Publications by authors named "Else A Tolner"

46 Publications

Headache in people with epilepsy.

Nat Rev Neurol 2021 Sep 26;17(9):529-544. Epub 2021 Jul 26.

Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands.

Epidemiological estimates indicate that individuals with epilepsy are more likely to experience headaches, including migraine, than individuals without epilepsy. Headaches can be temporally unrelated to seizures, or can occur before, during or after an episode; seizures and migraine attacks are mostly not temporally linked. The pathophysiological links between headaches (including migraine) and epilepsy are complex and have not yet been fully elucidated. Correct diagnoses and appropriate treatment of headaches in individuals with epilepsy is essential, as headaches can contribute substantially to disease burden. Here, we review the insights that have been made into the associations between headache and epilepsy over the past 5 years, including information on the pathophysiological mechanisms and genetic variants that link the two disorders. We also discuss the current best practice for the management of headaches co-occurring with epilepsy and highlight future challenges for this area of research.
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http://dx.doi.org/10.1038/s41582-021-00516-6DOI Listing
September 2021

Widespread brain parenchymal HMGB1 and NF-κB neuroinflammatory responses upon cortical spreading depolarization in familial hemiplegic migraine type 1 mice.

Neurobiol Dis 2021 08 10;156:105424. Epub 2021 Jun 10.

Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey. Electronic address:

Neuroinflammatory changes involving neuronal HMGB1 release and astrocytic NF-κB nuclear translocation occur following cortical spreading depolarization (CSD) in wildtype (WT) mice but it is unknown to what extent this occurs in the migraine brain. We therefore investigated in familial hemiplegic migraine type 1 (FHM1) knock-in mice, which express an intrinsic hyperexcitability phenotype, the extent of neuroinflammation without and after CSD. CSD was evoked in one hemisphere by pinprick (single CSD) or topical KCl application (multiple CSDs). Neuroinflammatory (HMGB1, NF-κB) and neuronal activation (pERK) markers were investigated by immunohistochemistry in the brains of WT and FHM1 mutant mice without and after CSD. Effects of NMDA receptor antagonism on basal and CSD-induced neuroinflammatory changes were examined by, respectively, systemically administered MK801 and ifenprodil or topical MK801 application. In FHM1 mutant mice, CSD caused enhanced neuronal HMGB1 release and astrocytic NF-κB nuclear translocation in the cortex and subcortical areas that were equally high in both hemispheres. In WT mice such effects were only pronounced in the hemisphere in which CSD was induced. Neuroinflammatory responses were associated with pERK expression indicating neuronal activation. Upon CSD, contralateral cortical and striatal HMGB1 release was reduced by topical application of MK801 in the hemisphere contralateral to the one in which CSD was induced. This study reveals that neuroinflammatory activation after CSD is widespread and extends to the contralateral hemisphere, particularly in brains of FHM1 mutant mice. Effective blockade of CSD-induced neuroinflammatory responses in the contralateral hemisphere in FHM1 mice by local NMDA receptor antagonism suggests that neuronal hyperexcitability-related neuroinflammation is relevant in migraine pathophysiology, but possibly also other neurological disorders in which spreading depolarization is involved.
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http://dx.doi.org/10.1016/j.nbd.2021.105424DOI Listing
August 2021

Single-pulse stimulation of cerebellar nuclei stops epileptic thalamic activity.

Brain Stimul 2021 Jul-Aug;14(4):861-872. Epub 2021 May 20.

Department of Neuroscience, Erasmus Medical Center, 3015, AA Rotterdam, the Netherlands; Department for Developmental Origins of Disease, University Medical Center Utrecht Brain Center and Wilhelmina Children's Hospital, Utrecht Medical Center, 3508, AB Utrecht, the Netherlands. Electronic address:

Background: Epileptic (absence) seizures in the cerebral cortex can be stopped by pharmacological and optogenetic stimulation of the cerebellar nuclei (CN) neurons that innervate the thalamus. However, it is unclear how such stimulation can modify underlying thalamo-cortical oscillations.

Hypothesis: Here we tested whether rhythmic synchronized thalamo-cortical activity during absence seizures can be desynchronized by single-pulse optogenetic stimulation of CN neurons to stop seizure activity.

Methods: We performed simultaneous thalamic single-cell and electrocorticographical recordings in awake tottering mice, a genetic model of absence epilepsy, to investigate the rhythmicity and synchronicity. Furthermore, we tested interictally the impact of single-pulse optogenetic CN stimulation on thalamic and cortical recordings.

Results: We show that thalamic firing is highly rhythmic and synchronized with cortical spike-and-wave discharges during absence seizures and that this phase-locked activity can be desynchronized upon single-pulse optogenetic stimulation of CN neurons. Notably, this stimulation of CN neurons was more effective in stopping seizures than direct, focal stimulation of groups of afferents innervating the thalamus. During interictal periods, CN stimulation evoked reliable but heterogeneous responses in thalamic cells in that they could show an increase or decrease in firing rate at various latencies, bi-phasic responses with an initial excitatory and subsequent inhibitory response, or no response at all.

Conclusion: Our data indicate that stimulation of CN neurons and their fibers in thalamus evokes differential effects in its downstream pathways and desynchronizes phase-locked thalamic neuronal firing during seizures, revealing a neurobiological mechanism that may explain how cerebellar stimulation can stop seizures.
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http://dx.doi.org/10.1016/j.brs.2021.05.002DOI Listing
May 2021

Impaired θ-γ Coupling Indicates Inhibitory Dysfunction and Seizure Risk in a Dravet Syndrome Mouse Model.

J Neurosci 2021 01 24;41(3):524-537. Epub 2020 Nov 24.

Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.

