T cells that reside in gut, brain, and other tissues. CD103 deficiency is well-known to impair gut immunity and resident T cell function, but it's impact on neurodevelopmental disorders has not been examined. We show here that CD8 T cells influence neural progenitor cell function, and that CD103 modulates this impact both directly and potentially by controlling CD8 levels in brain. CD103 knockout (CD103KO) mice exhibited a variety of behavioral abnormalities, including superior cognitive performance coupled with repetitive behavior, aversion to novelty and social impairment in females, with hyperactivity with delayed learning in males. Brain protein markers in female and male CD103KOs coincided with known aspects of ASD and ADHD in humans, respectively. Surprisingly, CD103 deficiency also decreased age-related cognitive decline in both sexes, albeit by distinct means. Together, our findings reveal a novel role for CD103 in brain developmental function, and identify it as a unique factor linking ASD and ADHD etiology. Our data also introduce a new animal model of combined ASD and ADHD with associated cognitive benefits, and reveal potential therapeutic targets for these disorders and age-related cognitive decline.

Object. An approach toward the treatment of intracranial gliomas was developed in a rat experimental model. The authors investigated the ability of “professional” antigen-presenting cells (dendritic cells) to enhance host antitumor immune responses when injected as a vaccine into tumor-bearing animals.Methods. Dendritic cells, the most potent antigen-presenting cells in the body, were isolated from rat bone marrow precursors stimulated in vitro with granulocyte—macrophage colony-stimulating factor (GM-CSF) and interleukin-4. Cultured cell populations were confirmed to be functional antigen-presenting cells on the basis of expressed major histocompatibility molecules, as analyzed by fluorescence-activated cell sorter cytofluorography. These dendritic cells were then pulsed (cocultured) ex vivo with acid-eluted tumor antigens from 9L glioma cells. Thirty-eight adult female Fischer 344 rats harboring 7-day-old intracranial 9L tumors were treated with three weekly subcutaneous injection...

Object The intraoperative clear delineation between brain tumor and normal tissue in real time is required to ensure near-complete resection without damaging the nearby eloquent brain. Tumor Paint BLZ-100, a tumor ligand chlorotoxin (CTX) conjugated to indocyanine green (ICG), has shown potential to be a targeted contrast agent. There are many infrared imaging systems in use, but they are not optimized to the low concentration and amount of ICG. The authors present a novel proof-of-concept near-infrared (NIR) imaging system using a standard charge-coupled device (CCD) camera for visualizing low levels of ICG attached to the tumors. This system is small, inexpensive, and sensitive. The imaging system uses a narrow-band laser at 785 nm and a notch filter in front of the sensor at the band. The camera is a 2-CCD camera, which uses identical CCDs for both visible and NIR light. Methods The NIR system is tested with serial dilution of BLZ-100 from 1 μM to 50 pM in 5% Intralipid solution ...

Emerging evidences suggest that cyclin-dependent kinase inhibitors (CKIs) can regulate cellular functions other than cell cycle progression, such as differentiation and migration. Here, we report that cytoplasmic expression of p27 kip1 affects microtubule (MT) stability following cell adhesion on extracellular matrix (ECM) constituents. This p27 kip1 activity is due to its ability to bind and impair the function of the MT-destabilizing protein stathmin. Accordingly, upregulation of p27 kip1 or downregulation of stathmin expression results in the inhibition of mesenchymal cell motility. Moreover, high stathmin and low cytoplasmic p27 kip1 expression correlate with the metastatic phenotype of human sarcomas in vivo. This study provides a functional link between proliferation and invasion of tumor cells based on diverse activities of p27 kip1 in different subcellular compartments.

