Coassembly and coupling of SK2 channels and mGlu5 receptors.

Group I metabotropic glutamate (mGlu) receptors regulate hippocampal CA1 pyramidal neuron excitability via Ca(2+) wave-dependent activation of small-conductance Ca(2+)-activated K(+) (SK) channels. Here, we show that mGlu5 receptors and SK2 channels coassemble in heterologous coexpression systems and in rat brain. Further, in cotransfected cells or rat primary hippocampal neurons, mGlu5 receptor stimulation activated apamin-sensitive SK2-mediated K(+) currents. In addition, coexpression of mGlu5 receptors and SK2 channels promoted plasma membrane targeting of both proteins and correlated with increased mGlu5 receptor function that was unexpectedly blocked by apamin. These results demonstrate a reciprocal functional interaction between mGlu5 receptors and SK2 channels that reflects their molecular coassembly.

Impact of mindfulness training on attentional control and anger regulation processes for psychotherapists in training.

OBJECTIVES: Little empirical literature focuses on psychotherapists' cultivation of internal states of mind necessary for controlling attention and responding empathically to the client. We explore the effects of mindfulness training on emotional and attentional measures in Spanish resident intern psychiatrists and clinical psychologists. METHOD: One hundred and three residents were assigned to an experimental group (n = 60) that completed an 8-week mindfulness training versus a wait-list control group (n = 43). We evaluated emotional variables (sadness, anxiety, and anger, using standard instruments), state of mindfulness (using the Mindfulness Awareness Attention Scale), and attentional control variables using objective measures such as a continuous performance task and the Stroop task before and after mindfulness training. RESULTS: Our study provides data that suggest that mindfulness training significantly improves measures of trait anger and attentional control. CONCLUSIONS: Further research is needed to replicate these findings, explore the effects of mindfulness training on other aspects of emotional regulation and cognition, and evaluate the impact of these effects within clinical situations.

Ethanol reversal of cellular tolerance to morphine in rat locus coeruleus neurons.

Consumption of ethanol is a considerable risk factor for death in heroin overdose. We sought to determine whether a mildly intoxicating concentration of ethanol could alter morphine tolerance at the cellular level. In rat locus coeruleus (LC) neurons, tolerance to morphine was reversed by acute exposure of the brain slice to ethanol (20 mM). Tolerance to the opioid peptide [d-Ala(2),N-MePhe(4),Gly-ol]-enkephalin was not reversed by ethanol. Previous studies in LC neurons have revealed a role for protein kinase C (PKC)α in µ-opioid receptor (MOPr) desensitization by morphine and in the induction and maintenance of morphine tolerance, but we have been unable to demonstrate that 20 mM ethanol produces significant inhibition of PKCα. The ability of ethanol to reverse cellular tolerance to morphine in LC neurons was absent in the presence of the phosphatase inhibitor okadaic acid, indicating that dephosphorylation is involved. In human embryonic kidney 293 cells expressing the MOPr, ethanol reduced the level of MOPr phosphorylation induced by morphine. Ethanol reversal of tolerance did not appear to result from a direct effect on MOPr since acute exposure to ethanol (20 mM) did not modify the affinity of binding of morphine to the MOPr or the efficacy of morphine for G-protein activation as measured by guanosine 5'-O-(3-[(35)S]thio)triphosphate binding. Similarly, ethanol did not affect MOPr trafficking. We conclude that acute exposure to ethanol enhances the effects of morphine by reversing the processes underlying morphine cellular tolerance.

Fluorescence resonance energy transfer-based technologies in the study of protein-protein interactions at the cell surface.

Understanding of the molecular mechanisms of protein-protein interactions (PPIs) at the cell surface of living cells is fundamental to comprehend the functional meaning of a large number of cellular processes. Here we discuss how new methodological strategies derived from non-invasive fluorescence-based approaches (i.e. fluorescence resonance energy transfer, FRET) have been successfully developed to characterize plasma membrane PPIs. Importantly, these technologies alone - or in concert with complementary methods (i.e. SNAP-tag/TR-FRET, TIRF/FRET) - can become extremely powerful approaches for visualizing cell surface PPIs, even between more than two proteins and also in native tissues. Interestingly, these methods would also be relevant in drug discovery in order to develop new high-throughput screening approaches or to identify new therapeutic targets. Accordingly, herein we provide a thorough assessment on all biotechnological aspects, including strengths and weaknesses, of these fluorescence-based methodologies when applied in the study of PPIs occurring at the cell surface of living cells.