Dravet syndrome (DS) is an epileptic encephalopathy that still lacks biomarkers for epileptogenesis and its treatment. Dysfunction of Na1.1 sodium channels, which are chiefly expressed in inhibitory interneurons, explains the epileptic phenotype. Understanding the network effects of these cellular deficits may help predict epileptogenesis. Here, we studied θ-γ coupling as a potential marker for altered inhibitory functioning and epileptogenesis in a DS mouse model. We found that cortical θ-γ coupling was reduced in both male and female juvenile DS mice and persisted only if spontaneous seizures occurred. θ-γ Coupling was partly restored by cannabidiol (CBD). Locally disrupting Na1.1 expression in the hippocampus or cortex yielded early attenuation of θ-γ coupling, which in the hippocampus associated with fast ripples, and which was replicated in a computational model when voltage-gated sodium currents were impaired in basket cells (BCs). Our results indicate attenuated θ-γ coupling as a promising early indicator of inhibitory dysfunction and seizure risk in DS.
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http://dx.doi.org/10.1523/JNEUROSCI.2132-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821857PMC
January 2021

Responsivity to light in familial hemiplegic migraine type 1 mutant mice reveals frequency-dependent enhancement of visual network excitability.

Eur J Neurosci 2021 03 26;53(5):1672-1686. Epub 2020 Nov 26.

Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

Migraine patients often report (inter)ictal hypersensitivity to light, but the underlying mechanisms remain an enigma. Both hypo- and hyperresponsivity of the visual network have been reported, which may reflect either intra-individual dynamics of the network or large inter-individual variation in the measurement of human visual evoked potential data. Therefore, we studied visual system responsivity in freely behaving mice using combined epidural electroencephalography and intracortical multi-unit activity to reduce variation in recordings and gain insight into visual cortex dynamics. For better clinical translation, we investigated transgenic mice that carry the human pathogenic R192Q missense mutation in the α subunit of voltage-gated Ca 2.1 Ca channels leading to enhanced neurotransmission and familial hemiplegic migraine type 1 in patients. Visual evoked potentials were studied in response to visual stimulation paradigms with flashes of light. Following intensity-dependent visual stimulation, FHM1 mutant mice displayed faster visual evoked potential responses, with lower initial amplitude, followed by less pronounced neuronal suppression compared to wild-type mice. Similar to what was reported for migraine patients, frequency-dependent stimulation in mutant mice revealed enhanced photic drive in the EEG beta-gamma band. The frequency-dependent increases in visual network responses in mutant mice may reflect the context-dependent enhancement of visual cortex excitability, which could contribute to our understanding of sensory hypersensitivity in migraine.
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http://dx.doi.org/10.1111/ejn.15041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048865PMC
March 2021

Focal and generalized seizure activity after local hippocampal or cortical ablation of Na 1.1 channels in mice.

Epilepsia 2020 04 19;61(4):e30-e36. Epub 2020 Mar 19.

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Early onset seizures are a hallmark of Dravet syndrome. Previous studies in rodent models have shown that the epileptic phenotype is caused by loss-of-function of voltage-gated Na 1.1 sodium channels, which are chiefly expressed in γ-aminobutyric acid (GABA)ergic neurons. Recently, a possibly critical role has been attributed to the hippocampus in the seizure phenotype, as local hippocampal ablation of Na 1.1 channels decreased the threshold for hyperthermia-induced seizures. However, the effect of ablation of Na 1.1 channels restricted to cortical sites has not been tested. Here we studied local field potential (LFP) and behavior in mice following local hippocampal and cortical ablation of Scn1a, a gene encoding the α1 subunit of Na 1.1 channels, and we compared seizure characteristics with those of heterozygous global knockout Scn1 mice. We found a high incidence of spontaneous seizures following either local hippocampal or cortical ablation, notably during a transient time window, similar to Scn1a mice. Nonconvulsive seizure activity in the injected area was common and preceded generalized seizures. Moreover, mice were susceptible to hyperthermia-induced seizures. In conclusion, local ablation of Na 1.1 channels in the hippocampus and cortex results in focal seizure activity that can generalize. These data indicate that spontaneous epileptic activity may initiate in multiple brain regions in Dravet syndrome.
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http://dx.doi.org/10.1111/epi.16482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216883PMC
April 2020

Enhanced pre-ictal cortical responsivity in migraine patients assessed by visual chirp stimulation.

Cephalalgia 2020 08 18;40(9):913-923. Epub 2020 Mar 18.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.

Background: Migraine is associated with altered sensory processing and cortical responsivity that may contribute to susceptibility to attacks by changing brain network excitability dynamics. To gain better insight into cortical responsivity changes in migraine we subjected patients to a short series of light inputs over a broad frequency range ("chirp" stimulation), designed to uncover dynamic features of visual cortex responsivity.

Methods: EEG responses to visual chirp stimulation (10-40 Hz) were measured in controls (n = 24) and patients with migraine with aura (n = 19) or migraine without aura (n = 20). Average EEG responses were assessed at (i) all EEG frequencies between 5 and 125 Hz, (ii) stimulation frequencies, and (iii) harmonic frequencies. We compared average responses in a low (10-18 Hz), medium (19-26 Hz) and high (27-40 Hz) frequency band.

Results: Responses to chirp stimulation were similar in controls and migraine subtypes. Eight measurements (n = 3 migraine with aura; n = 5 without aura) were assigned as "pre-ictal", based on reported headache within 48 hours after investigation. Pre-ictally, an increased harmonic response to 22-32 Hz stimulation (beta band) was observed ( = 0.001), compared to interictal state measurements.

Conclusions: We found chirp responses to be enhanced in the 48 hours prior to migraine headache onset. Visual chirp stimulation proved a simple and reliable technique with potential to detect changes in cortical responsivity associated with the onset of migraine attacks.
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http://dx.doi.org/10.1177/0333102420912725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412874PMC
August 2020

First FHM3 mouse model shows spontaneous cortical spreading depolarizations.

Ann Clin Transl Neurol 2020 01 27;7(1):132-138. Epub 2019 Dec 27.