Objective. Event Related Potentials (ERPs) reflecting cognitive response to external stimuli, are widely used in Brain Computer Interfaces (BCI). ERP waveforms are characterized by a series of components of particular latency and amplitude. The classical ERP decoding methods exploit this waveform characteristic and thus achieve a high performance only if there is sufficient time-and phase-locking across trials. The required condition is not fulfilled if the experimental tasks are challenging or if it is needed to generalize across various experimental conditions. Features based on spatial covariances across channels can potentially overcome the latency jitter and delays since they aggregate the information across time. Approach. We compared the performance stability of waveform and covariance-based features as well as their combination in two simulated scenarios: 1) generalization across experiments on Error-related Potentials and 2) dealing with larger latency jitter across trials. Main results. The features based on spatial covariances provide a stable performance with a minor decline under jitter levels of up to ± 300 ms, whereas the decoding performance with waveform features quickly drops from 0.85 to 0.55 AUC. The generalization across ErrP experiments also resulted in a significantly more stable performance with covariance-based features. Significance. The results confirmed our hypothesis that covariance-based features can be used to: 1) classify more reliably ERPs with higher intrinsic variability in more challenging real-life applications and 2) generalize across related experimental protocols.

The ability to recognize errors is crucial for efficient behavior. Numerous studies have identified electrophysiological correlates of error recognition in the human brain (error-related potentials, ErrPs). Consequently, it has been proposed to use these signals to improve human-computer interaction (HCI) or brain-machine interfacing (BMI). Here, we present a review of over a decade of developments toward this goal. This body of work provides consistent evidence that ErrPs can be successfully detected on a single-trial basis, and that they can be effectively used in both HCI and BMI applications. We first describe the ErrP phenomenon and follow up with an analysis of different strategies to increase the robustness of a system by incorporating single-trial ErrP recognition, either by correcting the machine&#39;s actions or by providing means for its error-based adaptation. These approaches can be applied both when the user employs traditional HCI input devices or in combination with ...

This chapter was originally published in the book International Review of Neurobiology, Vol. 86, published by Elsevier, and the attached copy is provided by Elsevier for the author's benefit and for the benefit of the author's institution, for noncommercial research and educational use including without limitation use in instruction at your institution, sending it to specific colleagues who know you, and providing a copy to your institution's administrator.

Objective. In this work we present-for the first time-the online operation of an electroencephalogram (EEG) brain-computer interface (BCI) system based on covert visuospatial attention (CVSA), without relying on any evoked responses. Electrophysiological correlates of pure top-down CVSA have only recently been proposed as a control signal for BCI. Such systems are expected to share the ease of use of stimulus-driven BCIs (e.g. P300, steady state visually evoked potential) with the autonomy afforded by decoding voluntary modulations of ongoing activity (e.g. motor imagery). Approach. Eight healthy subjects participated in the study. EEG signals were acquired with an active 64-channel system. The classification method was based on a time-dependent approach tuned to capture the most discriminant spectral features of the temporal evolution of attentional processes. The system was used by all subjects over two days without retraining, to verify its robustness and reliability. Main results. We report a mean online accuracy across the group of 70.6 ± 1.5%, and 88.8 ± 5.8% for the best subject. Half of the participants produced stable features over the entire duration of the study. Additionally, we explain drops in performance in subjects showing stable features in terms of known electrophysiological correlates of fatigue, suggesting the prospect of online monitoring of mental states in BCI systems. Significance. This work represents the first demonstration of the feasibility of an online EEG BCI based on CVSA. The results achieved suggest the CVSA BCI as a promising alternative to standard BCI modalities.