Endomorphin-2: a biased agonist at the µ-opioid receptor.

Previously we correlated the efficacy for G protein activation with that for arrestin recruitment for a number of agonists at the µ-opioid receptor (MOPr) stably expressed in HEK293 cells. We suggested that the endomorphins (endomorphin-1 and -2) might be biased toward arrestin recruitment. In the present study, we investigated this phenomenon in more detail for endomorphin-2, using endogenous MOPr in rat brain as well as MOPr stably expressed in HEK293 cells. For MOPr in neurons in brainstem locus ceruleus slices, the peptide agonists [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) and endomorphin-2 activated inwardly rectifying K(+) current in a concentration-dependent manner. Analysis of these responses with the operational model of pharmacological agonism confirmed that endomorphin-2 had a much lower operational efficacy for G protein-mediated responses than did DAMGO at native MOPr in mature neurons. However, endomorphin-2 induced faster desensitization of the K(+) current than did DAMGO. In addition, in HEK293 cells stably expressing MOPr, the ability of endomorphin-2 to induce phosphorylation of Ser375 in the COOH terminus of the receptor, to induce association of arrestin with the receptor, and to induce cell surface loss of receptors was much more efficient than would be predicted from its efficacy for G protein-mediated signaling. Together, these results indicate that endomorphin-2 is an arrestin-biased agonist at MOPr and the reason for this is likely to be the ability of endomorphin-2 to induce greater phosphorylation of MOPr than would be expected from its ability to activate MOPr and to induce activation of G proteins.

µ-Opioid receptor desensitization: homologous or heterologous?

There is considerable controversy over whether µ-opioid receptor (MOPr) desensitization is homologous or heterologous and over the mechanisms underlying such desensitization. In different cell types MOPr desensitization has been reported to involve receptor phosphorylation by various kinases, including G-protein-coupled receptor kinases (GRKs), second messenger and other kinases as well as perturbation of the MOPr effector pathway by GRK sequestration of G protein ßγ subunits or ion channel modulation. Here we report that in brainstem locus coeruleus (LC) neurons prepared from relatively mature rats (5-8 weeks old) rapid MOPr desensitization induced by the high-efficacy opioid peptides methionine enkephalin and DAMGO was homologous and not heterologous to α(2)-adrenoceptors and somatostatin SST(2) receptors. Given that these receptors all couple through G proteins to the same set of G-protein inwardly rectifying (GIRK) channels it is unlikely therefore that in mature neurons MOPr desensitization involves G protein ßγ subunit sequestration or ion channel modulation. In contrast, in slices from immature animals (less than postnatal day 20), MOPr desensitization was observed to be heterologous and could be downstream of the receptor. Heterologous MOPr desensitization was not dependent on protein kinase C or c-Jun N-terminal kinase activity, but the change from heterologous to homologous desensitization with age was correlated with a decrease in the expression levels of GRK2 in the LC and other brain regions. The observation that the mechanisms underlying MOPr desensitization change with neuronal development is important when extrapolating to the mature brain results obtained from experiments on expression systems, cell lines and immature neuronal preparations.

Altered Cerebellar Response to Somatosensory Stimuli in the Cntnap2 Mouse Model of Autism.

Atypical sensory processing is currently included within the diagnostic criteria of autism. The cerebellum is known to integrate sensory inputs of different modalities through its connectivity to the cerebral cortex. Interestingly, cerebellar malformations are among the most replicated features found in postmortem brain of individuals with autism. We studied sensory processing in the cerebellum in a mouse model of autism, knock-out (KO) for the Cntnap2 gene. Cntnap2 is widely expressed in Purkinje cells (PCs) and has been recently reported to regulate their morphology. Further, individuals with CNTNAP2 mutations display cerebellar malformations and CNTNAP2 antibodies are associated with a mild form of cerebellar ataxia. Previous studies in the Cntnap2 mouse model show an altered cerebellar sensory learning. However, a physiological analysis of cerebellar function has not been performed yet. We studied sensory evoked potentials in cerebellar Crus I/II region on electrical stimulation of the whisker pad in alert mice and found striking differences between wild-type and Cntnap2 KO mice. In addition, single-cell recordings identified alterations in both sensory-evoked and spontaneous firing patterns of PCs. These changes were accompanied by altered intrinsic properties and morphologic features of these neurons. Together, these results indicate that the Cntnap2 mouse model could provide novel insight into the pathophysiological mechanisms of autism core sensory deficits.