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Here we show, for the first time, spontaneous cortical spreading depolarization (CSD) events - the electrophysiological correlate of the migraine aura - in animals by using the first generated familial hemiplegic migraine type 3 (FHM3) transgenic mouse model. The mutant mice express L263V-mutated α1 subunits in voltage-gated Na 1.1 sodium channels (Scn1a ). CSDs consistently propagated from visual to motor cortex, recapitulating what has been shown in patients with migraine with aura. This model may be valuable for the preclinical study of migraine with aura and other diseases in which spreading depolarization is a prominent feature.
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http://dx.doi.org/10.1002/acn3.50971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952313PMC
January 2020

No Gastrointestinal Dysmotility in Transgenic Mouse Models of Migraine.

Headache 2020 02 26;60(2):396-404. Epub 2019 Dec 26.

Department of Neurological Sciences, The University of Vermont, Burlington, VT, USA.

Objective: To determine whether transgenic mouse models of migraine exhibit upper gastrointestinal dysmotility comparable to those observed in migraine patients.

Background: There is considerable evidence supporting the comorbidity of gastrointestinal dysmotility and migraine. Gastrointestinal motility, however, has never been investigated in transgenic mouse models of migraine.

Methods: Three transgenic mouse strains that express pathogenic gene mutations linked to monogenic migraine-relevant phenotypes were studied: CADASIL (Notch3-Tg88), FASP (CSNK1D-T44A), and FHM1 (CACNA1A-S218L). Upper gastrointestinal motility was quantified by measuring gastric emptying and small intestinal transit in mutant and control animals. Gastrointestinal motility was measured at baseline and after pretreatment with 10 mg/kg nitroglycerin (NTG).

Results: No significant differences were observed for gastric emptying or small intestinal transit at baseline for any of the 3 transgenic strains when compared to appropriate controls or after pretreatment with NTG when compared to vehicle.

Conclusions: We detected no evidence of upper gastrointestinal dysmotility in mice that express mutations in genes linked to monogenic migraine-relevant phenotypes. Future studies seeking to understand why humans with migraine experience delayed gastric emptying may benefit from pursuing other modifiers of gastrointestinal motility, such as epigenetic or microbiome-related factors.
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http://dx.doi.org/10.1111/head.13724DOI Listing
February 2020

Apnea Associated with Brainstem Seizures in Mice Is Caused by Medullary Spreading Depolarization.

J Neurosci 2019 11 18;39(48):9633-9644. Epub 2019 Oct 18.

Departments of Human Genetics,

Seizure-related apnea is common and can be lethal. Its mechanisms however remain unclear and preventive strategies are lacking. We postulate that brainstem spreading depolarization (SD), previously associated with lethal seizures in animal models, initiates apnea upon invasion of brainstem respiratory centers. To study this, we assessed effects of brainstem seizures on brainstem function and respiration in male and female mice carrying a homozygous S218L missense mutation that leads to gain-of-function of voltage-gated Ca2.1 Ca channels and high risk for fatal seizures. Recordings of brainstem DC potential and neuronal activity, cardiorespiratory activity and local tissue oxygen were performed in freely behaving animals. Brainstem SD occurred during all spontaneous fatal seizures and, unexpectedly, during a subset of nonfatal seizures. Seizure-related SDs in the ventrolateral medulla correlated with respiratory suppression. Seizures induced by stimulation of the inferior colliculus could evoke SD that spread in a rostrocaudal direction, preceding local tissue hypoxia and apnea, indicating that invasion of SD into medullary respiratory centers initiated apnea and hypoxia rather than Fatal outcome was prevented by timely resuscitation. Moreover, NMDA receptor antagonists MK-801 and memantine prevented seizure-related SD and apnea, which supports brainstem SD as a prerequisite for brainstem seizure-related apnea in this animal model and has translational value for developing strategies that prevent fatal ictal apnea. Apnea during and following seizures is common, but also likely implicated in sudden unexpected death in epilepsy (SUDEP). This underlines the need to understand mechanisms for potentially lethal seizure-related apnea. In the present work we show, in freely behaving SUDEP-prone transgenic mice, that apnea is induced when spontaneous brainstem seizure-related spreading depolarization (SD) reaches respiratory nuclei in the ventrolateral medulla. We show that brainstem seizure-related medullary SD is followed by local hypoxia and recovers during nonfatal seizures, but not during fatal events. NMDA receptor antagonists prevented medullary SD and apnea, which may be of translational value.
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http://dx.doi.org/10.1523/JNEUROSCI.1713-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880468PMC
November 2019

Current understanding of cortical structure and function in migraine.

Cephalalgia 2019 Nov 28;39(13):1683-1699. Epub 2019 Mar 28.

Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Objective: To review and discuss the literature on the role of cortical structure and function in migraine.

Discussion: Structural and functional findings suggest that changes in cortical morphology and function contribute to migraine susceptibility by modulating dynamic interactions across cortical and subcortical networks. The involvement of the cortex in migraine is well established for the aura phase with the underlying phenomenon of cortical spreading depolarization, while increasing evidence suggests an important role for the cortex in perception of head pain and associated sensations. As part of trigeminovascular pain and sensory processing networks, cortical dysfunction is likely to also affect initiation of attacks.

Conclusion: Morphological and functional changes identified across cortical regions are likely to contribute to initiation, cyclic recurrence and chronification of migraine. Future studies are needed to address underlying mechanisms, including interactions between cortical and subcortical regions and effects of internal (e.g. genetics, gender) and external (e.g. sensory inputs, stress) modifying factors, as well as possible clinical and therapeutic implications.
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http://dx.doi.org/10.1177/0333102419840643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859601PMC
November 2019

Phase clustering in transcranial magnetic stimulation-evoked EEG responses in genetic generalized epilepsy and migraine.

Epilepsy Behav 2019 04 13;93:102-112. Epub 2019 Mar 13.

Stichting Epilepsie Instellingen Nederland (SEIN), Achterweg 5, 2103 SW Heemstede, the Netherlands; Image Sciences Institute, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, the Netherlands.

Background: Epilepsy and migraine are paroxysmal neurological conditions associated with disturbances of cortical excitability. No useful biomarkers to monitor disease activity in these conditions are available. Phase clustering was previously described in electroencephalographic (EEG) responses to photic stimulation and may be a potential epilepsy biomarker.