Recently, several studies have started to explore covert visuospatial attention as a control signal for brain-computer interfaces (BCIs). Covert visuospatial attention represents the ability to change the focus of attention from one point in the space without overt eye movements. Nevertheless, the full potential and possible applications of this paradigm remain relatively unexplored. Voluntary covert visuospatial attention might allow a more natural and intuitive interaction with real environments as neither stimulation nor gazing is required. In order to identify brain correlates of covert visuospatial attention, classical approaches usually rely on the whole α-band over long time intervals. In this work, we propose a more detailed analysis in the frequency and time domains to enhance classification performance. In particular, we investigate the contribution of α sub-bands and the role of time intervals in carrying information about visual attention. Previous neurophysiological studies have already highlighted the role of temporal dynamics in attention mechanisms. However, these important aspects are not yet exploited in BCI. In this work, we studied different methods that explicitly cope with the natural brain dynamics during visuospatial attention tasks in order to enhance BCI robustness and classification performances. Results with ten healthy subjects demonstrate that our approach identifies spectro-temporal patterns that outperform the state-of-the-art classification method. On average, our time-dependent classification reaches 0.74 ± 0.03 of the area under the ROC (receiver operating characteristic) curve (AUC) value with an increase of 12.3% with respect to standard methods (0.65 ± 0.4). In addition, the proposed approach allows faster classification (<1 instead of 3 s), without compromising performances. Finally, our analysis highlights the fact that discriminant patterns are not stable for the whole trial period but are changing over short time intervals. These results support the hypothesis that visual attention information is actually indexed by subject-specific α sub-bands and is time dependent.

To be correctly mastered, brain-computer interfaces (BCIs) need an uninterrupted flow of feedback to the user. This feedback is usually delivered through the visual channel. Our aim was to explore the benefits of vibrotactile feedback during users&#39; training and control of EEG-based BCI applications. A protocol for delivering vibrotactile feedback, including specific hardware and software arrangements, was specified. In three studies with 33 subjects (including 3 with spinal cord injury), we compared vibrotactile and visual feedback, addressing: (I) the feasibility of subjects&#39; training to master their EEG rhythms using tactile feedback; (II) the compatibility of this form of feedback in presence of a visual distracter; (III) the performance in presence of a complex visual task on the same (visual) or different (tactile) sensory channel. The stimulation protocol we developed supports a general usage of the tactors; preliminary experimentations. All studies indicated that the ...

thought of as a stress-activated kinase that mediates apoptosis. However, additional studies indicate that the MEKK-1/JNK pathway mediates critical aspects of neuronal survival and differentiation. Herein, we demonstrate that transfection of differentiated NB2a/d1 cells with a construct expression constitutively activated (ca) MEKK-1 increases levels of phospho-dependent neurofilament (NF) immunoreactivity within perikarya, while expression of a dominant-negative (dn) form of MEKK-1 decreases it. Steady-state levels of perikaryal phospho-NF immunoreactivity are reduced and the increase resulting from expression of caMEKK-1 is prevented, by the JNK inhibitor SP600125, suggesting that JNK is a major downstream effector of MEKK-1 on NF phosphorylation. Unexpectedly, both caMEKK-1 and dnMEKK-1 inhibited neuritogenesis as well as translocation of NFs into newly elaborated neurites. The JNK inhibitor SP600125 also inhibited NF transport in a dosedependent manner. caMEKK-1 also prevented the increase in NF transport otherwise mediated by MAP kinase. Finally, both caMEKK-1 and dnMEKK-1 prevented initial neuritogenesis. These findings indicate that the MEKK-1/JNK pathway regulates critical aspects of initial outgrowth, and subsequent stabilization of axonal neurites.

Background: Subthalamic nucleus deep brain stimulation (STN DBS) is an established treatment in Parkinson's disease (PD). We investigate the effect of eye opening on neuronal activity and local field potentials (LFPs) in the STN. Methods: We prospectively enrolled 25 PD patients undergoing STN DBS in our institution. During DBS, single-unit activity (SUA) and LFPs were measured when eyes were open and closed. As movement is known to result in changes in LFPs, we tested response to eye opening in the presence and absence of movement. Results: Neither eye state nor arm movement has a significant influence on SUA recordings. There is a statistically significant interaction between eye state and arm movement (p < 0.05). In the presence of movement, STN SUA increase when eyes open (p < 0.05). When eyes are closed, STN SUA decrease with movement (p < 0.05). STN theta LFP oscillations decrease when eyes are open compared to closed, irrespective of movement status (p < 0.05). Discussion: STN activity is influenced by eye state and arm movement. It is unclear whether this is attributed to a change in the STN's role in oculomotor control or from a change in attentional state. Understanding how physiologic normal activity alters neural activity is critical for the optimization of DBS therapy, particularly in closed-loop neuromodulation.

