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Adolescence is an important developmental period associated with increased risk for excessive alcohol use, but also high rates of recovery from alcohol use-related problems, suggesting potential resilience to long-term effects compared to adults. The aim of this systematic review is to evaluate the current evidence for a moderating role of age on the impact of chronic alcohol exposure on the brain and cognition. We searched Medline, PsycInfo, and Cochrane Library databases up to February 3, 2021. All human and animal studies that directly tested whether the relationship between chronic alcohol exposure and neurocognitive outcomes differs between adolescents and adults were included. Study characteristics and results of age-related analyses were extracted into reference tables and results were separately narratively synthesized for each cognitive and brain-related outcome. The evidence strength for age-related differences varies across outcomes. Human evidence is largely missing, but animal research provides limited but consistent evidence of heightened adolescent sensitivity to chronic alcohol’s effects on several outcomes, including conditioned aversion, dopaminergic transmission in reward-related regions, neurodegeneration, and neurogenesis. At the same time, there is limited evidence for adolescent resilience to chronic alcohol-induced impairments in the domain of cognitive flexibility, warranting future studies investigating the potential mechanisms underlying adolescent risk and resilience to the effects of alcohol. The available evidence from mostly animal studies indicates adolescents are both more vulnerable and potentially more resilient to chronic alcohol effects on specific brain and cognitive outcomes. More human research directly comparing adolescents and adults is needed despite the methodological constraints. Parallel translational animal models can aid in the causal interpretation of observed effects. To improve their translational value, future animal studies should aim to use voluntary self-administration paradigms and incorporate individual differences and environmental context to better model human drinking behavior.

BACKGROUND: Brain monitors tracking quantitative brain activities from electroencephalogram (EEG) to predict hypnotic levels have been proposed as a labor-saving alternative to behavioral assessments. Expensive clinical trials are required to validate any newly developed processed EEG monitor for every drug and combinations of drugs due to drug-specific EEG patterns. There is a need for an alternative, efficient, and economical method.METHODS: Using deep learning algorithms, we developed a novel data-repurposing framework to predict hypnotic levels from sleep brain rhythms. We used an online large sleep data set (5723 clinical EEGs) for training the deep learning algorithm and a clinical trial hypnotic data set (30 EEGs) for testing during dexmedetomidine infusion. Model performance was evaluated using accuracy and the area under the receiver operator characteristic curve (AUC).RESULTS: The deep learning model (a combination of a convolutional neural network and long short-term memory units) trained on sleep EEG predicted deep hypnotic level with an accuracy (95% confidence interval [CI]) = 81 (79.2-88.3)%, AUC (95% CI) = 0.89 (0.82-0.94) using dexmedetomidine as a prototype drug. We also demonstrate that EEG patterns during dexmedetomidine-induced deep hypnotic level are homologous to nonrapid eye movement stage 3 EEG sleep.CONCLUSIONS: We propose a novel method to develop hypnotic level monitors using large sleep EEG data, deep learning, and a data-repurposing approach, and for optimizing such a system for monitoring any given individual. We provide a novel data-repurposing framework to predict hypnosis levels using sleep EEG, eliminating the need for new clinical trials to develop hypnosis level monitors.

BACKGROUND: In patients with phenylketonuria, stability of blood phenylalanine and tyrosine concentrations might influence brain chemistry and therefore patient outcome. This study prospectively investigated the effects of tetrahydrobiopterin (BH4), as a chaperone of phenylalanine hydroxylase on diurnal and day-to-day variations of blood phenylalanine and tyrosine concentrations.METHODS: Blood phenylalanine and tyrosine were measured in dried blood spots (DBS) four times daily for 2 days (fasting, before lunch, before dinner, evening) and once daily (fasting) for 6 days in a randomized cross-over design with a period with BH4 and a period without BH4. The sequence was randomized. Eleven proven BH4 responsive PKU patients participated, 5 of them used protein substitutes during BH4 treatment. Natural protein intake and protein substitute dosing was adjusted during the period without BH4 in order to keep DBS phenylalanine levels within target range. Patients filled out a 3-day food diary during both study periods. Variations of DBS phenylalanine and Tyr were expressed in standard deviations (SD) and coefficient of variation (CV).RESULTS: BH4 treatment did not significantly influence day-to-day phenylalanine and tyrosine variations nor diurnal phenylalanine variations, but decreased diurnal tyrosine variations (median SD 17.6 μmol/l, median CV 21.3%, p = 0.01) compared to diet only (median SD 34.2 μmol/l, median CV 43.2%). Consequently, during BH4 treatment diurnal phenylalanine/tyrosine ratio variation was smaller, while fasting tyrosine levels tended to be higher.CONCLUSION: BH4 did not impact phenylalanine variation but decreased diurnal tyrosine and phenylalanine/tyrosine ratio variations, possibly explained by less use of protein substitute and increased tyrosine synthesis.

Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. The brain’s utilization of ketones seems to depend mainly on the concentration in the blood, thus many dietary approaches such as ketogenic diets, ingestion of ketogenic medium-chain fatty acids or exogenous ketones, facilitate significant changes in the brain’s metabolism. Therefore, these approaches may ameliorate the energy crisis in neurodegenerative diseases, which are characterized by a deterioration of the brain’s glucose metabolism, providing a therapeutic advantage in these diseases. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimer’s disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. Likewise, a few studies show modest functional improvements in patients with Parkinson’s disease and cognitive benefits in patients with—or at risk of—Alzheimer’s disease after ketogenic interventions. Here, we summarize current knowledge on how ketogenic interventions support brain metabolism and discuss the therapeutic role of ketones in neurodegenerative disease, emphasizing clinical data.