Objective: The objective of this study was to investigate EEG phase clustering in response to transcranial magnetic stimulation (TMS), compare it with photic stimulation in controls, and explore its potential as a biomarker of genetic generalized epilepsy or migraine with aura.

Methods: People with (possible) juvenile myoclonic epilepsy (JME), migraine with aura, and healthy controls underwent single-pulse TMS with concomitant EEG recording during the interictal period. We compared phase clustering after TMS with photic stimulation across the groups using permutation-based testing.

Results: We included eight people with (possible) JME (five off medication, three on), 10 with migraine with aura, and 37 controls. The TMS and photic phase clustering spectra showed significant differences between those with epilepsy without medication and controls. Two phase clustering-based indices successfully captured these differences between groups. One participant was tested multiple times. In this case, the phase clustering-based indices were inversely correlated with the dose of antiepileptic medication. Phase clustering did not differ between people with migraine and controls.

Conclusion: We present methods to quantify phase clustering using TMS-EEG and show its potential value as a measure of brain network activity in genetic generalized epilepsy. Our results suggest that the higher propensity to phase clustering is not shared between genetic generalized epilepsy and migraine.
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http://dx.doi.org/10.1016/j.yebeh.2019.01.029DOI Listing
April 2019

A miniaturized push-pull-perfusion probe for few-second sampling of neurotransmitters in the mouse brain.

Lab Chip 2019 04;19(8):1332-1343

BIOS - Microdevices for Chemical Analysis group, MESA+ Institute for Nanotechnology, Techmed Centre, University of Twente, Hallenweg 15, 7522 NH Enschede, The Netherlands.

Measuring biomolecule concentrations in the brain of living animals, in real time, is a challenging task, especially when detailed information at high temporal resolution is also required. Traditionally, microdialysis probes are used that generally have sampling areas in the order of about 1 mm2, and provide information on concentrations with a temporal resolution of at least several minutes. In this paper, we present a novel miniaturized push-pull perfusion sampling probe that uses an array of small 3 μm-wide sampling channels to sample neurotransmitters at a typical recovery rate of 61%, with a reduced risk of clogging. The added feature to segment the dialysate inside the probe into small water-in-decane droplets enables the detection of concentrations with a temporal resolution of a few seconds. Here we used the probe for in vivo recordings of neurotransmitter glutamate released upon electrical stimulation in the brain of a mouse to demonstrate the feasibility of the probe for real-time neurochemical brain analysis.
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http://dx.doi.org/10.1039/c8lc01137kDOI Listing
April 2019

Brainstem spreading depolarization and cortical dynamics during fatal seizures in Cacna1a S218L mice.

Brain 2019 02;142(2):412-425

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Sudden unexpected death in epilepsy (SUDEP) is a fatal complication of epilepsy in which brainstem spreading depolarization may play a pivotal role, as suggested by animal studies. However, patiotemporal details of spreading depolarization occurring in relation to fatal seizures have not been investigated. In addition, little is known about behavioural and neurophysiological features that may discriminate spontaneous fatal from non-fatal seizures. Transgenic mice carrying the missense mutation S218L in the α1A subunit of Cav2.1 (P/Q-type) Ca2+ channels exhibit enhanced excitatory neurotransmission and increased susceptibility to spreading depolarization. Homozygous Cacna1aS218L mice show spontaneous non-fatal and fatal seizures, occurring throughout life, resulting in reduced life expectancy. To identify characteristics of fatal and non-fatal spontaneous seizures, we compared behavioural and electrophysiological seizure dynamics in freely-behaving homozygous Cacna1aS218L mice. To gain insight on the role of brainstem spreading depolarization in SUDEP, we studied the spatiotemporal distribution of spreading depolarization in the context of seizure-related death. Spontaneous and electrically-induced seizures were investigated by video monitoring and electrophysiological recordings in freely-behaving Cacna1aS218L and wild-type mice. Homozygous Cacna1aS218L mice showed multiple spontaneous tonic-clonic seizures and died from SUDEP in adulthood. Death was preceded by a tonic-clonic seizure terminating with hindlimb clonus, with suppression of cortical neuronal activity during and after the seizure. Induced seizures in freely-behaving homozygous Cacna1aS218L mice were followed by multiple spreading depolarizations and death. In wild-type or heterozygous Cacna1aS218L mice, induced seizures and spreading depolarization were never followed by death. To identify temporal and regional features of seizure-induced spreading depolarization related to fatal outcome, diffusion-weighted MRI was performed in anaesthetized homozygous Cacna1aS218L and wild-type mice. In homozygous Cacna1aS218L mice, appearance of seizure-related spreading depolarization in the brainstem correlated with respiratory arrest that was followed by cardiac arrest and death. Recordings in freely-behaving homozygous Cacna1aS218L mice confirmed brainstem spreading depolarization during spontaneous fatal seizures. These data underscore the value of the homozygous Cacna1aS218L mouse model for identifying discriminative features of fatal compared to non-fatal seizures, and support a key role for cortical neuronal suppression and brainstem spreading depolarization in SUDEP pathophysiology.
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http://dx.doi.org/10.1093/brain/awy325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351775PMC
February 2019

Determinants of Optogenetic Cortical Spreading Depolarizations.

Cereb Cortex 2019 03;29(3):1150-1161

Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.