Objective: Experimental work suggests a neuroprotective role for magnesium sulfate in aneurysmal subarachnoid hemorrhage. We retrospectively review the incidence of clinically relevant vasospasm in patients treated or not with continuous magnesium infusion after onset of subarachnoid hemorrhage. Methods: All patient records in Albany Medical Center with the diagnosis of SAH between January 1999 and June 2004 were reviewed. Patients who presented to the emergency department within 72 hours of onset were entered in the study. Patients were defined as in clinical vasospasm if there was an acute neurological change in association with abnormal trancranial Doppler (TCD), CT angiogram (CTA) or digital subtraction angiography (DSA). Results: A total of 85 patients were selected. Magnesium sulfate was infused in 43 patients. When compared with patients who did not receive MgSO 4 , there was a statistically significant lower incidence of clinical and radiological vasospasm in those who had the continuous infusion of magnesium sulfate (p,0.01). There was no statistically significant difference between patients who were coiled or clipped. Conclusion: Continuous magnesium sulfate infusion for the management of clinically significant cerebral vasospasm is safe and reduces the incidence of clinically significant cerebral vasospasm. Large, multicenter, controlled studies should be performed in order to determine the true effectiveness of the treatment in a controlled setting.

The development of the hippocampus and amygdala is particularly sensitive to environmental factors, including socioeconomic status (SES). Studies that have investigated associations between SES and brain development markers have rarely focused on connectivity. Accordingly, this longitudinal study examined whether SES in infancy (parental education and income-to-needs ratio) predicts the functional connectivity of the hippocampus and amygdala in late childhood, and in turn whether functional connectivity is associated with child socioemotional adjustment in a middle-class sample. SES indices were measured when children (n = 28) were 7 months old. When children were 10 years of age, they underwent a resting-state functional magnetic resonance imaging exam, and their school teachers completed a questionnaire assessing child socioemotional adjustment. Whole-brain regression analyses, including left and right hippocampi and amygdalae as seeds and SES indices as predictors, revealed that ...

Mindfulness meditation has been shown to promote emotional stability. Moreover, during the processing of aversive and self-referential stimuli, mindful awareness is associated with reduced medial prefrontal cortex (MPFC) activity, a central default mode network (DMN) component. However, it remains unclear whether mindfulness practice influences functional connectivity between DMN regions and, if so, whether such impact persists beyond a state of meditation. Consequently, this study examined the effect of extensive mindfulness training on functional connectivity within the DMN during a restful state. Resting-state data were collected from 13 experienced meditators (with over 1000 h of training) and 11 beginner meditators (with no prior experience, trained for 1 week before the study) using functional magnetic resonance imaging (fMRI). Pairwise correlations and partial correlations were computed between DMN seed regions time courses and were compared between groups utilizing a Bayesian sampling scheme. Relative to beginners, experienced meditators had weaker functional connectivity between DMN regions involved in self-referential processing and emotional appraisal. In addition, experienced meditators had increased connectivity between certain DMN regions (e.g. dorso-medial PFC and right inferior parietal lobule), compared to beginner meditators. These findings suggest that meditation training leads to functional connectivity changes between core DMN regions possibly reflecting strengthened present-moment awareness.