Studies about the pathogenesis of mood disorders have consistently shownthat multiple factors, including genetic and environmental, play a crucial roleon their development and neurobiology. Multiple pathological theories havebeen proposed, of which several ultimately affects or is a consequence ofdysfunction in brain neuroplasticity and homeostatic mechanisms. However,current clinical available pharmacological intervention, which is predominantlymonoamine-based, suffers from partial and lacking response even after weeks ofcontinuous treatment. These issues raise the need for better understanding ofaetiologies and brain abnormalities in depression, as well as developing noveltreatment strategies. Nitric oxide (NO) is a gaseous unconventional neurotransmitter, which regulates and governs several important physiological functions in the central nervous system, including processes, which can be associated with the development of mood disorders. This review will present general aspects of the NO system in depression, highlighting potential targets which may be utilized and further explored as novel therapeutic targets in the future pharmacotherapy of depression. In particular, the review will link the importance of neuroplasticity mechanisms governed by NO to a possible molecular basis for the antidepressant effects.

Essentials von Willebrand Factor (VWF) and ADAMTS13 may affect early injury after subarachnoid hemorrhage (SAH). Early brain injury was assessed in VWF−/−, ADAMTS13−/− and recombinant (r) ADAMTS13 treated mice. VWF−/− and rADAMTS13 treated mice had less brain injury than ADAMTS13−/− and wild-type mice. Early administration of rADAMTS13 may improve outcome after SAH by reducing early brain injury. Summary: Background Early brain injury is an important determinant of poor functional outcome and case fatality after aneurysmal subarachnoid hemorrhage (SAH), and is associated with early platelet aggregation. No treatment exists for early brain injury after SAH. We investigated whether von Willebrand factor (VWF) is involved in the pathogenesis of early brain injury, and whether ultra-early treatment with recombinant ADAMTS-13 (rADAMTS-13) reduces early brain injury after experimental SAH. Methods Experimental SAH in mice was induced by prechiasmatic injection of non-anticoagulated blood from a littermate. The following experimental SAH groups were investigated: C57BL/6J control (n = 21), VWF−/− (n = 25), ADAMTS-13−/− (n = 23), and C57BL/6J treated with rADAMTS-13 (n = 26). Mice were killed at 2 h after SAH. Primary outcome measures were microglial activation (IBA-1 surface area) and neuronal injury (number of cleaved caspase-3-positive neurons). Results As compared with controls, microglial activation was decreased in VWF−/− mice (mean difference of − 20.0%, 95% confidence interval [CI] − 4.0% to − 38.6%), increased in ADAMTS-13−/− mice (mean difference of + 34.0%, 95% CI 16.2–51.7%), and decreased in rADAMTS-13-treated mice (mean difference of − 22.1%, 95% CI − 3.4% to − 39.1%). As compared with controls (185 neurons, interquartile range [IQR] 133–353), neuronal injury in the cerebral cortex was decreased in VWF−/− mice (63 neurons, IQR 25–78), not changed in ADAMTS-13−/− mice (53 neurons, IQR 26–221), and reduced in rADAMTS-13-treated mice (45 neurons, IQR 9–115). Conclusions Our findings suggest that VWF is involved in the pathogenesis of early brain injury, and support the further study of rADAMTS-13 as a treatment option for early brain injury after SAH.

Cognitive function plays an important role in athletic performance, and it seems that brain functioning can be influenced by nutrition and dietary components. Thus, the central nervous system might be manipulated through changes in diet or supplementation with specific nutrients including branched-chain amino acids, tyrosine, carbohydrates, and caffeine. Despite some evidence that branched-chained amino acids can influence ratings of perceived exertion and mental performance, several well-controlled studies have failed to demonstrate a positive effect on exercise performance. Evidence of an ergogenic benefit of tyrosine supplementation during prolonged exercise is limited. There is evidence that mild dehydration can impair cognitive performance and mood. The beneficial effect of carbohydrate supplementation during prolonged exercise could relate to increased substrate delivery for the brain, with numerous studies indicating that hypoglycemia affects brain function and cognitive performance. Caffeine can enhance performance and reduce perception of effort during prolonged exercise and will influence specific reward centers of the brain. Plant products and herbal extracts such as polyphenols, ginseng, ginkgo biloba, etc. are marketed as supplements to enhance performance. In several animal studies, positive effects of these products were shown, however the literature on their effects on sports performance is scarce. Polyphenols have the potential to protect neurons against injury induced by neurotoxins, suppress neuroinflammation, and to promote memory, learning, and cognitive function. In general, there remains a need for controlled randomized studies with a strong design, sufficient statistical power, and well-defined outcome measures before "claims" on its beneficial effects on brain functioning can be established.

This consensus statement voices the agreement of scientific stakeholders from regulatory agencies, academia and industry that a new framework needs adopting for assessment of chemicals with the potential to disrupt brain development. An increased prevalence of neurodevelopmental disorders in children has been observed that cannot solely be explained by genetics and recently pre- and postnatal exposure to environmental chemicals has been suspected as a causal factor. There is only very limited information on neurodevelopmental toxicity, leaving thousands of chemicals, that are present in the environment, with high uncertainty concerning their developmental neurotoxicity (DNT) potential. Closing this data gap with the current test guideline approach is not feasible, because the in vivo bioassays are far too resource-intensive concerning time, money and number of animals. A variety of in vitro methods are now available, that have the potential to close this data gap by permitting mode-of-action-based DNT testing employing human stem cells-derived neuronal/glial models. In vitro DNT data together with in silico approaches will in the future allow development of predictive models for DNT effects. The ultimate application goals of these new approach methods for DNT testing are their usage for different regulatory purposes., Highlights • An increased prevalence of neurodevelopmental disorders in children is observed. • There is very limited information on neurodevelopmental toxicity (DNT) induced by environmental chemicals. • A new framework is required for assessment of chemicals with the potential to disrupt brain development. • In vitro DNT data together with in silico approaches should be used for regulatory purposes.