Cortical spreading depolarization (SD) is the electrophysiological event underlying migraine aura, and a critical contributor to secondary damage after brain injury. Experimental models of SD have been used for decades in migraine and brain injury research; however, they are highly invasive and often cause primary tissue injury, diminishing their translational value. Here we present a non-invasive method to trigger SDs using light-induced depolarization in transgenic mice expressing channelrhodopsin-2 in neurons (Thy1-ChR2-YFP). Focal illumination (470 nm, 1-10 mW) through intact skull using an optical fiber evokes power-dependent steady extracellular potential shifts and local elevations of extracellular [K+] that culminate in an SD when power exceeds a threshold. Using the model, we show that homozygous mice are significantly more susceptible to SD (i.e., lower light thresholds) than heterozygous ChR2 mice. Moreover, we show SD susceptibility differs significantly among cortical divisions (motor, whisker barrel, sensory, visual, in decreasing order of susceptibility), which correlates with relative channelrhodopsin-2 expression. Furthermore, the NMDA receptor antagonist MK-801 blocks the transition to SD without diminishing extracellular potential shifts. Altogether, our data show that the optogenetic SD model is highly suitable for examining physiological or pharmacological modulation of SD in acute and longitudinal studies.
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http://dx.doi.org/10.1093/cercor/bhy021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373833PMC
March 2019

Differential neuromodulatory role of endocannabinoids in the rodent trigeminal sensory ganglion and cerebral cortex relevant to pain processing.

Neuropharmacology 2018 03 7;131:39-50. Epub 2017 Dec 7.

Neuroscience Department, International School for Advanced Studies (SISSA), Trieste, Italy. Electronic address:

Endocannabinoids are suggested to control pain, even though their clinical use is not fully validated and the underlying mechanisms are incompletely understood. To clarify the targets of endocannabinoid actions, we studied how activation of the endocannabinoid CB1 receptor (CB1R) affects neuronal responses in two in vitro preparations of rodents, namely the trigeminal sensory ganglion (TG) in culture and a coronal slice of the cerebral cortex. On TG small-medium size neurons, we tested whether submicromolar concentrations of the endogenous CB1R agonist anandamide (AEA) modulated inhibitory GABA receptors and excitatory ATP-gated P2X3 receptors. AEA reversibly depressed GABA-mediated membrane currents without altering P2X3 receptor responses. The AEA antagonism was non-competitive, prevented by the CB1R antagonist AM-251, mimicked by the other cannabinoids 2-arachidonylglycerol and WIN 55,212-2, and insensitive to TRPV1 blocker capsazepine. AEA inhibited the potentiation of GABAergic responses by the cAMP activator forskolin, in line with the canonical inhibition of cAMP synthesis by CB1Rs. In the cerebral cortex, AEA or WIN 55,212-2 did not affect electrically-evoked local field potentials or characteristics of cortical spreading depolarization (CSD) elicited by high potassium application. The GABA receptor blocker gabazine, however, strongly enhanced field potentials without affecting CSD properties, suggesting that CSD was not dominantly controlled by GABAergic mechanisms. Our data propose that, despite the widespread expression of CB1Rs peripherally and centrally, the functional effects of AEA are region-specific and depend on CB1R coupling to downstream effectors. Future studies concerned with the mechanisms of AEA analgesia should perhaps be directed to discrete subcortical nuclei processing trigeminal inputs.
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http://dx.doi.org/10.1016/j.neuropharm.2017.12.013DOI Listing
March 2018

Dynamics of convulsive seizure termination and postictal generalized EEG suppression.

Brain 2017 03;140(3):655-668

Stichting Epilepsie Instellingen Nederland (SEIN), Achterweg 5, 2103 SW Heemstede, The Netherlands.

It is not fully understood how seizures terminate and why some seizures are followed by a period of complete brain activity suppression, postictal generalized EEG suppression. This is clinically relevant as there is a potential association between postictal generalized EEG suppression, cardiorespiratory arrest and sudden death following a seizure. We combined human encephalographic seizure data with data of a computational model of seizures to elucidate the neuronal network dynamics underlying seizure termination and the postictal generalized EEG suppression state. A multi-unit computational neural mass model of epileptic seizure termination and postictal recovery was developed. The model provided three predictions that were validated in EEG recordings of 48 convulsive seizures from 48 subjects with refractory focal epilepsy (20 females, age range 15-61 years). The duration of ictal and postictal generalized EEG suppression periods in human EEG followed a gamma probability distribution indicative of a deterministic process (shape parameter 2.6 and 1.5, respectively) as predicted by the model. In the model and in humans, the time between two clonic bursts increased exponentially from the start of the clonic phase of the seizure. The terminal interclonic interval, calculated using the projected terminal value of the log-linear fit of the clonic frequency decrease was correlated with the presence and duration of postictal suppression. The projected terminal interclonic interval explained 41% of the variation in postictal generalized EEG suppression duration (P < 0.02). Conversely, postictal generalized EEG suppression duration explained 34% of the variation in the last interclonic interval duration. Our findings suggest that postictal generalized EEG suppression is a separate brain state and that seizure termination is a plastic and autonomous process, reflected in increased duration of interclonic intervals that determine the duration of postictal generalized EEG suppression.
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http://dx.doi.org/10.1093/brain/aww322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837448PMC
March 2017

Animal models of monogenic migraine.

Cephalalgia 2016 Jun 6;36(7):704-21. Epub 2016 May 6.

Neurovascular Research Lab, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, USA

Migraine is a highly prevalent and disabling neurological disorder with a strong genetic component. Rare monogenic forms of migraine, or syndromes in which migraine frequently occurs, help scientists to unravel pathogenetic mechanisms of migraine and its comorbidities. Transgenic mouse models for rare monogenic mutations causing familial hemiplegic migraine (FHM), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and familial advanced sleep-phase syndrome (FASPS), have been created. Here, we review the current state of research using these mutant mice. We also discuss how currently available experimental approaches, including epigenetic studies, biomolecular analysis and optogenetic technologies, can be used for characterization of migraine genes to further unravel the functional and molecular pathways involved in migraine.
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http://dx.doi.org/10.1177/0333102416645933DOI Listing
June 2016

Optogenetic induction of cortical spreading depression in anesthetized and freely behaving mice.

J Cereb Blood Flow Metab 2017 May 1;37(5):1641-1655. Epub 2016 Jan 1.