Synthesis, Pharmacological, and Biological Evaluation of 2-Furoyl-Based MIF-1 Peptidomimetics and the Development of a General-Purpose Model for Allosteric Modulators (ALLOPTML).

This work describes the synthesis and pharmacological evaluation of 2-furoyl-based Melanostatin (MIF-1) peptidomimetics as dopamine D2 modulating agents. Eight novel peptidomimetics were tested for their ability to enhance the maximal effect of tritiated N-propylapomorphine ([3H]-NPA) at D2 receptors (D2R). In this series, 2-furoyl-l-leucylglycinamide (6a) produced a statistically significant increase in the maximal [3H]-NPA response at 10 pM (11 ± 1%), comparable to the effect of MIF-1 (18 ± 9%) at the same concentration. This result supports previous evidence that the replacement of proline residue by heteroaromatic scaffolds are tolerated at the allosteric binding site of MIF-1. Biological assays performed for peptidomimetic 6a using cortex neurons from 19-day-old Wistar-Kyoto rat embryos suggest that 6a displays no neurotoxicity up to 100 µM. Overall, the pharmacological and toxicological profile and the structural simplicity of 6a makes this peptidomimetic a potential lead compound for further development and optimization, paving the way for the development of novel modulating agents of D2R suitable for the treatment of CNS-related diseases. Additionally, the pharmacological and biological data herein reported, along with >20 000 outcomes of preclinical assays, was used to seek a general model to predict the allosteric modulatory potential of molecular candidates for a myriad of target receptors, organisms, cell lines, and biological activity parameters based on perturbation theory (PT) ideas and machine learning (ML) techniques, abbreviated as ALLOPTML. By doing so, ALLOPTML shows high specificity Sp = 89.2/89.4%, sensitivity Sn = 71.3/72.2%, and accuracy Ac = 86.1%/86.4% in training/validation series, respectively. To the best of our knowledge, ALLOPTML is the first general-purpose chemoinformatic tool using a PTML-based model for the multioutput and multicondition prediction of allosteric compounds, which is expected to save both time and resources during the early drug discovery of allosteric modulators.

µ-opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization.

We have compared the ability of a number of µ-opioid receptor (MOPr) ligands to activate G proteins with their abilities to induce MOPr phosphorylation, to promote association of arrestin-3 and to cause MOPr internalization. For a model of G protein-coupled receptor (GPCR) activation where all agonists stabilize a single active conformation of the receptor, a close correlation between signaling outputs might be expected. Our results show that overall there is a very good correlation between efficacy for G protein activation and arrestin-3 recruitment, whereas a few agonists, in particular endomorphins 1 and 2, display apparent bias toward arrestin recruitment. The agonist-induced phosphorylation of MOPr at Ser(375), considered a key step in MOPr regulation, and agonist-induced internalization of MOPr were each found to correlate well with arrestin-3 recruitment. These data indicate that for the majority of MOPr agonists the ability to induce receptor phosphorylation, arrestin-3 recruitment, and internalization can be predicted from their ability as agonists to activate G proteins. For the prototypic MOPr agonist morphine, its relatively weak ability to induce MOPr internalization can be explained by its low agonist efficacy.

Neurobiological Mechanisms of Autism Spectrum Disorder and Epilepsy, Insights from Animal Models.

Autism Spectrum Disorder (ASD) and epilepsy are two neurodevelopmental disorders that have a high comorbidity rate, suggesting that a common neurodevelopmental mechanism exists. However, to date there is no conclusive way to predict whether a child will develop either syndrome or both and to what degree associated phenotypes will be affected. Failure to consistently identify predictive patterns of ASD and/or epilepsy diagnosis stems from the fact that they are etiologically heterogeneous conditions and research into their neuropathological mechanisms becomes challenging. Whole genome/exome sequencing has advanced our understanding of the genetic causes of ASD and epilepsy to an extent that currently about half of all ASD as well as epilepsy cases are known to have a genetic basis. In fact, a picture is emerging of both conditions as a collection of distinct genetically defined disorders, although the role of environmental factors has also been established. A plethora of animal models, most of them based on identified human genetic mutations and a few on known environmental causes, have been developed. Animal models provide a major experimental avenue for studying the underlying cellular and molecular mechanisms of human disorders. They also provide invaluable preclinical tools that can be used to test therapeutic approaches. In this review, we first summarize the methods for validating mouse models of ASD and epilepsy. Second, we present the current models validated for the comorbidity and finally, we recapitulate the common pathomechanisms identified in these models with special emphasis on synaptic plasticity.