All commonly used general anesthetics have been shown to cause neurotoxicity in animal models, including nonhuman primates. Opinion, however, remains divided over how cumulative evidence from preclinical and human studies in this field should be interpreted and its translation to current practices in pediatric anesthesia and surgery. A group of international experts in laboratory and clinical sciences recently convened in Genoa, Italy, to evaluate the current state of both laboratory and clinical research and discuss future directions for basic, translational, and clinical studies in this field. This paper describes those discussions and conclusions. A central goal identified was the importance of continuing to pursue laboratory research efforts to better understand the biological pathways underlying anesthesia neurotoxicity. The distinction between basic and translational experimental designs in this field was highlighted, and it was acknowledged that it will be important for future animal research to try to causally link structural changes with long-term cognitive abnormalities. While inherent limitations will continue to affect the ability of even large observational cohorts to determine if anesthesia impacts neurodevelopment or behavioral outcomes, the importance of conducting further large well-designed cohort studies was also emphasized. Adequately powered cohorts could clarify which populations are at increased risk, provide information on environmental and healthcare-related risk modifiers, and guide future interventional trials. If anesthetics cause structural or functional adverse neurological effects in young children, alternative or mitigating strategies need to be considered. While protective or mitigating strategies have been repeatedly studied in animals, there are currently no human data to support alternative anesthetic strategies in clinical practice. Lastly, it was noted that there is still considerable debate over the clinical relevance of anesthesia neurotoxicity, and the need to evaluate the impact of other aspects of perioperative care on neurodevelopment must also be considered.

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by progressive loss of memory and cognitive function. The cerebral metabolic rate of glucose oxidation has been shown to be reduced in AD. The present study evaluated efficacy of dietary Amalaki Rasayana (AR), an Ayurvedic formulation used in Indian traditional system, in AbPP-PS1 mouse model of AD in ameliorating memory and neurometabolism, and compared with donepezil, a standard FDA approved drug for AD. The memory of mice was measured using Morris Water Maze analysis. The cerebral metabolism was followed by 13C labelling of brain amino acids in tissue extracts ex vivo using 1H-[13C]-NMR spectroscopy together with a short time infusion of [1,6-13C2]glucose to mice. The intervention with Amalaki Rasayana showed improved learning and memory in AbPP-PS1 mice. The 13C labelings of GluC4, GABAC2 and GlnC4 were reduced in AbPP-PS1 mice when compared with wild-type controls. Intervention of AR increased the 13C labelling of amino acids suggesting a significant enhancement in glutamatergic and GABAergic metabolic activity in AbPP-PS1 mice similar to that observed with donepezil treatment. These data suggest that AR has potential to improve memory and cognitive function in AD.

Background. Despite widespread application, little is known about the neurophysiological effects of light sedation with midazolam or propofol, particularly in older subjects. The aim of this study was to assess the effects of light sedation with midazolam or propofol on a variety of EEG measures in older subjects. Methods. In patients (≥60 years without neuropsychiatric disease such as delirium), 2 EEG recordings were performed, before and after administration of either midazolam (n = 22) or propofol (n = 26) to facilitate an endoscopic procedure. Power spectrum, functional connectivity, and network topology based on the minimum spanning tree (MST) were compared within subjects. Results. Midazolam and propofol administration resulted in Richmond Agitation and Sedation Scale levels between 0 and −4 and between −2 and −4, respectively. Both agents altered the power spectra with increased delta (0.5-4 Hz) and decreased alpha (8-13 Hz) power. Only propofol was found to significantly reduce functional connectivity. In the beta frequency band, the MST was more integrated during midazolam sedation. Propofol sedation resulted in a less integrated network in the alpha frequency band. Conclusion. Despite the different levels of light sedation with midazolam and propofol, similar changes in power were found. Functional connectivity and network topology showed differences between midazolam and propofol sedation. Future research should establish if these differences are caused by the different levels of sedation or the mechanism of action of these agents.

Despite the long history of paediatric anaesthesia, there is still much to be discovered regarding how exposure to anaesthesia affects the developing brain. Given that commonly used anaesthetic agents are thought to exert their effect via N-Methyl-D-Aspartate (NMDA) and gamma-aminobutyric acid A (GABAA) receptors, it is biologically plausible that exposure during periods of vulnerable brain development may affect long term outcome. There are numerous animal studies which suggest lasting neurological changes. However, whether this risk also applies to humans is unclear given the varying physiological development of different species and humans. Human studies are emerging and ongoing and their results are producing conflicting data. The purpose of this review is to summarize the currently available evidence and consider how this may be used to minimize harm to the paediatric population undergoing anaesthesia.