1 Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

Cortical spreading depression, which plays an important role in multiple neurological disorders, has been studied primarily with experimental models that use highly invasive methods. We developed a relatively non-invasive optogenetic model to induce cortical spreading depression by transcranial stimulation of channelrhodopsin-2 ion channels expressed in cortical layer 5 neurons. Light-evoked cortical spreading depression in anesthetized and freely behaving mice was studied with intracortical DC-potentials, multi-unit activity and/or non-invasive laser Doppler flowmetry, and optical intrinsic signal imaging. In anesthetized mice, cortical spreading depression induction thresholds and propagation rates were similar for invasive (DC-potential) and non-invasive (laser Doppler flowmetry) recording paradigms. Cortical spreading depression-related vascular and parenchymal optical intrinsic signal changes were similar to those evoked with KCl. In freely behaving mice, DC-potential and multi-unit activity recordings combined with laser Doppler flowmetry revealed cortical spreading depression characteristics comparable to those under anesthesia, except for a shorter cortical spreading depression duration. Cortical spreading depression resulted in a short increase followed by prolonged reduction of spontaneous active behavior. Motor function, as assessed by wire grip tests, was transiently and unilaterally suppressed following a cortical spreading depression. Optogenetic cortical spreading depression induction has significant advantages over current models in that multiple cortical spreading depression events can be elicited in a non-invasive and cell type-selective fashion.
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http://dx.doi.org/10.1177/0271678X16645113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435281PMC
May 2017

Cortical Spreading Depression Causes Unique Dysregulation of Inflammatory Pathways in a Transgenic Mouse Model of Migraine.

Mol Neurobiol 2017 05 31;54(4):2986-2996. Epub 2016 Mar 31.

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Familial hemiplegic migraine type 1 (FHM1) is a rare monogenic subtype of migraine with aura caused by mutations in CACNA1A that encodes the α subunit of voltage-gated Ca2.1 calcium channels. Transgenic knock-in mice that carry the human FHM1 R192Q missense mutation ('FHM1 R192Q mice') exhibit an increased susceptibility to cortical spreading depression (CSD), the mechanism underlying migraine aura. Here, we analysed gene expression profiles from isolated cortical tissue of FHM1 R192Q mice 24 h after experimentally induced CSD in order to identify molecular pathways affected by CSD. Gene expression profiles were generated using deep serial analysis of gene expression sequencing. Our data reveal a signature of inflammatory signalling upon CSD in the cortex of both mutant and wild-type mice. However, only in the brains of FHM1 R192Q mice specific genes are up-regulated in response to CSD that are implicated in interferon-related inflammatory signalling. Our findings show that CSD modulates inflammatory processes in both wild-type and mutant brains, but that an additional unique inflammatory signature becomes expressed after CSD in a relevant mouse model of migraine.
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http://dx.doi.org/10.1007/s12035-015-9681-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390001PMC
May 2017

Funnel-freezing versus heat-stabilization for the visualization of metabolites by mass spectrometry imaging in a mouse stroke model.

Proteomics 2016 06 9;16(11-12):1652-9. Epub 2016 May 9.

Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.

Tissue preparation is the key to a successful matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) experiment. Rapid post-mortem changes contribute a significant challenge to the use of MSI approaches for the analysis of peptides and metabolites. In this technical note we aimed to compare the tissue fixation method ex-vivo heat-stabilization with in-situ funnel-freezing in a middle cerebral artery occlusion (MCAo) mouse model of stroke, which causes profound alterations in metabolite concentrations. The influence of the duration of the thaw-mounting of the tissue sections on metabolite stability was also determined. We demonstrate improved stability and biomolecule visualization when funnel-freezing was used to sacrifice the mouse compared with heat-stabilization. Results were further improved when funnel-freezing was combined with fast thaw-mounting of the brain sections.
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http://dx.doi.org/10.1002/pmic.201500402DOI Listing
June 2016

Mass spectrometry imaging of amino neurotransmitters: a comparison of derivatization methods and application in mouse brain tissue.

Metabolomics 2016;12:30. Epub 2016 Jan 8.

Center for Proteomics and Metabolomics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands ; Fondazione Pisana per la Scienza ONLUS, Pisa, Italy.

The detection of small polar compounds such as amino neurotransmitters by MALDI mass spectrometry imaging has been hindered by low-detection sensitivity and background interferences. Recently, several of on-tissue chemical derivatization strategies have been independently reported that enable their detection. Here, we present a comparison between these methods, and demonstrate the visualization of the distributions of up to 23 amino metabolites in tissue. We applied this methodology to detect alterations of these compounds after inducing an experimental cortical spreading depression in mouse brain, which causes profound transient alterations in key neurotransmitters in one hemisphere and is relevant for migraine and various other neurological disorders.
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http://dx.doi.org/10.1007/s11306-015-0926-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705126PMC
January 2016

Slowing Down of Recovery as Generic Risk Marker for Acute Severity Transitions in Chronic Diseases.

Crit Care Med 2016 Mar;44(3):601-6

1Department of Geriatrics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.2Integrative Ecology Group, Bascompte Lab, Consejo Superior de Investigaciones Científicas, Estación Biológica de Doñana, CSIC, Sevilla, Spain.3Emory Center for Critical Care, Woodruff Health Sciences Center, Emory University, Atlanta, GA.4Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, The Netherlands.5Department of Physiology, McGill University, Montreal, Quebec, Canada.6Department of Psychology, University of Amsterdam, Amsterdam, The Netherlands.7Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ.8Aquatic Ecology and Water Quality Management, Wageningen University, Wageningen, The Netherlands.9Scripps Institution of Oceanography, University Centre San Diego, San Diego, CA.10Department of Neurology and Leiden Center for Translational Neuroscience, Leiden University Medical Centre, Leiden, The Netherlands.11Department of Internal Medicine, Haga Hospital, Den Haag, The Netherlands.

Objective: We propose a novel paradigm to predict acute attacks and exacerbations in chronic episodic disorders such as asthma, cardiac arrhythmias, migraine, epilepsy, and depression. A better generic understanding of acute transitions in chronic dynamic diseases is increasingly important in critical care medicine because of the higher prevalence and incidence of these chronic diseases in our aging societies.