Purpose: Multiple sclerosis (MS) is a long-lasting disabling disease with psychological implications. Hospital Anxiety and Depression Scale (HADS) is a questionnaire developed to screen anxiety and depression among patients in hospital settings. The objective of this report was to study the metric properties of the Portuguese version of HADS regarding MS. Materials and methods: This was a cross-sectional study. Three hundred and eighty individuals with a diagnosis of MS, according to the revised McDonald criteria, were recruited from an outpatient Neuroimmunology Clinic of the city of Porto. Participants had a mean age of 40.04 years (SD =10.86), 63.9% of them were female. HADS consists of two subscalesanxiety and depression -scored separately, with seven items each. The results of our study show the appropriateness of HADS for the identification of mood changes in people with MS and show good metric properties. Conclusion: It seems to be a useful tool for the scrutiny of mood disorders in Portuguese patients with MS. The questionnaire is also sensitive to disease when compared to people with other severe illnesses, and with people without the disease.

Objectives: Natalizumab (NTZ) is very effective for treatment of relapsing-remitting multiple sclerosis (RRMS), its use is mainly limited by safety issues. Discontinuation of NTZ is associated with recurrence of disease activity (reactivation and rebound). The best strategy for subsequent therapy and the predictive factors for recurrence in such patients are areas of active research. We aimed to evaluate predictors of reactivation in a multicentric study. Patients and methods: Multicentric retrospective observational study in five portuguese MS referral centers. Demographic, clinical and imagiological data were collected in the year prior, during and in the year following NTZ discontinuation. Predictors of reactivation and rebound after NTZ suspension were studied using a multivariate Cox model. Results: Sixty-nine patients were included. They were mainly non-naïve patients (97%), with a mean age of 29.1 ± 8.3 years at diagnosis, and a mean age of 37.2 ± 10.3 years at NTZ initiation. The mean annualized relapse rate (ARR) previous, during and after NTZ was 1.6 ± 1.2, 0.2 ± 0.5 and 0.6 ± 1.0, respectively. The median EDSS before, during and after NTZ was 3.5 (IQR 3.3), 3.5 (IQR 3.5) and 4.0 (IQR 3.8), respectively. The median number of infusions was 26.0 (IQR 12.5) and the main reason to NTZ discontinuation was progressive multifocal leukoencephalopathy (PML) risk (70%). After NTZ suspension, reactivation was observed in 25 (36%) patients after a median time of 20.0 (IQR 29.0) weeks. Reactivation predictors in our sample included NTZ suspension for reasons other than PML (adjusted HR = 0.228, 95% CI [0.084-0.616], p = 0.004), ARR before NTZ (adjusted HR = 1.914 95% [CI 1.330-2.754], p < 0.001) and a longer disease duration at time of NTZ initiation (adjusted HR = 1.154, 95% CI [1.020-1.306], p = 0.023). Rebound occurred in 5 (7%) patients after a median time of 20 (IQR 34.5) weeks. Conclusion: Significant predictors of disease reactivation in our cohort were discontinuation of NTZ for reasons other than PML risk, higher disease activity before NTZ treatment, and longer disease duration. Our study provides valuable data of portuguese patients after NTZ withdrawal.

Background: Cognitive dysfunction as a predictor of clinical progression and mortality in multiple sclerosis (MS) is still a matter of debate. Objective: The aim of this study was to explore the long-term outcome associated with neuropsychological performance in a cohort of patients with MS. Methods: A series of 408 MS patients had previously undergone a comprehensive neuropsychological assessment and a contemporaneous neurological evaluation (T1). A retrospective review of the clinical records was conducted 102–192 months after T1. Demographic and clinical data regarding the last clinical appointment with EDSS measurement (T2) were collected and the date of the last clinical contact or death (TS) was recorded. Results: This review revealed that cognitive dysfunction (T1) was associated with higher odds of transitioning from relapsing–remitting course to a progressive disease course (adjusted odds ratio (OR) = 2.29, p = 0.043) and higher hazard of death in the total sample (adjusted...