Neuropsychological profile and social cognition in congenital central hypoventilation syndrome (CCHS): Correlation with neuroimaging in a clinical case.

INTRODUCTION: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder due to paired-like homeobox gene (PHOX2B) mutations. CCHS patients suffer from dysregulation of the autonomic nervous system characterized by the absence of or extremely reduced response to hypercapnia and hypoxia, with neuropsychological deficits. The aim of this exploratory study is to describe the longitudinal neuropsychological profile and its correlations with magnetic resonance imaging (MRI) of a child with CCHS with a PHOX2B mutation. METHOD: A comprehensive neuropsychological evaluation was conducted serially at age 7 years 4 months and 10 years 3 months, including assessment of intellectual functioning (IQ), motor functioning, perception, attention, executive functions, language, memory, social cognition, academic skills, and psychopathology. Reliable change index (RCI) scores were used to assess changes between assessments. We collected spin lattice relaxation time (T1)-weighted, fluid-attenuated inversion recovery (FLAIR), and spin spin lattice relaxation time (T2)-weighted images from the child at age 10 years 3 months using a 1.5-tesla MRI scanner. RESULTS: IQ, processing speed index (PSI), social cognition (theory of mind and facial emotion recognition), selective attention, naming, academic skills (reading/comprehension), and manual speed with right hand declined in the second evaluation relative to the initial evaluation, while visuoconstructional praxis, receptive vocabulary, working memory, and arithmetic skill improved. The patient showed a remarkable global deterioration in executive functions (planning, task flexibility, behavioral regulation, and metacognition) as revealed by parental report and clinical evaluation. MRI revealed gliosis from the head to tail of the hippocampus and thinning of parahippocampal gyri. CONCLUSIONS: In a clinical case of CCHS, serial evaluation revealed deterioration of executive functions and social cognition over a 3-year interval. These changes corresponded to hippocampal damage as revealed in MRI, which may have affected social cognition through its role in the default mode network. Serial neuropsychological assessment is clinically useful in managing the needs of these patients.

[Reversible neuropsychological deterioration associated to zonisamide in a paediatric patient with tuberous sclerosis]. / Deterioro neuropsicologico reversible asociado a zonisamida en un paciente pediatrico con esclerosis tuberosa.

AIM: To document reversible cognitive deterioration associated to high doses of zonisamide, using the Reliable Change Index to control practice effects derived from repetitive neuropsychological assessments. CASE REPORT: A 11 year-old boy with tuberous sclerosis complex and left frontal refractory epilepsy, evaluated within a paediatric epilepsy surgery program. The epileptogenic zone was found to be related with a tuber situated on the left inferior frontal gyrus. The effects of high doses of zonisamide simulate a disturbance of eloquent cortex within the epileptogenic zone and the impact of uncontrolled seizures on cognitive functioning over the language-dominant hemisphere. Drug withdrawal significantly improved total intelligence index, verbal comprehension intellectual index and specific language-sustained cognitive abilities, beyond practice effects. CONCLUSIONS: The differentiation between cognitive effects of drugs and functional deficits resulting from eloquent cortex involvement within the epileptogenic zone can be of crucial importance in the decision-making process for epilepsy surgery.

TITLE: Deterioro neuropsicologico reversible asociado a zonisamida en un paciente pediatrico con esclerosis tuberosa.Objetivo. Documentar el deterioro cognitivo reversible asociado a altas dosis de zonisamida, utilizando indices de cambio fiable para controlar los efectos de practica derivados de evaluaciones neuropsicologicas repetidas. Caso clinico. Niño de 11 años con complejo esclerosis tuberosa y epilepsia refractaria del lobulo frontal izquierdo, evaluado en el contexto de un programa de cirugia de la epilepsia pediatrica. La zona epileptogena se relaciono con un tuber epileptogeno localizado en el giro frontal inferior del hemisferio izquierdo. Los efectos de altas dosis de zonisamida mimetizaron una afectacion de la corteza elocuente en la zona epileptogena y un impacto de las crisis no controladas en el funcionamiento cognitivo asociado al hemisferio dominante para el lenguaje. La retirada del farmaco mejoro significativamente, mas alla de los efectos de practica, el cociente intelectual total, el indice intelectual de comprension verbal y habilidades cognitivas especificas sustentadas en el lenguaje. Conclusiones. La diferenciacion entre los efectos cognitivos de los farmacos y la existencia de un deficit funcional por afectacion de la corteza elocuente en el area epileptogena puede ser crucial para la toma de decisiones en cirugia de la epilepsia.