Data Sources: PubMed, Medline, and Web of Science.

Study Selection: We selected studies from biology and medicine providing evidence of slowing down after a perturbation as a warning signal for critical transitions.

Data Extraction: Recent work in ecology, climate, and systems biology has shown that slowing down of recovery upon perturbations can indicate loss of resilience across complex, nonlinear biologic systems that are approaching a tipping point. This observation is supported by the empiric studies in pathophysiology and controlled laboratory experiments with other living systems, which can flip from one state of clinical balance to a contrasting one. We discuss examples of such evidence in bodily functions such as blood pressure, heart rate, mood, and respiratory regulation when a tipping point for a transition is near.

Conclusions: We hypothesize that in a range of chronic episodic diseases, indicators of critical slowing down, such as rising variance and temporal correlation, may be used to assess the risk of attacks, exacerbations, and even mortality. Identification of such early warning signals over a range of diseases will enhance the understanding of why, how, and when attacks and exacerbations will strike and may thus improve disease management in critical care medicine.
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http://dx.doi.org/10.1097/CCM.0000000000001564DOI Listing
March 2016

Brain Region-Specific Dynamics of On-Tissue Protein Digestion Using MALDI Mass Spectrometry Imaging.

J Proteome Res 2015 Dec 13;14(12):5348-54. Epub 2015 Nov 13.

Center for Proteomics and Metabolomics, Leiden University Medical Center , Leiden 2333 ZA, The Netherlands.

In mass spectrometry imaging (MSI), on-tissue proteolytic digestion is performed to access larger protein species and to assign protein identities through matching the detected peaks with those obtained by LC-MS/MS analyses of tissue extracts. The on-tissue proteolytic digestion also allows the analysis of proteins from formalin-fixed, paraffin-embedded tissues. For these reasons, on-tissue digestion-based MSI is frequently used in clinical investigations, for example, to determine changes in protein content and distribution associated with a disease. In this work, we sought to investigate the completeness and uniformity of the digestion in on-tissue digestion MSI. On the basis of an extensive experiment investigating three groups with varying incubation times: (i) 1.5 h, (ii) 3 h, and (iii) 18 h, we have found that longer incubation times improve the repeatability of the analyses. Furthermore, we discovered morphology-associated differences in the completeness of the proteolysis for short incubation times. These results support the notion that a more complete proteolysis allows better quantitation.
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http://dx.doi.org/10.1021/acs.jproteome.5b00849DOI Listing
December 2015

Large-scale mass spectrometry imaging investigation of consequences of cortical spreading depression in a transgenic mouse model of migraine.

J Am Soc Mass Spectrom 2015 Jun 16;26(6):853-61. Epub 2015 Apr 16.

Center for Proteomics and Metabolomics, Leiden University Medical Center, Einthovenweg 20, 2333, ZC, Leiden, The Netherlands.

Cortical spreading depression (CSD) is the electrophysiological correlate of migraine aura. Transgenic mice carrying the R192Q missense mutation in the Cacna1a gene, which in patients causes familial hemiplegic migraine type 1 (FHM1), exhibit increased propensity to CSD. Herein, mass spectrometry imaging (MSI) was applied for the first time to an animal cohort of transgenic and wild type mice to study the biomolecular changes following CSD in the brain. Ninety-six coronal brain sections from 32 mice were analyzed by MALDI-MSI. All MSI datasets were registered to the Allen Brain Atlas reference atlas of the mouse brain so that the molecular signatures of distinct brain regions could be compared. A number of metabolites and peptides showed substantial changes in the brain associated with CSD. Among those, different mass spectral features showed significant (t-test, P < 0.05) changes in the cortex, 146 and 377 Da, and in the thalamus, 1820 and 1834 Da, of the CSD-affected hemisphere of FHM1 R192Q mice. Our findings reveal CSD- and genotype-specific molecular changes in the brain of FHM1 transgenic mice that may further our understanding about the role of CSD in migraine pathophysiology. The results also demonstrate the utility of aligning MSI datasets to a common reference atlas for large-scale MSI investigations.
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http://dx.doi.org/10.1007/s13361-015-1136-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422864PMC
June 2015

Plasma metabolic profiling after cortical spreading depression in a transgenic mouse model of hemiplegic migraine by capillary electrophoresis--mass spectrometry.

Mol Biosyst 2015 May;11(5):1462-71

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Migraine is a common brain disorder characterized by recurrent attacks of severe headaches and other neurological symptoms. In one-third of patients headaches are accompanied by auras, which consist of transient visual and sensory disturbances, believed to be caused by cortical spreading depression (CSD). CSD is characterized by a wave of neuronal and glial depolarization with concomitant changes in metabolite concentrations in the brain and cerebrospinal fluid. It remains unknown whether CSD-induced brain metabolic changes can be captured outside the central nervous system, i.e., in peripheral fluids. This study investigated plasma metabolic changes in transgenic mice that harbor a gene mutation in voltage-gated CaV2.1 Ca(2+) channels previously identified in patients with familial hemiplegic migraine, a subtype of migraine with auras. The use of a mouse model allows investigation of molecular changes occurring shortly after CSD, which is notoriously difficult in patients. Capillary electrophoresis - mass spectrometry was used for the analysis of plasma samples to obtain, for the first time, a comprehensive view of molecular changes immediately after experimentally induced CSD. Multivariate data analysis showed a clear distinction between profiles of transgenic and wild-type animals after CSD. Two metabolites considered important for this discrimination were tentatively identified as being lysine and its by-product pipecolic acid with additional evidence provided by hydrophilic interaction chromatography combined with tandem mass spectrometry. The changed metabolites suggest a compensatory increase in GABAergic neurotransmission upon enhanced excitatory neurotransmission. These results show that CSD induces metabolic remodeling in transgenic migraine mice that can be captured and measured in plasma.
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http://dx.doi.org/10.1039/c5mb00049aDOI Listing
May 2015

From migraine genes to mechanisms.