Background Microglia play a central role in most neurological disorders, but the impact of microgliosis on brain environment and clinical functions is not fully understood. Mice lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, develop a fatal disorder characterized by motor problems similar to the milder form of MFP2 deficiency in humans. The hallmark of disease in mice is the chronic proliferation of microglia in the brain, but molecular pathomechanisms that drive rapid clinical deterioration in human and mice remain unknown. In the present study, we identified the effects of specific deletion of MFP2 from microglia in the brain on immune responses, neuronal functioning, and behavior. Methods We created a novel Cx3cr1-Mfp2−/− mouse model and studied the impact of MFP2 deficiency on microglial behavior at different ages using immunohistochemistry and real-time PCR. Pro- and anti-inflammatory responses of Mfp2−/− microglia were assessed in vitro and in vivo after stimulation with IL-1β/INFγ and IL-4 (in vitro) and LPS and IL-4 (in vivo). Facial nerve axotomy was unilaterally performed in Cx3cr1-Mfp2−/− and control mice, and microglial functioning in response to neuronal injury was subsequently analyzed by histology and real-time PCR. Finally, neuronal function, motor function, behavior, and cognition were assessed using brainstem auditory evoked potentials, grip strength and inverted grid test, open field exploration, and passive avoidance learning, respectively. Results We found that Mfp2−/− microglia in a genetically intact brain environment adopt an inflammatory activated and proliferative state. In addition, we found that acute inflammatory and neuronal injury provoked normal responses of Mfp2−/− microglia in Cx3cr1-Mfp2−/− mice during the post-injury period. Despite chronic pro-inflammatory microglial reactivity, Cx3cr1-Mfp2−/− mice exhibited normal neuronal transmission, clinical performance, and cognition. Conclusion Our data demonstrate that MFP2 deficiency in microglia causes intrinsic dysregulation of their inflammatory profile, which is not harmful to neuronal function, motor function, and cognition in mice during their first year of life. Electronic supplementary material The online version of this article (10.1186/s12974-019-1442-3) contains supplementary material, which is available to authorized users.

In an increasing number of states and countries, cannabis now stands poised to join alcohol and tobacco as a legal drug. Quantifying the relative adverse and beneficial effects of cannabis and its constituent cannabinoids should therefore be prioritized. Whereas newspaper headlines have focused on links between cannabis and psychosis, less attention has been paid to the much more common problem of cannabis addiction. Certain cognitive changes have also been attributed to cannabis use, although their causality and longevity are fiercely debated. Identifying why some individuals are more vulnerable than others to the adverse effects of cannabis is now of paramount importance to public health. Here, we review the current state of knowledge about such vulnerability factors, the variations in types of cannabis, and the relationship between these and cognition and addiction.

The current study investigated the combined effects of N-acetylcysteine and working memory (WM) training on behavioral and neural mechanisms of cue reactivity and WM in cocaine users in a randomized, double-blind design. Twenty-four of 38 cocaine-using men completed a 25-day treatment with either 2400 mg/day NAC or placebo. Both groups performed WM-training. During pre- and post-test lab-visits, neural mechanisms of cue reactivity and WM, and cue-induced craving and WM performance were assessed. Additionally, exploratory whole brain analyses were performed. Overall, the hypotheses were not confirmed, possibly due to small sample size, low WM-training adherence and/or ongoing substance use.

Underwater divers face several potential neurological hazards when breathing compressed gas mixtures including nitrogen narcosis which can impact diver's safety. Various human studies have clearly demonstrated brain impairment due to nitrogen narcosis in divers at 4 ATA using critical flicker fusion frequency (CFFF) as a cortical performance indicator. However, recently some authors have proposed a probable adaptive phenomenon during repetitive exposure to high nitrogen pressure in rats, where they found a reversal effect on dopamine release., info:eu-repo/semantics/published

Prenatal alcohol exposure causes alterations to the brain and can lead to numerous cognitive and behavioral outcomes. Long-lasting effects of early ethanol exposure have been registered in glutamatergic and dopaminergic systems. The purinergic system has been registered as an additional target of ethanol exposure. The objective of this research was to evaluate if the ecto‑5'‑nucleotidase and adenosine deaminase activities and gene expression of adult zebrafish exposed to 1% ethanol during early development could be part of the long-lasting targets of ethanol. Zebrafish embryos were exposed to 1% ethanol in two distinct developmental phases: gastrula/segmentation (5-24 h post-fertilization) or pharyngula (24-48 h post-fertilization). At the end of three months, after checking for morphological outcomes, the evaluation of enzymatic activity and gene expression was performed. Exposure to ethanol did not promote gross morphological defects; however, a significant decrease in the body length was observed (17% in the gastrula and 22% in the pharyngula stage, p 0.05). Although the mechanism underlying these findings requires further investigation, these results indicate that ethanol exposure during restricted periods of brain development can have long-term consequences on ecto‑5'‑nucleotidase activity, which could have an impact on subtle sequels of ethanol early exposure.

The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX. Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression. In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib, n = 64; crizotinib, n = 58), 43 had measurable lesions (alectinib, n = 21; crizotinib, n = 22), and 46 had received prior radiotherapy (alectinib, n = 25; crizotinib, n = 21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25-0.64] and those without (HR 0.51, 95% CI: 0.33-0.80, P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P < 0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy and 78.6% versus 40.0%, respectively, in those who had not. Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK+ NSCLC, irrespective of prior CNS disease or radiotherapy. ClinicalTrials.gov NCT02075840.

This consensus statement voices the agreement of scientific stakeholders from regulatory agencies, academia and industry that a new framework needs adopting for assessment of chemicals with the potential to disrupt brain development. An increased prevalence of neurodevelopmental disorders in children has been observed that cannot solely be explained by genetics and recently pre- and postnatal exposure to environmental chemicals has been suspected as a causal factor. There is only very limited information on neurodevelopmental toxicity, leaving thousands of chemicals, that are present in the environment, with high uncertainty concerning their developmental neurotoxicity (DNT) potential. Closing this data gap with the current test guideline approach is not feasible, because the in vivo bioassays are far too resource-intensive concerning time, money and number of animals. A variety of in vitro methods are now available, that have the potential to close this data gap by permitting mode-of-action-based DNT testing employing human stem cells-derived neuronal/glial models. In vitro DNT data together with in silico approaches will in the future allow development of predictive models for DNT effects. The ultimate application goals of these new approach methods for DNT testing are their usage for different regulatory purposes.