Agmatine-morphine interaction on nociception in mice.

The aim of this study was to investigate the possible participation of nitric oxide in the agmatine-mediated potentiation of morphine-induced analgesia in mice. Agmatine and L-NAME (a nitric oxide synthesis inhibitor) enhanced morphine-induced analgesia in the tail flick test, but not in the hot plate test. L-NAME did not block the agmatine-induced potentiation of morphine effect. Our results indicate that agmatine potentiates morphine-induced spinal but not supraspinal analgesia, and that this effect is not mediated by a nitric oxide-dependent mechanism.

Involvement of neuronal nitric oxide synthase in desensitisation of µ-opioid receptors in the rat locus coeruleus.

Nitric oxide (NO) has been recently shown to enhance µ-opioid receptor (MOR) desensitisation in locus coeruleus (LC) neurons. The aim of this study was to evaluate by single-unit extracellular recordings in rat brain slices whether the neuronal NO synthase is involved in MOR desensitisation in LC neurons. As expected, a high concentration of the opioid agonist Met(5)-enkephalin (ME; 10 µM, 10 min) strongly desensitised the inhibition induced by a test application of ME (0.8 µM, 1 min), whereas lower ME concentrations (1 and 3 µM) only weakly desensitised it. The neuronal NO synthase inhibitors 7-nitroindazole (10-100 µM), S-methyl-L-thiocitrulline (0.01-10 µM) and N(ω)-propyl-L-arginine (1-10 µM) attenuated ME (10 µM)-induced opioid desensitisation, although the endothelial NO synthase inhibitor N(5)-(1-iminoethyl)-L-ornithine (3-30 µM) failed to change it. The NO donor sodium nitroprusside (1 mM), but not its inactive analog potassium ferricyanide (1 mM), enhanced the ME (3 µM)-induced desensitisation and prevented the effect of S-methyl-L-thiocitrulline (10 µM). Sodium nitroprusside (1 mM) failed to change the desensitisation of α2-adrenoceptors by noradrenaline (100 µM, 10 min). These results suggest the contribution of NO and a neuronal type of NO synthase in homologous MOR desensitisation in rat LC neurons.

G protein-coupled receptor oligomerization and brain integration: focus on adenosinergic transmission.

The control of glutamatergic corticostriatal transmission is essential for the induction and expression of plasticity mechanisms in the striatum, a phenomenon thickly regulated by G protein-coupled receptors (GPCRs). Interestingly, in addition to dopamine receptors, adenosine and metabotropic glutamate receptors also play a key role in striatal functioning. The existence of a supramolecular organization (i.e. oligomer) containing dopamine, adenosine and metabotropic glutamate receptors in the striatal neurons is now being widely accepted by the scientific community. Indeed, these oligomers may enhance the diversity and performance by which extracellular striatal signals are transferred to the G-proteins in the process of receptor transduction, and also may allow unpredictable receptor-receptor allosteric regulations. Overall, here we want to review how formations of adenosine, dopamine and metabotropic glutamate receptors-containing oligomers impinge into striatal functioning in both normal and pathological conditions. This article is part of a Special Issue entitled: Brain Integration.

[Primary stabbing headache: clinical characteristics and response to treatment in a series of 67 patients]. / Cefalea primaria punzante: caracteristicas clínicas y respuesta al tratamiento en una serie de 67 pacientes.

INTRODUCTION: Primary stabbing headache (PSH) is defined by the presence of short stabbing pains in the first branch of the trigeminal nerve. According to population-based studies, it is very prevalent, but most cases present stabbing pains with low frequencies and intensities that do not lead the patient to seek medical attention. AIMS: We report on 67 cases of PSH attended in the headache service of a tertiary hospital. In the study, the demographic and clinical characteristics are studied, treatment response is reviewed and the features of PSH are compared in terms of whether it was the only headache or was accompanied by others. PATIENTS AND METHODS: The study involved 67 patients (51 females and 16 males) diagnosed with PSH between January 2008 and January 2012, of a total number of 1668 (4%) patients attended in the above-mentioned service. RESULTS: Age at onset: 34.5 ± 16.7 years. Forty-nine cases (73.1%) were associated to another headache, above all migraine. Stabbing pains were often bilateral; 38 (56.7%) patients suffered more than one a day and 11 (16.4%) had more than 10 per day. They lasted less than five seconds in 48 patients (71.6%) and more than 10 seconds in 11 of them (16.4%), with an intensity of 6.8 ± 1.5. The age of onset of PSH was higher if it was the only type of headache than if it was accompanied by others. Twenty-six (38.8%) patients required preventive treatment for the associated headache and 16 (23.8%) took indomethacin, with a similar response in the two groups (73 versus 75%). CONCLUSIONS; PSH is not infrequent in headache clinics, but its phenotype differs from that reported in population-based studies. The characteristics of PSH vary depending on whether it is the only headache or is associated with others. Preventive treatment is often required and patients respond well to it.