Pain 2015 Apr;156 Suppl 1:S64-S74

Departments of Neurology and Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands.

Migraine is a common multifactorial episodic brain disorder with strong genetic basis. Monogenic subtypes include rare familial hemiplegic migraine, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, familial advanced sleep-phase syndrome (FASPS), and retinal vasculopathy with cerebral leukodystrophy. Functional studies of disease-causing mutations in cellular and/or transgenic models revealed enhanced (glutamatergic) neurotransmission and abnormal vascular function as key migraine mechanisms. Common forms of migraine (both with and without an aura), instead, are thought to have a polygenic makeup. Genome-wide association studies have already identified over a dozen genes involved in neuronal and vascular mechanisms. Here, we review the current state of molecular genetic research in migraine, also with respect to functional and pathway analyses. We will also discuss how novel experimental approaches for the identification and functional characterization of migraine genes, such as next-generation sequencing, induced pluripotent stem cell, and optogenetic technologies will further our understanding of the molecular pathways involved in migraine pathogenesis.
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http://dx.doi.org/10.1097/01.j.pain.0000460346.00213.16DOI Listing
April 2015

Cerebellar output controls generalized spike-and-wave discharge occurrence.

Ann Neurol 2015 Jun;77(6):1027-49

Department of Neuroscience, Erasmus Medical Center, Rotterdam, the Netherlands.

Objective: Disrupting thalamocortical activity patterns has proven to be a promising approach to stop generalized spike-and-wave discharges (GSWDs) characteristic of absence seizures. Here, we investigated to what extent modulation of neuronal firing in cerebellar nuclei (CN), which are anatomically in an advantageous position to disrupt cortical oscillations through their innervation of a wide variety of thalamic nuclei, is effective in controlling absence seizures.

Methods: Two unrelated mouse models of generalized absence seizures were used: the natural mutant tottering, which is characterized by a missense mutation in Cacna1a, and inbred C3H/HeOuJ. While simultaneously recording single CN neuron activity and electrocorticogram in awake animals, we investigated to what extent pharmacologically increased or decreased CN neuron activity could modulate GSWD occurrence as well as short-lasting, on-demand CN stimulation could disrupt epileptic seizures.

Results: We found that a subset of CN neurons show phase-locked oscillatory firing during GSWDs and that manipulating this activity modulates GSWD occurrence. Inhibiting CN neuron action potential firing by local application of the γ-aminobutyric acid type A (GABA-A) agonist muscimol increased GSWD occurrence up to 37-fold, whereas increasing the frequency and regularity of CN neuron firing with the use of GABA-A antagonist gabazine decimated its occurrence. A single short-lasting (30-300 milliseconds) optogenetic stimulation of CN neuron activity abruptly stopped GSWDs, even when applied unilaterally. Using a closed-loop system, GSWDs were detected and stopped within 500 milliseconds.

Interpretation: CN neurons are potent modulators of pathological oscillations in thalamocortical network activity during absence seizures, and their potential therapeutic benefit for controlling other types of generalized epilepsies should be evaluated.
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http://dx.doi.org/10.1002/ana.24399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008217PMC
June 2015

Comprehensive analysis of the mouse brain proteome sampled in mass spectrometry imaging.

Anal Chem 2015 Feb 13;87(3):1867-75. Epub 2015 Jan 13.

Center for Proteomics and Metabolomics, Leiden University Medical Center , Leiden, 2333ZA The Netherlands.

On-tissue enzymatic digestion is performed in mass spectrometry imaging (MSI) experiments to access larger proteins and to assign protein identities. Most on-tissue digestion MSI studies have focused on method development rather than identifying the molecular features observed. Herein, we report a comprehensive study of the mouse brain proteome sampled by MSI. Using complementary proteases, we were able to identify 5337 peptides in the matrix-assisted laser desorption/ionization (MALDI) matrix, corresponding to 1198 proteins. 630 of these peptides, corresponding to 280 proteins, could be assigned to peaks in MSI data sets. Gene ontology and pathway analyses revealed that many of the proteins are involved in neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's disease.
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http://dx.doi.org/10.1021/ac503952qDOI Listing
February 2015

Stress hormone corticosterone enhances susceptibility to cortical spreading depression in familial hemiplegic migraine type 1 mutant mice.

Exp Neurol 2015 Jan 29;263:214-20. Epub 2014 Oct 29.

Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address:

Stress is a putative migraine trigger, but the pathogenic mechanisms involved are unknown. Stress and stress hormones increase neuronal excitability by enhancing glutamatergic neurotransmission, but inhibitory effects have also been reported. We hypothesise that an acute rise in stress hormones, such as corticosteroids which are released after stress, increase neuronal excitability and thereby may increase susceptibility to cortical spreading depression (CSD), the mechanism underlying the migraine aura. Here we investigated effects of acute restraint stress and of the stress hormone corticosterone on CSD susceptibility as surrogate migraine marker, in a transgenic mouse model of familial hemiplegic migraine type 1 (FHM1), which displays increased glutamatergic cortical neurotransmission and increased propensity for CSD. We found that 20-min and 3-h restraint stress did not influence CSD susceptibility in mutant or wild-type mice, despite elevated levels of plasma corticosterone. By contrast, subcutaneous administration of 20mg/kg corticosterone increased CSD frequency exclusively in mutant mice, while corticosterone plasma levels were similarly elevated in mutants and wild types. The effect of corticosterone on CSD frequency was normalised by pre-administration of the glucocorticoid receptor (GR) antagonist mifepristone. These findings suggest that corticosteroid-induced GR activation can enhance susceptibility to CSD in genetically susceptible individuals, and may predispose to attacks of migraine. Although corticosterone levels rise also during acute stress, the latter likely triggers a spatiotemporally more complex biological response with multiple positive and negative modulators which may not be adequately modeled by exogenous administration of corticosterone alone.
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http://dx.doi.org/10.1016/j.expneurol.2014.10.015DOI Listing
January 2015
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