To investigate the enormous complexity of the functional and pathological brain there are a number of possible experimental model systems to choose from. Depending on the research question choosing the appropriate model may not be a trivial task, and given the dynamic and intricate nature of an intact living brain several models might be needed to properly address certain questions. In this review, we aim to provide an overview of neural cell and tissue culture, reflecting on historic methodological milestones and providing a brief overview of the state-of-the-art. We additionally present an example of an effective model system pipeline, composed of dissociated mouse cultures, organotypics, acute mouse brain slices, and acute human brain slices, in that order. The sequential use of these four model systems allows a balance and progression from experimental control to human applicability, and provides a meta-model that can help validate basic research findings in a translational setting. We then conclude with a few remarks regarding the necessity of an integrated approach when performing translational and neuropharmacological studies.

BACKGROUND: Fremanezumab (TEV-48125) is a fully humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) that has shown positive results in the prevention of episodic migraine and chronic migraine. Previous preclinical studies have revealed CGRP antagonistic effects on intracranial arteries (ICA). The aim of the study was to evaluate the in vitro antagonistic effects of fremanezumab on human arteries.METHODS: Arteries were removed in conjunction with neurosurgery (cerebral, CA, and middle meningeal artery, MMA, n = 7) or reconstructive abdominal surgery (abdominal artery, AA, n = 6). Ring segments of the vessels were mounted in a sensitive myograph, the functional responses of vasoactive intestinal peptide (VIP), substance P and CGRP in increasing concentrations (10- 10-10- 7 M) were studied using pre-contraction with 30 mM potassium chloride (KCl). The concentrations of fremanezumab or isotype control antibody (66.7 nM, 0.33 μM, 0.67 μM) were given 30 min prior to CGRP administration.RESULTS: All included arteries responded with a strong stable contraction to the application of 30 mM KCl. During this pre-contraction, CGRP caused a concentration-dependent relaxation which differed slightly in maximum effect (Imax) between the types of arteries (ICA = 100%; AA 80%). Fremanezumab (66.7 nM) showed a shift in the IC50 value of CGRP, but no significant change in Imax. At higher doses there was also a reduction of Imax. For AA, the Imax decreased from 71% at 66.7 nM, to 4.5% with 0.33 μM of fremanezumab. Isotype control antibody did not modify the responses. There was no effect on concentration-dependent relaxation with VIP with 66.7 nM of fremanezumab or isotype control.CONCLUSION: CGRP relaxes pre-contracted human arteries by 80-100%, but with different IC50; the potency range was ICA

EEG biomarkers have shown promise in predicting non-response to stimulant medication in ADHD and could serve as translational biomarkers. This study aimed to replicate and extend previous EEG biomarkers. The international Study to Predict Optimized Treatment for ADHD (iSPOT-A), a multi-center, international, prospective open-label trial, enrolled 336 children and adolescents with ADHD (11.9 yrs; 245 males; prescribed methylphenidate) and 158 healthy children. Treatment response was established after six weeks using the clinician rated ADHD-Rating Scale-IV. Theta/Beta ratio (TBR) and alpha peak frequency (APF) were assessed at baseline as predictors for treatment outcome. No differences between ADHD and controls were found for TBR and APF. 62% of the ADHD group was classified as a responder. Responders did not differ from non-responders in age, medication dosage, and baseline severity of ADHD symptoms. Male-adolescent non-responders exhibited a low frontal APF (Fz: R = 9.2 Hz vs. NR = 8.1 Hz; ES = 0.83), whereas no effects were found for TBR. A low APF in male adolescents was associated with non-response to methylphenidate, replicating earlier work. Our data suggest that the typical maturational EEG changes observed in ADHD responders and controls are absent in non-responders to methylphenidate and these typical changes start emerging in adolescence. Clinical trials registration: www.clinicaltrials.gov ; NCT00863499 ( https://clinicaltrials.gov/ct2/show/NCT00863499 ).

Antipsychotics are the most widely used medications for the treatment of schizophrenia spectrum disorders. While such drugs generally ameliorate positive symptoms, clinical responses are highly variable in terms of negative symptoms and cognitive impairments. However, predictors of individual responses have been elusive. Here, we report a pharmacogenetic interaction related to a core cognitive dysfunction in patients with schizophrenia. We show that genetic variations reducing dysbindin-1 expression can identify individuals whose executive functions respond better to antipsychotic drugs, both in humans and in mice. Multilevel ex vivo and in vivo analyses in postmortem human brains and genetically modified mice demonstrate that such interaction between antipsychotics and dysbindin-1 is mediated by an imbalance between the short and long isoforms of dopamine D2 receptors, leading to enhanced presynaptic D2 function within the prefrontal cortex. These findings reveal one of the pharmacodynamic mechanisms underlying individual cognitive response to treatment in patients with schizophrenia, suggesting a potential approach for improving the use of antipsychotic drugs.

Trigeminal autonomic cephalalgia (TAC) encompasses 4 unique primary headache types: cluster headache, paroxysmal hemicrania, hemicrania continua, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms. They are grouped on the basis of their shared clinical features of unilateral headache of varying durations and ipsilateral cranial autonomic symptoms. The shared clinical features reflect the underlying activation of the trigeminal–autonomic reflex. The treatment for TACs has been limited and not specific to the underlying pathogenesis. There is a proportion of patients who are refractory or intolerant to the current standard medical treatment. From instrumental bench work research and neuroimaging studies, there are new therapeutic targets identified in TACs. Treatment has become more targeted and aimed towards the pathogenesis of the conditions. The therapeutic targets range from the macroscopic and structural level down to the molecular and receptor level. The structural targets for surgical and noninvasive neuromodulation include central neuromodulation targets: posterior hypothalamus and, high cervical nerves, and peripheral neuromodulation targets: occipital nerves, sphenopalatine ganglion, and vagus nerve. In this review, we will also discuss the neuropeptide and molecular targets, in particular, calcitonin gene-related peptide, somatostatin, transient receptor potential vanilloid-1 receptor, nitric oxide, melatonin, orexin, pituitary adenylate cyclase-activating polypeptide, and glutamate. Electronic supplementary material The online version of this article (10.1007/s13311-018-0618-3) contains supplementary material, which is available to authorized users.

