Noradrenergic and Cholinergic Modulation of Belief Updating.

To make optimal predictions in a dynamic environment, the impact of new observations on existing beliefs-that is, the learning rate-should be guided by ongoing estimates of change and uncertainty. Theoretical work has proposed specific computational roles for various neuromodulatory systems in the control of learning rate, but empirical evidence is still sparse. The aim of the current research was to examine the role of the noradrenergic and cholinergic systems in learning rate regulation. First, we replicated our recent findings that the centroparietal P3 component of the EEG-an index of phasic catecholamine release in the cortex-predicts trial-to-trial variability in learning rate and mediates the effects of surprise and belief uncertainty on learning rate (Study 1, n = 17). Second, we found that pharmacological suppression of either norepinephrine or acetylcholine activity produced baseline-dependent effects on learning rate following nonobvious changes in an outcome-generating process (Study 1). Third, we identified two genes, coding for α2A receptor sensitivity (ADRA2A) and norepinephrine reuptake (NET), as promising targets for future research on the genetic basis of individual differences in learning rate (Study 2, n = 137). Our findings suggest a role for the noradrenergic and cholinergic systems in belief updating and underline the importance of studying interactions between different neuromodulatory systems.

Clinical spectrum of hemiplegic migraine and chances of finding a pathogenic mutation.

OBJECTIVE: To investigate whether the clinical characteristics of patients with hemiplegic migraine with and without autosomal dominant mutations in CACNA1A, ATP1A2, or SCN1A differ, and whether the disease may be caused by mutations in other genes. METHODS: We compared the clinical characteristics of 208 patients with familial (n = 199) or sporadic (n = 9) hemiplegic migraine due to a mutation in CACNA1A, ATP1A2, or SCN1A with those of 73 patients with familial (n = 49) or sporadic (n = 24) hemiplegic migraine without a mutation in these genes. In addition, 47 patients (familial: n = 33; sporadic: n = 14) without mutations in CACNA1A, ATP1A2, or SCN1A were scanned for mutations in novel genes using whole exome sequencing. RESULTS: Patients with mutations in CACNA1A, ATP1A2, or SCN1A had a lower age at disease onset, larger numbers of affected family members, and more often attacks (1) triggered by mild head trauma, (2) with extensive motor weakness, and (3) with brainstem features, confusion, and brain edema. Mental retardation and progressive ataxia were exclusively found in patients with a mutation. Whole exome sequencing failed to identify pathogenic mutations in new genes. CONCLUSIONS: Most patients with hemiplegic migraine without a mutation in CACNA1A, ATP1A2, or SCN1A display a mild phenotype that is more akin to that of common (nonhemiplegic) migraine. A major fourth autosomal dominant gene for hemiplegic migraine remains to be identified. Our observations might guide physicians in selecting patients for mutation screening and in providing adequate genetic counseling.

Cluster headache and the hypocretin receptor 2 reconsidered: a genetic association study and meta-analysis.

BACKGROUND: Cluster headache is a severe neurological disorder with a complex genetic background. A missense single nucleotide polymorphism (rs2653349; p.Ile308Val) in the HCRTR2 gene that encodes the hypocretin receptor 2 is the only genetic factor that is reported to be associated with cluster headache in different studies. However, as there are conflicting results between studies, we re-evaluated its role in cluster headache. METHODS: We performed a genetic association analysis for rs2653349 in our large Leiden University Cluster headache Analysis (LUCA) program study population. Systematic selection of the literature yielded three additional studies comprising five study populations, which were included in our meta-analysis. Data were extracted according to predefined criteria. RESULTS: A total of 575 cluster headache patients from our LUCA study and 874 controls were genotyped for HCRTR2 SNP rs2653349 but no significant association with cluster headache was found (odds ratio 0.91 (95% confidence intervals 0.75-1.10), p = 0.319). In contrast, the meta-analysis that included in total 1167 cluster headache cases and 1618 controls from the six study populations, which were part of four different studies, showed association of the single nucleotide polymorphism with cluster headache (random effect odds ratio 0.69 (95% confidence intervals 0.53-0.90), p = 0.006). The association became weaker, as the odds ratio increased to 0.80, when the meta-analysis was repeated without the initial single South European study with the largest effect size. CONCLUSIONS: Although we did not find evidence for association of rs2653349 in our LUCA study, which is the largest investigated study population thus far, our meta-analysis provides genetic evidence for a role of HCRTR2 in cluster headache. Regardless, we feel that the association should be interpreted with caution as meta-analyses with individual populations that have limited power have diminished validity.

Two novel SCN1A mutations identified in families with familial hemiplegic migraine.