Hereditary transthyretin (TTR) amyloidosis associated with the TTRV30M (p.TTRV50M) mutation presents predominantly as an axonal polyneuropathy, with variable involvement of other organs. Serious central nervous system (CNS) and eye manifestations, including stroke, dementia, vitreous opacities and glaucoma, have been reported in untreated V30M TTR amyloidosis patients, and in these patients after treatment with liver transplantation (LT). Distinct therapies for V30M TTR amyloidosis developed during the last decade exhibit promising results in slowing the peripheral and autonomic nervous system pathology. However, the effect of these therapies on the CNS and eye manifestations of V30M TTR amyloidosis is not known. Herein, we show that in a small cohort of patients taking tafamidis orally (20 mg tafamidis meglumine daily) we could detect this small molecule in the cerebrospinal fluid (CSF) and the vitreous body. In the CSF, the ratio of TTR tetramer to tafamidis was ≈ 2:1, leading to a moderate kinetic stabilization of TTR in the CSF of these patients. Our data suggests that tafamidis can cross the CSF-blood and eye-blood barriers. Future studies comparing CNS and eye manifestations in patients treated with LT, kinetic stabilizers and TTR lowering drugs are essential to understand the clinical effect of our observations. Declaration of interest statement J.W.K. receives royalties related to tafamidis sales and sales milestones. T.C. has received funding from Pfizer Inc., Alnylam Pharmaceuticals and Ionis Pharmaceuticals for scientific meeting expenses (travel, accommodation, and registration), and received honoraria from Pfizer Inc. and Alnylam Pharmaceuticals for training. C.M., A.M.S., N.F., J.M. and M.N. declare that they have no competing conflict of interest.

Tafamidis, a transthyretin (TTR) kinetic stabilizer, delayed neuropathic progression in patients with Val30Met TTR familial amyloid polyneuropathy (TTR-FAP) in an 18-month randomized controlled trial (study Fx-005). This 12-month, open-label extension study evaluated the long-term safety, tolerability, and efficacy of tafamidis 20 mg once daily in 86 patients who earlier received blinded treatment with tafamidis or placebo. Efficacy measures included the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy total quality of life (TQOL) score, and changes in neurologic function and nutritional status. We quantified the monthly rates of change in efficacy measures, and TTR stabilization, and monitored adverse events (AEs). Patients who continued on tafamidis had stable rates of change in NIS-LL (from 0.08 to 0.11/ month; p = 0.60) and TQOL (from -0.03 to 0.25; p = 0.16). In patients switched from placebo, the monthly rate of change in NIS-LL declined (from 0.34 to 0.16/ month; p = 0.01), as did TQOL score (from 0.61 to -0.16; p \ 0.001). Patients treated with tafamidis for 30 months had 55.9 % greater preservation of neurologic function as measured by the NIS-LL than patients in whom tafamidis was initiated later. Plasma TTR was stabilized in 94.1 % of patients treated with tafamidis for 30 months. AEs were similar between groups; no patients discontinued because of an AE. Long-term tafamidis was well tolerated, with the reduced rate of neurologic deterioration sustained over 30 months. Tafamidis also slowed neurologic impairment in patients previously given placebo, but treatment benefits were greater when tafamidis was begun earlier.

Purpose: Cancer is one of the serious diseases of our time, claiming the lives of many people annually. Numerous experiments have been conducted to treat various types of cancer, but most have not yielded satisfactory results. The aim of this article is to explore the topic of cancer treatment and the destruction of cancerous tumors by sending signals using neuroprostheses.
Method:
In this method, we use healthy cells from the region containing cancer as a sample. We then determine their frequency and continuously send signals to the cancerous area using a
prosthesis or electrode, thereby strengthening the healthy cells. Alternatively, we use cancer cells as a sample, determine their frequency, and send signals to the cancerous area to destroy the cancer cells. We have explained both methods in detail.
Result:
Based on the experiments conducted in this field (of which we have provided many examples) and the existing devices and methods, we can easily sample the cells, obtain their frequency, and simulate these frequencies using the devices and methods we have introduced.
Conclusion:
According to the findings of this research and its combination with the phenomena of resonance and cymatics, we can treat cancers by sending signals to the cancerous area using
prostheses or electrodes. This method can weaken and eliminate cancer cells.