Background Cisplatin-based chemotherapy may have neurotoxic effects within the central nervous system. The aims of this study were 1) to longitudinally investigate the impact of cisplatin-based chemotherapy on whole-brain networks in testicular cancer patients undergoing treatment and 2) to explore whether possible changes are related to decline in cognitive functioning. Methods Sixty-four newly orchiectomized TC patients underwent structural magnetic resonance imaging (T1-weighted and diffusion-weighted imaging) and cognitive testing at baseline prior to further treatment and again at a six-month follow-up. At follow-up, 22 participants had received cisplatin-based chemotherapy (CT) while 42 were in active surveillance (S). Brain structural networks were constructed for each participant, and network properties were investigated using graph theory and longitudinally compared across groups. Cognitive functioning was evaluated using standardized neuropsychological tests. All statistical tests were two-sided. Results Compared with the S group, the CT group demonstrated altered global and local brain network properties from baseline to follow-up as evidenced by decreases in important brain network properties such as small-worldness (P = .04), network clustering (P = .04), and local efficiency (P = .02). In the CT group, poorer overall cognitive performance was associated with decreased small-worldness (r = -0.46, P = .04) and local efficiency (r = -0.51, P = .02), and verbal fluency was associated with decreased local efficiency (r = -0.55, P = .008). Conclusions Brain structural networks may be disrupted following treatment with cisplatin-based chemotherapy. Impaired brain networks may underlie poorer performance over time on both specific and nonspecific cognitive functions in patients undergoing chemotherapy. To the best of our knowledge, this is the first study to longitudinally investigate changes in structural brain networks in a cancer population, providing novel insights regarding the neurobiological mechanisms of cancer-related cognitive impairment.

Several studies indicate that the outcome of nutritional and lifestyle interventions can be linked to brain 'signatures' in terms of neural reactivity to food cues. However, 'dieting' is often considered in a rather broad sense, and no study so far investigated modulations in brain responses to food cues occurring over an intervention specifically aiming to reduce sugar intake. We studied neural activity and liking in response to visual food cues in 14 intensive consumers of sugar-sweetened beverages before and after a 3-month replacement period by artificially-sweetened equivalents. Each time, participants were presented with images of solid foods differing in fat content and taste quality while high-density electroencephalography was recorded. Contrary to our hypotheses, there was no significant weight loss over the intervention period and no changes were observed in food liking or in neural activity in regions subserving salience and reward attribution. However, neural activity in response to high-fat, sweet foods was significantly reduced from pre-to post-intervention in prefrontal regions often linked to impulse control. This decrease in activity was associated with weight loss failure, suggesting an impairment in individuals' ability to exert control and adjust their solid food intake over the intervention period. Our findings highlight the need to implement multidisciplinary approaches when aiming to help individuals lose body weight.

Contributions of glial cells to neuroenergetics have been the focus of extensive debate. Here we provide positron emission tomography evidence that activation of astrocytic glutamate transport via the excitatory amino acid transporter GLT-1 triggers widespread but graded glucose uptake in the rodent brain. Our results highlight the need for a reevaluation of the interpretation of [(18)F]FDG positron emission tomography data, whereby astrocytes would be recognized as contributing to the [(18)F]FDG signal.

International audience; Bisphenol A (BPA) is a widely used chemical that has been extensively studied as an endocrine-disrupting chemical (EDC). Other bisphenols sharing close structural features with BPA, are increasingly being used as alternatives, increasing the need to assess associated hazards to the endocrine system. In the present study, the estrogenic activity of BPA, bisphenol S (BPS) and bisphenol F (BPF) was assessed by using a combination of zebrafish-specific mechanism-based in vitro and in vivo assays. The three bisphenols were found to efficiently transactivate all zebrafish estrogen receptor (zfER) subtypes in zebrafish hepatic reporter cell lines (ZELH-zfERs). BPA was selective for zfERα while BPS and BPF were slightly more potent on zfERβ subtypes. We further documented the estrogenic effect in vivo by quantifying the expression of brain aromatase using a transgenic cyp19a1b-GFP zebrafish embryo assay. All three bisphenols induced GFP in a concentration-dependent manner. BPS only partially induced brain aromatase at the highest tested concentrations (>30µM) while BPA and BPF strongly induced GFP, in an ER-dependent manner, at 1-10µM. Furthermore, we show that BPF strongly induced vitellogenin synthesis in adult male zebrafish. Overall, this study demonstrates the estrogenic activity of BPA, BPF and BPS in different cell- and tissue-contexts and at different stages of development. Differences between in vitro and in vivo responses are discussed in light of selective ER activation and the fate of the compounds in the models. This study confirms the relevance of combining cellular and whole-organism bioassays in a unique model species for the hazard assessment of candidate EDCs.

