The modified elevated gap interaction test: a novel paradigm to assess social preference.

Social deficits play a role in numerous psychiatric, neurological and neurodevelopmental disorders. Relating complex behaviour, such as social interaction, to brain activity remains one of the biggest goals and challenges in neuroscience. Availability of standardized tests that assess social preference is however, limited.

Spontaneous spreading depolarizations originate subcortically in a novel mouse model of familial hemiplegic migraine type 2.

The mechanisms of initiation of spreading depolarization (SD) are understudied due to a paucity of disease models with spontaneously occurring events. We here present a novel mouse model of familial hemiplegic migraine type 2 (FHM2), expressing the missense T345A-mutated α2 subunit of the Na/K adenosine triphosphatase pump (Atp1a2). Homozygous Atp1a2 mice showed regular spontaneous SDs that exhibit a diurnal rhythm and typically originate from the hippocampus.

Self-assembling 3D vessel-on-chip model with hiPSC-derived astrocytes.

Functionality of the blood-brain barrier (BBB) relies on the interaction between endothelial cells (ECs), pericytes, and astrocytes to regulate molecule transport within the central nervous system. Most experimental models for the BBB rely on freshly isolated primary brain cells. Here, we explored human induced pluripotent stem cells (hiPSCs) as a cellular source for astrocytes in a 3D vessel-on-chip (VoC) model.

Detection of short-lasting and ictal spike-and-wave discharges in around-the-ears EEG recordings in children with absence epilepsy.

Purpose: Long-term ambulatory EEG recordings can improve the monitoring of absence epilepsy in children, but signal quality and increased review workload are a concern. We evaluated the feasibility of around-the-ears EEG arrays (cEEGrids) to capture 3-Hz short-lasting and ictal spike-and-wave discharges and assessed the performance of automated detection software in cEEGrids data. We compared patterns of bilateral synchronisation between short-lasting and ictal spike-and-wave discharges.

Changes in Migraine Symptoms after Ischemic Stroke: A Cohort Study.

Introduction: Migraine symptoms are postulated to improve post-stroke. We aimed to determine post-stroke changes in patients with active migraine pre-stroke and explored the relation with stroke location and stroke-preventive medication use.

Methods: Patients with active migraine who had an ischemic stroke were retrieved from three research-cohorts between 2014 and 2021.

Spontaneous and optogenetically induced cortical spreading depolarization in familial hemiplegic migraine type 1 mutant mice.

Mechanisms underlying the migraine aura are incompletely understood, which to large extent is related to a lack of models in which cortical spreading depolarization (CSD), the correlate of the aura, occurs spontaneously. Here, we investigated electrophysiological and behavioural CSD features in freely behaving mice expressing mutant Ca2.1 Ca channels, either with the milder R192Q or the severer S218L missense mutation in the α1 subunit, known to cause familial hemiplegic migraine type 1 (FHM1) in patients.

Exome sequencing of ATP1A3-negative cases of alternating hemiplegia of childhood reveals SCN2A as a novel causative gene.

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopment disorder that is typically characterized by debilitating episodic attacks of hemiplegia, seizures, and intellectual disability. Over 85% of individuals with AHC have a de novo missense variant in ATP1A3 encoding the catalytic α3 subunit of neuronal NaK ATPases. The remainder of the patients are genetically unexplained.

Alterations in DNA methylation associate with reduced migraine and headache days after medication withdrawal treatment in chronic migraine patients: a longitudinal study.

Background: Chronic migraine, a highly disabling migraine subtype, affects nearly 2% of the general population. Understanding migraine chronification is vital for developing better treatment and prevention strategies. An important factor in the chronification of migraine is the overuse of acute headache medication.

Genetics of migraine: Delineation of contemporary understanding of the genetic underpinning of migraine.

Migraine is a disabling episodic brain disorder with an increased familial relative risk, an increased concordance in monozygotic twins, and an estimated heritability of approximately 50%. Various genetic approaches have been applied to identify genetic factors conferring migraine risk. Initially, candidate gene associations studies (CGAS) have been performed that test DNA variants in genes prioritized based on presumed a priori knowledge of migraine pathophysiology.

Optogenetic cortical spreading depolarization induces headache-related behaviour and neuroinflammatory responses some prolonged in familial hemiplegic migraine type 1 mice.

Background: Cortical spreading depolarization (CSD), the neurophysiological correlate of the migraine aura, can activate trigeminal pain pathways, but the neurobiological mechanisms and behavioural consequences remain unclear. Here we investigated effects of optogenetically-induced CSDs on headache-related behaviour and neuroinflammatory responses in transgenic mice carrying a familial hemiplegic migraine type 1 (FHM1) mutation.

Methods: CSD events (3 in total) were evoked in a minimally invasive manner by optogenetic stimulation through the intact skull in freely behaving wildtype (WT) and FHM1 mutant mice.

Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor.

Objective: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights.

Methods: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry.

Neurological and psychiatric comorbidities of migraine: Concepts and future perspectives.

Background: This narrative review aims to discuss several common neurological and psychiatric disorders that show comorbidity with migraine. Not only can we gain pathophysiological insights by studying these disorders, comorbidities also have important implications for treating migraine patients in clinical practice.