Glioblastoma development should be subdivided in three phases, one prehypoxic and two post-hypoxic phases. The pre-hypoxic phase, ranging from 10% to 5% oxygen (normal brain oxygen levels), should be characterized only by CD133-cells, and these cells are inevitably also those that first conquer and microinfiltrate the brain parenchyma. In some areas of the bulk, the oxygen concentration falls to about 5% or less, and hypoxia develops. The second phase ranges from about 5% to about 1% oxygen concentration. This phase of mild and severe hypoxia is regulated by the epigenetic shift driven by HIF2a, which is expressed only in cancer stem cells (CSCs) and is correlated with CD133 expression. When oxygen levels fall in certain regions of the tumor to about 1% or less, the third phase of very severe hypoxia begins. This phase is driven by HIF1a, which is expressed both by CSCs and committed cells. To date, the only way to monitor the development of the growing tumor in animal model is imaging. However, in order to reproduce what really happens in a human patient affected by a glioblastoma, we need a model that allows cells, biopsies, and sections to be obtained throughout tumor development. I recently proposed an original animal model that can enable us to study and monitor the entire development of the glioblastoma in only one generation of mice. The model allows the creation of a pool of twin transplanted animals in the same condition and the study of glioblastoma development, both in the bulk and in the brain parenchyma. This is done by taking multiple biopsies and by performing multiple stainings on sections. Through parenchymal biopsies and stainings on sections, we have four means to identify the CSCs microinfiltrated in the brain with the possibility of targeting them.

The degree to which COVID-19 severity influences the development of acute cerebrovascular events (ACVE) is unknown. Therefore, we aimed to describe the prevalence and risk of ACVE in patients with severe and nonsevere COVID-19. We systematically reviewed MEDLINE, EMBASE, Web of Science, and Scopus and identified observational and interventional studies of patients with COVID-19 allocated by respiratory severity that reported ACVE development. Case reports/series were excluded. The main outcome assessed was the pooled rate of ACVE in patients with severe and nonsevere COVID-19. To determine the risk of ACVE development by COVID-19 severity, a meta-analysis was performed. PROSPERO registration number: CRD42020178905. About 19 of 5758 identified studies were analyzed. From 11,886 COVID-19 patients analyzed, 421 had at least one ACVE [3.6%, 95% confidence interval (CI) 2.904–4.179]. Severe COVID-19 increased the risk of ACVE (odds ratio 1.96, 95% CI 1.22–3.15; P = 0.005; I 2 = 64%), spe...

Today, neurorehabilitation has become in a widely used therapeutic approach in spinocerebellar ataxias; however, there are scarce powerful clinical studies supporting this notion, and these studies require extension to other specific SCA subtypes in order to be able to form conclusions concerning its beneficial effects. Therefore, in this study, we perform for the first time a case-control pilot randomized, single-blinded, cross-sectional, and observational study to evaluate the effects of physical neurorehabilitation on the clinical and biochemical features of patients with spinocerebellar ataxia type 7 (SCA7) in 18 patients diagnosed with SCA7. In agreement with the exercise regimen, the participants were assigned to groups as follows: (a) the intensive training group, (b) the moderate training group, and (c) the non-training group (control group). We found that both moderate and intensive training groups showed a reduction in SARA scores but not INAS scores, compared with the control group (p < 0.05). Furthermore, trained patients exhibited improvement in the SARA sub-scores in stance, gait, dysarthria, dysmetria, and tremor, as compared with the control group (p < 0.05). No significant improvements were found in daily living activities, as revealed by Barthel and Lawton scales (p > 0.05). Patients under physical training exhibited significantly decreased levels in lipid-damage biomarkers and malondialdehyde, as well as a significant increase in the activity of the antioxidant enzyme PON-1, compared with the control group (p < 0.05). Physical exercise improved some cerebellar characteristics and the oxidative state of patients with SCA7, which suggest a beneficial effect on the general health condition of patients.