Background Fetal alcohol spectrum disorder (FASD) is one of the most common causes of preventable intellectual disability, and the key associated deficits are in executive function (EF). Aspects of EF can be improved using cognitive training interventions. The highest prevalence of FASD globally (at a rate of 135.1 per 1000) has been found in a South African population in the Western Cape province. There is a shortage of specialized health service personnel, and there are limited remedial services. Computer-based cognitive training, if age and culturally appropriate, could be an effective way to provide the interventions with minimal need for skilled personnel and other resources. The Foundation for Alcohol Related Research has developed such a program for the South African context. Objective This protocol aimed to evaluate whether it is feasible to use computerized cognitive training in a resource-poor context to improve cognitive function in children exposed to alcohol in utero. Methods We are conducting a randomized controlled trial in the Saldanha Bay Municipal area, evaluating a custom-developed cognitive training program to improve the cognitive function of children aged between 4 and 6 years who were exposed to alcohol in the prenatal stage. Participants will be recruited from local Early Childhood Development centers. Community workers will interview biological mothers to identify alcohol-exposed pregnancies. Alcohol-exposed children will be randomized into an intervention or a control group of 40 participants each using block randomization. A group of 40 children not exposed to alcohol will be included in a normative group using individual randomization. The intervention group will play the game for 6 months (40 sessions). Normative and control groups will receive no intervention. Neurodevelopmental assessments will be done at baseline and upon completion of the study with all participants. Results The intervention has started, and all baseline assessments have been done at the time of submission. Conclusions This study will provide insight into whether computerized cognitive training is viable and effective in the South African context. It has the potential to provide a means of intervention globally and in other resource-poor context and expand the knowledge base regarding executive functioning and FASD. This paper presents the research protocol and intervention design of the study. Trial Registration ISRCTN Registry ISRCTN17244156; http://www.isrctn.com/ISRCTN17244156. International Registered Report Identifier (IRRID) DERR1-10.2196/14489

Hyperargininemia is an inborn error of metabolism (IEM) characterized by tissue accumulation of arginine (Arg). Mental retardation and other neurological features are common symptoms in hyperargininemic patients. Considering purinergic signaling has a crucial role from the early stages of development and underlying mechanisms of this disease are poorly established, we investigated the effect of Arg administration on locomotor activity, morphological alterations, and extracellular nucleotide hydrolysis in larvae and adult zebrafish. We showed that 0.1 mM Arg was unable to promote changes in locomotor activity. In addition, 7-day-post-fertilization (dpf) larvae treated with Arg demonstrated a decreased body size. Arg exposure (0.1 mM) promoted an increase in ATP, ADP, and AMP hydrolysis when compared to control group. These findings demonstrated that Arg might affect morphological parameters and ectonucleotidase activities in zebrafish larvae, suggesting that purinergic system is a target for neurotoxic effects induced by Arg.

OBJECTIVE: A direct link between the mouth cavity and the brain for glucose (GLUC) and caffeine (CAF) has been established. The aim of this study is to determine whether a direct link for both substrates also exist between the nasal cavity and the brain. METHODS: Ten healthy male subjects (age 22 ± 1 years) performed three experimental trials, separated by at least 2 days. Each trial included a 20-s nasal spray (NAS) period in which solutions placebo (PLAC), GLUC, or CAF were provided in a double-blind, randomized order. During each trial, four cognitive Stroop tasks were performed: two familiarization trials and one pre- and one post-NAS trial. Reaction times and accuracy for different stimuli (neutral, NEUTR; congruent, CON; incongruent INCON) were determined. Electroencephalography was continuously measured throughout the trials. During the Stroop tasks pre- and post-NAS, the P300 was assessed and during NAS, source localization was performed using standardized low-resolution brain electromagnetic tomography (sLORETA). RESULTS AND DISCUSSION: NAS activated the anterior cingulate cortex (ACC). CAF-NAS also increased θ and β activity in frontal cortices. Furthermore, GLUC-NAS increased the β activity within the insula. GLUC-NAS also increased the P300 amplitude with INCON (P = 0.046) and reduced P300 amplitude at F3-F4 and P300 latency at CP1-CP2-Cz with NEUTR (P = 0.001 and P = 0.016, respectively). The existence of nasal bitter and sweet taste receptors possibly induce these brain responses. CONCLUSION: Greater cognitive efficiency was observed with GLUC-NAS. CAF-NAS activated cingulate, insular, and sensorymotor cortices, whereas GLUC-NAS activated sensory, cingulate, and insular cortices. However, no effect on the Stroop task was found.

Item does not contain fulltext OBJECTIVE: The past decades have seen a surge in stimulant prescriptions for the treatment of attention-deficit/hyperactivity disorder (ADHD). Stimulants acutely alleviate symptoms and cognitive deficits associated with ADHD by modulating striatal dopamine neurotransmission and induce therapeutic changes in brain activation patterns. Long-term functional changes after treatment are unknown, as long-term studies are scarce and have focused on brain structure. In this observational study (2009-2012), we investigated associations between lifetime stimulant treatment history and neural activity during reward processing. METHODS: Participants fulfilling DSM-5 criteria for ADHD (N = 269) were classified according to stimulant treatment trajectory. Of those, 124 performed a monetary incentive delay task during magnetic resonance imaging, all in their nonmedicated state (nEARLY&INTENSE = 51; nLATE&MODERATE = 49; nEARLY&MODERATE = 9; nNAIVE = 15; mean age = 17.4 years; range, 10-26 years). Whole-brain analyses were performed with additional focus on the striatum, concentrating on the 2 largest treatment groups. RESULTS: Compared to the late-and-moderate treatment group, the early-and-intense treatment group showed more activation in the supplementary motor area and dorsal anterior cingulate cortex (SMA/dACC) during reward outcome (cluster size = 8,696 mm(3); PCLUSTER < .001). SMA/dACC activation of the control group fell in between the 2 treatment groups. Treatment history was not associated with striatal activation during reward processing. CONCLUSIONS: Our findings are compatible with previous reports of acute increases of SMA/dACC activity in individuals with ADHD after stimulant administration. Higher SMA/dACC activity may indicate that patients with a history of intensive stimulant treatment, but currently off medication, recruit brain regions for cognitive control and/or decision-making upon being rewarded. No striatal or structural changes were found.