Methods: A literature search on PubMed and Embase was conducted with the keywords "comorbidity", "migraine disorders", "migraine with aura", "migraine without aura", "depression", "depressive disorders", "epilepsy", "stroke", "patent foramen ovale", "sleep wake disorders", "restless legs syndrome", "genetics", "therapeutics".

Spinocerebellar Ataxia Type 1 Characteristics in Patient-Derived Fibroblast and iPSC-Derived Neuronal Cultures.

Background: Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by a polyglutamine expansion in the ataxin-1 protein resulting in neuropathology including mutant ataxin-1 protein aggregation, aberrant neurodevelopment, and mitochondrial dysfunction.

Objectives: Identify SCA1-relevant phenotypes in patient-specific fibroblasts and SCA1 induced pluripotent stem cells (iPSCs) neuronal cultures.

Methods: SCA1 iPSCs were generated and differentiated into neuronal cultures.

An organ-on-chip device with integrated charge sensors and recording microelectrodes.

Continuous monitoring of tissue microphysiology is a key enabling feature of the organ-on-chip (OoC) approach for in vitro drug screening and disease modeling. Integrated sensing units are particularly convenient for microenvironmental monitoring. However, sensitive in vitro and real-time measurements are challenging due to the inherently small size of OoC devices, the characteristics of commonly used materials, and external hardware setups required to support the sensing units.

Potent dual MAGL/FAAH inhibitor AKU-005 engages endocannabinoids to diminish meningeal nociception implicated in migraine pain.

Background: Engaging the endocannabinoid system through inhibition of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), degrading endocannabinoids (endoCBs) 2-arachidonoylglycerol (2-AG) and anandamide (AEA), was proposed as a promising approach to ameliorate migraine pain. However, the activity of MAGL and FAAH and action of endoCB on spiking activity of meningeal afferents, from which migraine pain originates, has not been explored thus far. Therefore, we here explored the analgesic effects of endoCB enhancement in rat and human meningeal tissues.

Whole Exome Sequencing of Hemiplegic Migraine Patients Shows an Increased Burden of Missense Variants in CACNA1H and CACNA1I Genes.

Hemiplegic migraine (HM) is a rare subtype of migraine with aura. Given that causal missense mutations in the voltage-gated calcium channel α1A subunit gene CACNA1A have been identified in a subset of HM patients, we investigated whether HM patients without a mutation have an increased burden of such variants in the "CACNA1x gene family". Whole exome sequencing data of an Australian cohort of unrelated HM patients (n = 184), along with public data from gnomAD, as controls, was used to assess the burden of missense variants in CACNA1x genes.

Migraine genetics: Status and road forward.

Background: Migraine is considered a multifactorial genetic disorder. Different platforms and methods are used to unravel the genetic basis of migraine. Initially, linkage analysis in multigenerational families followed by Sanger sequencing of protein-coding parts (exons) of genes in the genomic region shared by affected family members identified high-effect risk DNA mutations for rare Mendelian forms of migraine, foremost hemiplegic migraine.

Migraine, inflammatory bowel disease and celiac disease: A Mendelian randomization study.

Objective: To assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease.

Background: Migraine has been linked to IBD and celiac disease in observational studies, but whether this link may be explained by a shared genetic basis or could be causal has not been established. The presence of a causal association could be clinically relevant, as treating one of these medical conditions might mitigate the symptoms of a causally linked condition.

Prostaglandin-E levels over the course of glyceryl trinitrate provoked migraine attacks.

Administration of glyceryl trinitrate (GTN), a donor of nitric oxide, can induce migraine-like attacks in subjects with migraine. Provocation with GTN typically follows a biphasic pattern; it induces immediate headache in subjects with migraine, as well as in healthy controls, whereafter only subjects with migraine may develop a migraine-like headache several hours later. Interestingly, intravenous infusion with prostaglandin-E (PGE) can also provoke a migraine-like headache, but seems to have a more rapid onset compared to GTN.

Insights into familial adult myoclonus epilepsy pathogenesis: How the same repeat expansion in six unrelated genes may lead to cortical excitability.

Familial adult myoclonus epilepsy (FAME) results from the same pathogenic TTTTA/TTTCA pentanucleotide repeat expansion in six distinct genes encoding proteins with different subcellular localizations and very different functions, which poses the issue of what causes the neurobiological disturbances that lead to the clinical phenotype. Postmortem and electrophysiological studies have pointed to cortical hyperexcitability as well as dysfunction and neurodegeneration of both the cortex and cerebellum of FAME subjects. FAME expansions, contrary to the same expansion in DAB1 causing spinocerebellar ataxia type 37, seem to have no or limited impact on their recipient gene expression, which suggests a pathophysiological mechanism independent of the gene and its function.

Cerebrospinal Fluid and Plasma Amine Profiles in Interictal Migraine.

Objective: Impaired amine metabolism has been associated with the etiology of migraine, that is, why patients continue to get migraine attacks. However, evidence from cerebrospinal fluid (CSF) is lacking. Here, we evaluated individual amine levels, global amine profiles, and amine pathways in CSF and plasma of interictal migraine patients and healthy controls.