[Hemicrania continua: characteristics and therapeutic experience in a series of 36 patients]. / Hemicránea continua: características y experiencia terapéutica en una serie de 36 pacientes.

INTRODUCTION: Hemicrania continua is characterised by a continuous unilateral pain, which frequently gets worse in association with autonomic symptoms. It is probably little known and underdiagnosed. Its diagnosis requires a response to indomethacin, which is not always well tolerated. AIMS: We report a series of 36 cases of hemicrania continua that were treated in the headache service of a tertiary hospital. We analyse their demographic and clinical features and the therapeutic alternatives to indomethacin. PATIENTS AND METHODS: Between January 2008 and April 2012, 36 patients (28 females, eight males) were diagnosed with hemicrania continua from among 1800 (2%) who were treated in that service. RESULTS: The age of onset was 46.3 ± 18.4 years. In four patients (11.1%) there were pain remissions that lasted over three months. The baseline pain was chiefly oppressive or burning with an intensity of 5.2 ± 1.4 on the verbal analogue scale. Exacerbations lasted 32.3 ± 26.1 minutes, were of a predominantly stabbing nature with an intensity of 8.3 ± 1.4, and in 69.4% of cases were accompanied by autonomic symptoms. Altogether 16.7% of the patients did not tolerate indomethacin beyond an indotest and 50% did so with side effects. In 13 cases at least one anaesthetic blockade was performed in the supraorbital or the greater occipital nerve or a trochlear injection of corticoids was carried out with a full response in 53.8% and a partial response in 38.5%. CONCLUSIONS: Hemicrania continua is not an infrequent diagnosis in a headache clinic and, because it is a treatable condition, further knowledge on the subject is needed. Anaesthetic blockades of the supraorbital or greater occipital nerves or a trochlear injection of corticoids are the therapeutic options that must be taken into consideration when indomethacin is not well tolerated.

[Epicrania fugax: the clinical characteristics of a series of 18 patients]. / Epicrania fugax: características clínicas de una serie de 18 pacientes.

INTRODUCTION: Epicrania fugax is a recently reported condition consisting in brief painful paroxysms that begin in the posterior regions of the brain and irradiate towards the ipsilateral eye, nose or temple. AIMS: To present 18 cases of epicrania fugax from a monographic headache centre in a tertiary hospital and to analyse their demographic and clinical features, as well as the indication and response to prophylactic treatment. PATIENTS AND METHODS: Between March 2008, when epicrania fugax was first reported, and March 2011, of a total of 1210 patients who were attended in that service (1.48%), 18 (12 females and 6 males) were diagnosed as suffering from this condition. Six of these cases had been published earlier. RESULTS: The mean age at onset was 42.5 ± 17.7 years (range: 23-82 years). They presented painful paroxysms that began in the occipital (n = 11; 61.1%), parietal (n = 6; 33.3%) or parieto-occipital (n = 1; 5.6%) regions and irradiated towards the ipsilateral eye (n = 12; 66.6%) or temple (n = 6; 33.3%); the whole process lasted less than 15 seconds. Most of them described the pain as lancinating or stabbing. In 10 cases (55.5%) a pain remained in the area where the paroxysms began, which in 6 cases (33.3%) was limited to a well-defined circular area and met the criteria for classification as nummular headache. In 12 cases (66.6%), prophylactic treatment was used, above all lamotrigine and gabapentin, with varying results. CONCLUSION: Our aim is to back the proposal of epicrania fugax as a new syndrome with a well-defined clinical spectrum. It does not appear to be an exceptional condition and further knowledge about it will probably give rise to the description of new series. Treatment is often necessary and, although further information and experience are needed, gabapentin and lamotrigine both play a promising role.