Department of Anaesthesia and Intensive Care – Paediatric Section, Odense University Hospital, Odense, Denmark Institute of Clinical Research – Anaesthesiology, University of Southern Denmark, Odense, Denmark Department of Paediatric Anaesthesia and Intensive Care, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden Department of Physiology and Pharmacology – Section of Anaesthesiology and Intensive Care, Karolinska Institute, Stockholm, Sweden

OBJECTIVE: To evaluate the contributions of autophagic, necrotic, and apoptotic cell death mechanisms after neonatal cerebral ischemia and hence define the most appropriate neuroprotective approach for postischemic therapy. METHODS: Rats were exposed to transient focal cerebral ischemia on postnatal day 12. Some rats were treated by postischemic administration of pan-caspase or autophagy inhibitors. The ischemic brain tissue was studied histologically, biochemically, and ultrastructurally for autophagic, apoptotic, and necrotic markers. RESULTS: Lysosomal and autophagic activities were increased in neurons in the ischemic area from 6 to 24 hours postinjury, as shown by immunohistochemistry against lysosomal-associated membrane protein 1 and cathepsin D, by acid phosphatase histochemistry, by increased expression of autophagosome-specific LC3-II and by punctate LC3 staining. Electron microscopy confirmed the presence of large autolysosomes and putative autophagosomes in neurons. The increases in lysosomal activity and autophagosome formation together demonstrate increased autophagy, which occurred mainly in the border of the lesion, suggesting its involvement in delayed cell death. We also provide evidence for necrosis near the center of the lesion and apoptotic-like cell death in its border, but in nonautophagic cells. Postischemic intracerebroventricular injections of autophagy inhibitor 3-methyladenine strongly reduced the lesion volume (by 46%) even when given >4 hours after the beginning of the ischemia, whereas pan-caspase inhibitors, carbobenzoxy-valyl-alanyl-aspartyl(OMe)-fluoromethylketone and quinoline-val-asp(OMe)-Ch2-O-phenoxy, provided no protection. INTERPRETATION: The prominence of autophagic neuronal death in the ischemic penumbra and the neuroprotective efficacy of postischemic autophagy inhibition indicate that autophagy should be a primary target in the treatment of neonatal cerebral ischemia.

Background Increasing evidences link T helper 17 (Th17) cells with multiple sclerosis (MS). In this context, interleukin-22 (IL-22), a Th17-linked cytokine, has been implicated in blood brain barrier breakdown and lymphocyte infiltration. Furthermore, polymorphism between MS patients and controls has been recently described in the gene coding for IL-22 binding protein (IL-22BP). Here, we aimed to better characterize IL-22 in the context of MS. Methods IL-22 and IL-22BP expressions were assessed by ELISA and qPCR in the following compartments of MS patients and control subjects: (1) the serum, (2) the cerebrospinal fluid, and (3) immune cells of peripheral blood. Identification of the IL-22 receptor subunit, IL-22R1, was performed by immunohistochemistry and immunofluorescence in human brain tissues and human primary astrocytes. The role of IL-22 on human primary astrocytes was evaluated using 7-AAD and annexin V, markers of cell viability and apoptosis, respectively. Results In a cohort of 141 MS patients and healthy control (HC) subjects, we found that serum levels of IL-22 were significantly higher in relapsing MS patients than in HC but also remitting and progressive MS patients. Monocytes and monocyte-derived dendritic cells contained an enhanced expression of mRNA coding for IL-22BP as compared to HC. Using immunohistochemistry and confocal microscopy, we found that IL-22 and its receptor were detected on astrocytes of brain tissues from both control subjects and MS patients, although in the latter, the expression was higher around blood vessels and in MS plaques. Cytometry-based functional assays revealed that addition of IL-22 improved the survival of human primary astrocytes. Furthermore, tumor necrosis factor α-treated astrocytes had a better long-term survival capacity upon IL-22 co-treatment. This protective effect of IL-22 seemed to be conferred, at least partially, by a decreased apoptosis. Conclusions We show that (1) there is a dysregulation in the expression of IL-22 and its antagonist, IL-22BP, in MS patients, (2) IL-22 targets specifically astrocytes in the human brain, and (3) this cytokine confers an increased survival of the latter cells. Electronic supplementary material The online version of this article (doi:10.1186/s12974-015-0335-3) contains supplementary material, which is available to authorized users.

It is now well established that many general anesthetics have a variety of effects on the developing brain in animal models. In contrast, human cohort studies show mixed evidence for any association between neurobehavioural outcome and anesthesia exposure in early childhood. In spite of large volumes of research, it remains very unclear if the animal studies have any clinical relevance; or indeed how, or if, clinical practice needs to be altered. Answering these questions is of great importance given the huge numbers of young children exposed to general anesthetics. A recent meeting in Genoa brought together researchers and clinicians to map a path forward for future clinical studies. This paper describes these discussions and conclusions. It was agreed that there is a need for large, detailed, prospective, observational studies, and for carefully designed trials. It may be impossible to design or conduct a single study to completely exclude the possibility that anesthetics can, under certain circumstances, produce long-term neurobehavioural changes in humans; however , observational studies will improve our understanding of which children are at greatest risk, and may also suggest potential underlying etiologies, and clinical trials will provide the strongest evidence to test the effectiveness of different strategies or anesthetic regimens with respect to better neurobehavioral outcome.