BACKGROUND: Familial hemiplegic migraine (FHM) is a rare monogenic subtype of migraine with aura, characterized by motor auras. The majority of FHM families have mutations in the CACNA1A and ATP1A2 genes; less than 5% of FHM families are explained by mutations in the SCN1A gene. Here we screened two Spanish FHM families for mutations in the FHM genes. METHODS: We assessed the clinical features of both FHM families and performed direct sequencing of all coding exons (and adjacent sequences) of the CACNA1A, ATP1A2, PRRT2 and SCN1A genes. RESULTS: FHM patients in both families had pure hemiplegic migraine with highly variable severity and frequency of attacks. We identified a novel SCN1A missense mutation p.Ile1498Met in all three tested hemiplegic migraine patients of one family. In the other family, novel SCN1A missense mutation p.Phe1661Leu was identified in six out of eight tested hemiplegic migraine patients. Both mutations affect amino acid residues that either reside in an important functional domain (in the case of Ile(1498)) or are known to be important for kinetic properties of the NaV1.1 channel (in the case of Phe(1661)). CONCLUSIONS: We identified two mutations in families with FHM. SCN1A mutations are an infrequent but important cause of FHM. Genetic testing is indicated in families when no mutations are found in other FHM genes.

RNA expression profiling in brains of familial hemiplegic migraine type 1 knock-in mice.

BACKGROUND: Various CACNA1A missense mutations cause familial hemiplegic migraine type 1 (FHM1), a rare monogenic subtype of migraine with aura. FHM1 mutation R192Q is associated with pure hemiplegic migraine, whereas the S218L mutation causes hemiplegic migraine, cerebellar ataxia, seizures, and mild head trauma-induced brain edema. Transgenic knock-in (KI) migraine mouse models were generated that carried either the FHM1 R192Q or the S218L mutation and were shown to exhibit increased CaV2.1 channel activity. Here we investigated their cerebellar and caudal cortical transcriptome. METHODS: Caudal cortical and cerebellar RNA expression profiles from mutant and wild-type mice were studied using microarrays. Respective brain regions were selected based on their relevance to migraine aura and ataxia. Relevant expression changes were further investigated at RNA and protein level by quantitative polymerase chain reaction (qPCR) and/or immunohistochemistry, respectively. RESULTS: Expression differences in the cerebellum were most pronounced in S218L mice. Particularly, tyrosine hydroxylase, a marker of delayed cerebellar maturation, appeared strongly upregulated in S218L cerebella. In contrast, only minimal expression differences were observed in the caudal cortex of either mutant mice strain. CONCLUSION: Despite pronounced consequences of migraine gene mutations at the neurobiological level, changes in cortical RNA expression in FHM1 migraine mice compared to wild-type are modest. In contrast, pronounced RNA expression changes are seen in the cerebellum of S218L mice and may explain their cerebellar ataxia phenotype.

PRRT2 mutation causes benign familial infantile convulsions.

Benign familial infantile convulsions (BFIC) is an autosomal dominantly inherited epilepsy syndrome with onset between 3 and 12 months of age. It is characterized by brief seizures with motor arrest, cyanosis, hypertonia, and limb jerks. Seizures respond well to antiepileptic drugs and remission occurs before the age of 3 years.(1) Several recent publications described heterozygous mutations in the proline-rich transmembrane protein 2 (PRRT2) gene on chromosome 16p11.2, one of the known BFIC loci,(2,3) in an increasingly large number of families with paroxysmal kinesigenic dyskinesia (PKD) and PKD with infantile convulsions (PKD/IC).(4-6) The majority of PRRT2 mutations result in a premature truncation of PRRT2 protein. Although its exact function is unknown, recent studies indicated that PRRT2 is highly expressed in the developing nervous system and localized in axons in primary neuronal cultures.(6) Through binding to synaptic protein SNAP25, PRRT2 may be involved in vesicle docking and calcium-triggered neuronal exocytosis.(6) Preliminary functional studies of truncated PRRT2 mutants showed either a loss of membrane localization in COS-7 cells(5) or near absence of mutant protein in hippocampal neuronal cultures(6) that is likely due to nonsense mediated RNA decay. One can speculate that mutant PRRT2 protein may result in abnormal neurotransmitter release and neuronal hyperexcitability that could explain the clinical symptoms seen with PKD and PKD/IC. We tested whether PRRT2 is also the causal gene in families with BFIC without associated paroxysmal dyskinesia.

Meta-analysis of genome-wide association for migraine in six population-based European cohorts.

Migraine is a common neurological disorder with a genetically complex background. This paper describes a meta-analysis of genome-wide association (GWA) studies on migraine, performed by the Dutch-Icelandic migraine genetics (DICE) consortium, which brings together six population-based European migraine cohorts with a total sample size of 10,980 individuals (2446 cases and 8534 controls). A total of 32 SNPs showed marginal evidence for association at a P-value<10(-5). The best result was obtained for SNP rs9908234, which had a P-value of 8.00 × 10(-8). This top SNP is located in the nerve growth factor receptor (NGFR) gene. However, this SNP did not replicate in three cohorts from the Netherlands and Australia. Of the other 31 SNPs, 18 SNPs were tested in two replication cohorts, but none replicated. In addition, we explored previously identified candidate genes in the meta-analysis data set. This revealed a modest gene-based significant association between migraine and the metadherin (MTDH) gene, previously identified in the first clinic-based GWA study (GWAS) for migraine (Bonferroni-corrected gene-based P-value=0.026). This finding is consistent with the involvement of the glutamate pathway in migraine. Additional research is necessary to further confirm the involvement of glutamate.