Background: Epilepsy is highly prevalent among children worldwide, making it one of the most common neurological disorders. Drug-Resistant Epilepsy (DRE) significantly impacts the quality of life (QoL) of affected children, attributed to factors such as seizure frequency and severity, low vitamin D levels, comorbidities, radiological abnormalities, and elevated IL-1β levels. Objective: This study aims to identify the factors most significantly affecting the QoL in children with DRE. Methods: This cross-sectional study at Adam Malik Hospital involved children with DRE. Participants' QoL was assessed with the QOLCE-55 score, while epilepsy severity was measured using the HASS score. Vitamin D status was quantified by serum 25-hydroxy vitamin D (25(OH)D) levels, and IL-1β levels were measured using the ELISA method. Multivariate logistic regression analysis using Pearson and Spearman test was conducted to evaluate risk factors that significantly impact the QoL of children with DRE. Results: The findings revealed several factors significantly influencing QoL in children with DRE. Comorbidities (OR = 24.98, p = 0.004, 95% CI) and high IL-1β levels (OR = 8.36, p = 0.022, 95% CI) were strongly correlated and significant factors in determining QoL, indicating 24.98-and 8.36-times higher likelihood of decreased QoL, respectively. Vitamin D levels had no statistically significant effect on QoL. Conclusion: Vitamin D levels have no substantial impact on QoL in children with DRE. IL-1β levels and comorbidities are crucial components affecting QoL in these patients. These findings highlight the importance of considering these factors in the management of children with DRE.

AMPA-type gultamate receptors (AMPARs) mediate excitatory signaling in the brain and are therapeutic targets for the treatment of diverse neurological disorders. The receptors interact with a variety of auxiliary subunits, including the transmembrane AMPAR regulatory proteins (TARPs). The TARPs influence AMPAR biosynthesis and trafficking and enhance receptor responses by slowing desensitization and deactivation and increasing single-channel conductance. TARP c8 has an expression pattern that is distinct from that of other TARPs, being enriched in the hippocampus. Recently, several compounds have been identified that selectivity inhibit c8containing AMPARs. One such inhibitor, JNJ-55511118, has shown considerable promise for the treatment of epilepsy. However, key details of its mechanism of action are still lacking. Here, using patch-clamp electrophysiological recording from heterologously expressed AMPARs, we show that JNJ-55511118 inhibits peak currents of c8-containing AMPARs by decreasing their singlechannel conductance. The drug also modifies hallmark features of AMPAR pharmacology, including the TARP-dependent actions of intracellular polyamines and the partial agonist kainate. Moreover, we find that JNJ-55511118 reduces the influence of c8 on all biophysical measures, aside from its effect on the recovery from desensitization. The drug is also effective when applied intracellularly, suggesting it may access its binding site from within the membrane. Additionally, we find that AMPARs incorporating TARP c2 mutated to contain the JNJ-55511118 binding site, exhibit greater block than seen with AMPARs containing c8, potentially reflecting differences in TARP stoichiometry. Taken together, our data provide new insight into the mechanism by which c8-selective drugs inhibit AMPARs. Although modulation of AMPA-type glutamate receptors shows promise for the treatment various neurological conditions, the absence of subtype-selective drugs has hindered adoption of this therapeutic strategy. We made patch-clamp recordings to characterize the actions of the g8-selective AMPAR inhibitor JNJ-55511118 on GluA2(Q) receptors expressed in HEK cells. We report that JNJ-55511118 inhibits AMPAR-mediated currents by reducing single-channel conductance, providing clear insight into the mechanism of action of this important class of AMPAR modulators.

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.