Insular and occipital changes in visual snow syndrome: a BOLD fMRI and MRS study.

OBJECTIVE To investigate the pathophysiology of visual snow (VS), through a combined functional neuroimaging and magnetic resonance spectroscopy (1 H-MRS) approach. METHODS We applied a functional MRI block-design protocol studying the responses to a visual stimulation mimicking VS, in combination with 1 H-MRS over the right lingual gyrus, in 24 patients with VS compared to an equal number of age- and gender-matched healthy controls. RESULTS We found reduced BOLD responses to the visual stimulus with respect to baseline in VS patients compared to controls, in the left (k = 291; P = 0.025; peak MNI coordinate [-34 12 -6]) and right (k = 100; P = 0.003; peak MNI coordinate [44 14 -2]) anterior insula. Our spectroscopy analysis revealed a significant increase in lactate concentrations in patients with respect to controls (0.66 ± 0.9 mmol/L vs. 0.07 ± 0.2 mmol/L; P < 0.001) in the right lingual gyrus. In this area, there was a significant negative correlation between lactate concentrations and BOLD responses to visual stimulation (P = 0.004; r = -0.42), which was dependent on belonging to the patient group. INTERPRETATION As shown by our BOLD analysis, VS is characterized by a difference in bilateral insular responses to a visual stimulus mimicking VS itself, which could be due to disruptions within the salience network. Our results also suggest that patients with VS have a localized disturbance in extrastriate anaerobic metabolism, which may in turn cause a decreased metabolic reserve for the regular processing of visual stimuli

Secondary headaches: secondary or still primary?

The second edition of the International Classification of Headache Disorders makes a distinction between primary and secondary headaches. The diagnosis of a secondary headache is made if the underlying disease is thought to cause headache or if a close temporal relationship is present together with the occurrence of the headache. At first glance, this may allow clearly secondary headaches to be distinguished from primary headaches. However, by reviewing the available literature concerning several selected secondary headaches, we will discuss the hypothesis that some secondary headaches can also be understood as a variation of primary headaches in the sense that the underlying cause (e.g. infusion of glyceryl trinitrate [ICHD-II 8.1.1], epilepsy [7.6.2], brain tumours [7.4], craniotomy [5.7], etc.) triggers the same neurophysiologic mechanisms that are responsible for the pain in primary headache attacks

Negative emotional stimuli reduce contextual cueing but not response times in inefficient search

In visual search, previous work has shown that negative stimuli narrow the focus of attention and speed reaction times (RTs). This paper investigates these two effects by first asking whether negative emotional stimuli narrow the focus of attention to reduce the learning of a display context in a contextual cueing task and, second, whether exposure to negative stimuli also reduces RTs in inefficient search tasks. In Experiment 1, participants viewed either negative or neutral images (faces or scenes) prior to a contextual cueing task. In a typical contextual cueing experiment, RTs are reduced if displays are repeated across the experiment compared with novel displays that are not repeated. The results showed that a smaller contextual cueing effect was obtained after participants viewed negative stimuli than when they viewed neutral stimuli. However, in contrast to previous work, overall search RTs were not faster after viewing negative stimuli (Experiments 2 to 4). The findings are discussed in terms of the impact of emotional content on visual processing and the ability to use scene context to help facilitate search

Anxiety disorders in headache patients in a specialised clinic: prevalence and symptoms in comparison to patients in a general neurological clinic

Data from several studies indicate an association of headache with anxiety disorders. In this study, we assessed and differentiated anxiety disorders in 100 headache patients by using the PSWQ (Penn State Worry Questionnaire) screening tool for generalised anxiety disorder (GAD) and the ACQ (Agoraphobic Cognitions Questionnaire) and BSQ (Body Sensation Questionnaire) for panic disorder (PD). Control groups were constructed: (1) on the basis of epidemiological studies on PD and GAD in the general population and (2) by including neurological patients. 37.0% of headache patients had a GAD. 27% of headache patients met the score for PD in the BSQ, 4.0% in the ACQ. Significant results were obtained in comparison to the general population (p < 0.001) and with regard to GAD in comparison with a sample of neurological patients (p < 0.005). The BSQ significantly correlated with the number of medication days (p < 0.005). The results confirm the increased prevalence of GAD in headache patients. PD seems to increase the risk of medication overuse

Headache in juvenile myoclonic epilepsy

The objective of this study was to assess the prevalence of and risk factors for primary headaches in juvenile myoclonic epilepsy (JME). Headache was classified in 75 patients with JME using a questionnaire, and its prevalence was correlated with the literature on the general population and clinical data. Headache was present in 47 patients. Thirty-one had migraine [20 migraine without aura (MO), 11 migraine with aura (MA)]. Fourteen patients with migraine had tension-type headache (TTH) in addition. Sixteen had only TTH. Comparison with the general population revealed a significantly higher prevalence of migraine (RR 4.4), MO (3.6), MA (7.3) and TTH (3.4) in JME. Risk factors for migraine and MO were female gender and for MA family history of migraine in first-degree relatives. Migraine and MA were associated with fairly controlled generalized tonic clonic seizures, MO with absences. Together with its strong genetic background, JME appears to be an attractive homogenous subtype of epilepsy for genetic research on migraine

Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology

Методы и механизмы геттерирования кремниевых структур в производстве интегральных микросхем

Увеличение степени интеграции элементной базы предъявляет все более жесткие требования к уменьшению концентрации загрязняющих примесей и окислительных дефектов упаковки в исходных кремниевых пластинах с ее сохранением в технологическом цикле изготовления ИМС. Это обуславливает высокую актуальность применения геттерирования в современной технологии микроэлектроники. В статье рассмотрены существующие методы геттерирования кремниевых пластин и механизмы их протекания.Збільшення ступеня інтеграції елементної бази пред'являє все більш жорсткі вимоги до зменшення концентрації забруднюючих домішок та окислювальних дефектів упаковки у вихідних кремнієвих пластинах за її збереження у технологічному циклі виготовлення ІМС. Це обумовлює високу актуальність застосування гетерування в сучасній технології мікроелектроніки. Розглянуто існуючі методи гетерування кремнієвих пластин та розглянуто механізми їх перебігу.Increasing the degree of integration of hardware components imposes more stringent requirements for the reduction of the concentration of contaminants and oxidation stacking faults in the original silicon wafers with its preservation in the IC manufacturing process cycle. This causes high relevance of the application of gettering in modern microelectronic technology. The existing methods of silicon wafers gettering and the mechanisms of their occurrence are considered

Polygenic burden in focal and generalized epilepsies

Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japaneseancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64 710-15; Cleveland: P = 2.85 710-4; Finnish-ancestry Epi25: P = 1.80 710-4) or population controls (Epi25: P = 2.35 710-70; Cleveland: P = 1.43 710-7; Finnish-ancestry Epi25: P = 3.11 710-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99 710-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74 710-19; Cleveland: P = 1.69 710-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60 710-15; Cleveland: P = 1.39 710-2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls-in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment

Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy