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1.
Proc Natl Acad Sci U S A ; 121(14): e2309000121, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38547067

RESUMO

Apneic events are frightening but largely benign events that often occur in infants. Here, we report apparent life-threatening apneic events in an infant with the homozygous SCN1AL263V missense mutation, which causes familial hemiplegic migraine type 3 in heterozygous family members, in the absence of epilepsy. Observations consistent with the events in the infant were made in an Scn1aL263V knock-in mouse model, in which apnea was preceded by a large brainstem DC-shift, indicative of profound brainstem depolarization. The L263V mutation caused gain of NaV1.1 function effects in transfected HEK293 cells. Sodium channel blockade mitigated the gain-of-function characteristics, rescued lethal apnea in Scn1aL263V mice, and decreased the frequency of severe apneic events in the patient. Hence, this study shows that SCN1AL263V can cause life-threatening apneic events, which in a mouse model were caused by profound brainstem depolarization. In addition to being potentially relevant to sudden infant death syndrome pathophysiology, these data indicate that sodium channel blockers may be considered therapeutic for apneic events in patients with these and other gain-of-function SCN1A mutations.


Assuntos
Apneia , Mutação com Ganho de Função , Bloqueadores dos Canais de Sódio , Animais , Humanos , Camundongos , Apneia/tratamento farmacológico , Apneia/genética , Tronco Encefálico , Células HEK293 , Enxaqueca com Aura/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Bloqueadores dos Canais de Sódio/uso terapêutico , Lactente , Feminino
2.
Neurobiol Dis ; 192: 106405, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38211710

RESUMO

Mechanisms underlying the migraine aura are incompletely understood, which to large extent is related to a lack of models in which cortical spreading depolarization (CSD), the correlate of the aura, occurs spontaneously. Here, we investigated electrophysiological and behavioural CSD features in freely behaving mice expressing mutant CaV2.1 Ca2+ channels, either with the milder R192Q or the severer S218L missense mutation in the α1 subunit, known to cause familial hemiplegic migraine type 1 (FHM1) in patients. Very rarely, spontaneous CSDs were observed in mutant but never in wildtype mice. In homozygous Cacna1aR192Q mice exclusively single-wave CSDs were observed whereas heterozygous Cacna1aS218L mice displayed multiple-wave events, seemingly in line with the more severe clinical phenotype associated with the S218L mutation. Spontaneous CSDs were associated with body stretching, one-directional slow head turning, and rotating movement of the body. Spontaneous CSD events were compared with those induced in a controlled manner using minimally invasive optogenetics. Also in the optogenetic experiments single-wave CSDs were observed in Cacna1aR192Q and Cacna1aS218L mice (whereas the latter also showed multiple-wave events) with movements similar to those observed with spontaneous events. Compared to wildtype mice, FHM1 mutant mice exhibited a reduced threshold and an increased propagation speed for optogenetically induced CSD with a more profound CSD-associated dysfunction, as indicated by a prolonged suppression of transcallosal evoked potentials and a reduction of unilateral forepaw grip performance. When induced during sleep, the optogenetic CSD threshold was particularly lowered, which may explain why spontaneous CSD events predominantly occurred during sleep. In conclusion, our data show that key neurophysiological and behavioural features of optogenetically induced CSDs mimic those of rare spontaneous events in FHM1 R192Q and S218L mutant mice with differences in severity in line with FHM1 clinical phenotypes seen with these mutations.


Assuntos
Ataxia Cerebelar , Depressão Alastrante da Atividade Elétrica Cortical , Epilepsia , Transtornos de Enxaqueca , Enxaqueca com Aura , Humanos , Camundongos , Animais , Enxaqueca com Aura/genética , Camundongos Transgênicos , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Transtornos de Enxaqueca/genética , Potenciais Evocados
3.
J Headache Pain ; 24(1): 96, 2023 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-37495957

RESUMO

BACKGROUND: Cortical spreading depolarization (CSD), the neurophysiological correlate of the migraine aura, can activate trigeminal pain pathways, but the neurobiological mechanisms and behavioural consequences remain unclear. Here we investigated effects of optogenetically-induced CSDs on headache-related behaviour and neuroinflammatory responses in transgenic mice carrying a familial hemiplegic migraine type 1 (FHM1) mutation. METHODS: CSD events (3 in total) were evoked in a minimally invasive manner by optogenetic stimulation through the intact skull in freely behaving wildtype (WT) and FHM1 mutant mice. Related behaviours were analysed using mouse grimace scale (MGS) scoring, head grooming, and nest building behaviour. Neuroinflammatory changes were investigated by assessing HMGB1 release with immunohistochemistry and by pre-treating mice with a selective Pannexin-1 channel inhibitor. RESULTS: In both WT and FHM1 mutant mice, CSDs induced headache-related behaviour, as evidenced by increased MGS scores and the occurrence of oculotemporal strokes, at 30 min. Mice of both genotypes also showed decreased nest building behaviour after CSD. Whereas in WT mice MGS scores had normalized at 24 h after CSD, in FHM1 mutant mice scores were normalized only at 48 h. Of note, oculotemporal stroke behaviour already normalized 5 h after CSD, whereas nest building behaviour remained impaired at 72 h; no genotype differences were observed for either readout. Nuclear HMGB1 release in the cortex of FHM1 mutant mice, at 30 min after CSD, was increased bilaterally in both WT and FHM1 mutant mice, albeit that contralateral release was more pronounced in the mutant mice. Only in FHM1 mutant mice, contralateral release remained higher at 24 h after CSD, but at 48 h had returned to abnormal, elevated, baseline values, when compared to WT mice. Blocking Panx1 channels by TAT-Panx308 inhibited CSD-induced headache related behaviour and HMGB1 release. CONCLUSIONS: CSDs, induced in a minimally invasive manner by optogenetics, investigated in freely behaving mice, cause various migraine relevant behavioural and neuroinflammatory phenotypes that are more pronounced and longer-lasting in FHM1 mutant compared to WT mice. Prevention of CSD-related neuroinflammatory changes may have therapeutic potential in the treatment of migraine.


Assuntos
Depressão Alastrante da Atividade Elétrica Cortical , Proteína HMGB1 , Transtornos de Enxaqueca , Enxaqueca com Aura , Camundongos , Animais , Enxaqueca com Aura/genética , Enxaqueca com Aura/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/farmacologia , Optogenética , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Modelos Animais de Doenças , Transtornos de Enxaqueca/genética , Camundongos Transgênicos , Cefaleia , Inflamação , Proteínas do Tecido Nervoso/genética , Conexinas/genética , Conexinas/farmacologia
4.
Brain Topogr ; 36(2): 269-281, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36781512

RESUMO

Migraine is associated with altered sensory processing, that may be evident as changes in cortical responsivity due to altered excitability, especially in migraine with aura. Cortical excitability can be directly assessed by combining transcranial magnetic stimulation with electroencephalography (TMS-EEG). We measured TMS evoked potential (TEP) amplitude and response consistency as these measures have been linked to cortical excitability but were not yet reported in migraine.We recorded 64-channel EEG during single-pulse TMS on the vertex interictally in 10 people with migraine with aura and 10 healthy controls matched for age, sex and resting motor threshold. On average 160 pulses around resting motor threshold were delivered through a circular coil in clockwise and counterclockwise direction. Trial-averaged TEP responses, frequency spectra and phase clustering (over the entire scalp as well as in frontal, central and occipital midline electrode clusters) were compared between groups, including comparison to sham-stimulation evoked responses.Migraine and control groups had a similar distribution of TEP waveforms over the scalp. In migraine with aura, TEP responses showed reduced amplitude around the frontal and occipital N100 peaks. For the migraine and control groups, responses over the scalp were affected by current direction for the primary motor cortex, somatosensory cortex and sensory association areas, but not for frontal, central or occipital midline clusters.This study provides evidence of altered TEP responses in-between attacks in migraine with aura. Decreased TEP responses around the N100 peak may be indicative of reduced cortical GABA-mediated inhibition and expand observations on enhanced cortical excitability from earlier migraine studies using more indirect measurements.


Assuntos
Excitabilidade Cortical , Transtornos de Enxaqueca , Enxaqueca com Aura , Humanos , Potencial Evocado Motor/fisiologia , Potenciais Evocados , Eletroencefalografia , Estimulação Magnética Transcraniana
5.
Front Neurol ; 14: 1274059, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38348113

RESUMO

Introduction: Migraine is associated with enhanced visual sensitivity during and outside attacks. Processing of visual information is a highly non-linear process involving complex interactions across (sub)cortical networks. In this exploratory study, we combined electroencephalography with bi-sinusoidal light stimulation to assess non-linear features of visual processing in participants with migraine. Methods: Twenty participants with migraine (10 with aura, 10 without aura) and ten non-headache controls were measured (outside attacks). Participants received bi-sinusoidal 13 + 23 Hz red light visual stimulation. Electroencephalography spectral power and multi-spectral phase coherence were compared between groups at the driving stimulation frequencies together with multiples and combinations of these frequencies (harmonic and intermodulation frequencies) caused by non-linearities. Results: Only at the driving frequency of 13 Hz higher spectral power was found in migraine with aura participants compared with those with migraine without aura and controls. Differences in phase coherence were present for 2nd, 4th, and 5th-order non-linearities in those with migraine (migraine with and without aura) compared with controls. Bi-sinusoidal light stimulation revealed evident non-linearities in the brain's electroencephalography response up to the 5th order with reduced phase coherence for higher order interactions in interictal participants with migraine. Discussion: Insight into interictal non-linear visual processing may help understand brain dynamics underlying migraine attack susceptibility. Future research is needed to determine the clinical value of the results.

6.
Neuroinformatics ; 20(4): 1077-1092, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35680724

RESUMO

Functional assessment of in vitro neuronal networks-of relevance for disease modelling and drug testing-can be performed using multi-electrode array (MEA) technology. However, the handling and processing of the large amount of data typically generated in MEA experiments remains a huge hurdle for researchers. Various software packages have been developed to tackle this issue, but to date, most are either not accessible through the links provided by the authors or only tackle parts of the analysis. Here, we present ''MEA-ToolBox'', a free open-source general MEA analytical toolbox that uses a variety of literature-based algorithms to process the data, detect spikes from raw recordings, and extract information at both the single-channel and array-wide network level. MEA-ToolBox extracts information about spike trains, burst-related analysis and connectivity metrics without the need of manual intervention. MEA-ToolBox is tailored for comparing different sets of measurements and will analyze data from multiple recorded files placed in the same folder sequentially, thus considerably streamlining the analysis pipeline. MEA-ToolBox is available with a graphic user interface (GUI) thus eliminating the need for any coding expertise while offering functionality to inspect, explore and post-process the data. As proof-of-concept, MEA-ToolBox was tested on earlier-published MEA recordings from neuronal networks derived from human induced pluripotent stem cells (hiPSCs) obtained from healthy subjects and patients with neurodevelopmental disorders. Neuronal networks derived from patient's hiPSCs showed a clear phenotype compared to those from healthy subjects, demonstrating that the toolbox could extract useful parameters and assess differences between normal and diseased profiles.


Assuntos
Células-Tronco Pluripotentes Induzidas , Humanos , Potenciais de Ação/fisiologia , Microeletrodos , Neurônios/fisiologia , Algoritmos
7.
Metabolites ; 12(3)2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35323663

RESUMO

Metabolite levels in peripheral body fluids can correlate with attack features in migraine patients, which underscores the potential of plasma metabolites as possible disease biomarkers. Migraine headache can be preceded by an aura that is caused by cortical spreading depolarization (CSD), a transient wave of neuroglial depolarization. We previously identified plasma amino acid changes after CSD in familial hemiplegic migraine type 1 (FHM1) mutant mice that exhibit increased neuronal excitability and various migraine-related features. Here, we aimed to uncover lipid metabolic pathways affected by CSD, guided by findings on the involvement of lipids in hemiplegic migraine pathophysiology. Using targeted lipidomic analysis, we studied plasma lipid metabolite levels at different time points after CSD in wild-type and FHM1 mutant mice. Following CSD, the most prominent plasma lipid change concerned a transient increase in PGD2, which lasted longer in mutant mice. In wild-type mice only, levels of anti-inflammatory lipid mediators DPAn-3, EPA, ALA, and DHA were elevated 24 h following CSD compared to Sham-treated animals. Given the role of PGs and neuroinflammation in migraine pathophysiology, our findings underscore the potential of monitoring peripheral changes in lipids to gain insight in central brain mechanisms.

8.
Ann Clin Transl Neurol ; 9(4): 540-551, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35297209

RESUMO

INTRODUCTION: The lack of reliable biomarkers constrain epilepsy management. We assessed the potential of repeated transcranial magnetic stimulation with electromyography (TMS-EMG) to track dynamical changes in cortical excitability on a within-subject basis. METHODS: We recruited people with refractory focal epilepsy who underwent video-EEG monitoring and drug tapering as part of the presurgical evaluation. We performed daily TMS-EMG measurements with additional postictal assessments 1-6 h following seizures to assess resting motor threshold (rMT), and motor evoked potentials (MEPs) with single- and paired-pulse protocols. Anti-seizure medication (ASM) regimens were recorded for the day before each measurement and expressed in proportion to the dosage before tapering. Additional measurements were performed in healthy controls to evaluate day-to-day rMT variability. RESULTS: We performed 77 (58 baseline, 19 postictal) measurements in 16 people with focal epilepsy and 35 in seven healthy controls. Controls showed minimal day-to-day rMT variation. Withdrawal of ASMs was associated with a lower rMT without affecting MEPs of single- and paired-pulse TMS-EMG paradigms. Postictal measurements following focal to bilateral tonic-clonic seizures demonstrated unaltered rMT and increased short interval intracortical inhibition, while measurements following focal seizures with impaired awareness showed decreased rMT's and reduced short and long interval intracortical inhibition. CONCLUSION: Serial within-subject rMT measurements yielded reproducible, stable results in healthy controls. ASM tapering and seizures had distinct effects on TMS-EMG excitability indices in people with epilepsy. Drug tapering decreased rMT, indicating increased overall corticospinal excitability, whereas seizures affected intracortical inhibition with contrasting effects between seizure types.


Assuntos
Excitabilidade Cortical , Epilepsias Parciais , Epilepsia , Córtex Motor , Humanos , Convulsões , Estimulação Magnética Transcraniana/métodos
9.
Neuroimage ; 245: 118757, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34838751

RESUMO

The mouse is widely used as an experimental model to study visual processing. To probe how the visual system detects changes in the environment, functional paradigms in freely behaving mice are strongly needed. We developed and validated the first EEG-based method to investigate visual deviance detection in freely behaving mice. Mice with EEG implants were exposed to a visual deviant detection paradigm that involved changes in light intensity as standard and deviant stimuli. By subtracting the standard from the deviant evoked waveform, deviant detection was evident as bi-phasic negativity (starting around 70 ms) in the difference waveform. Additionally, deviance-associated evoked (beta/gamma) and induced (gamma) oscillatory responses were found. We showed that the results were stimulus-independent by applying a "flip-flop" design and the results showed good repeatability in an independent measurement. Together, we put forward a validated, easy-to-use paradigm to measure visual deviance processing in freely behaving mice.


Assuntos
Eletroencefalografia , Percepção Visual/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estimulação Luminosa , Reprodutibilidade dos Testes
10.
Nat Rev Neurol ; 17(9): 529-544, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34312533

RESUMO

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.


Assuntos
Epilepsia/epidemiologia , Epilepsia/fisiopatologia , Transtornos de Enxaqueca/epidemiologia , Transtornos de Enxaqueca/fisiopatologia , Comorbidade , Eletroencefalografia/tendências , Epilepsia/genética , Cefaleia/epidemiologia , Cefaleia/genética , Cefaleia/fisiopatologia , Humanos , Transtornos de Enxaqueca/genética , Mutação de Sentido Incorreto/genética
11.
Neurobiol Dis ; 156: 105424, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34118418

RESUMO

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.


Assuntos
Encéfalo/metabolismo , Ataxia Cerebelar/metabolismo , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Proteína HMGB1/metabolismo , Transtornos de Enxaqueca/metabolismo , NF-kappa B/metabolismo , Tecido Parenquimatoso/metabolismo , Animais , Astrócitos/metabolismo , Encéfalo/fisiopatologia , Ataxia Cerebelar/genética , Ataxia Cerebelar/fisiopatologia , Feminino , Proteína HMGB1/genética , Humanos , Camundongos , Camundongos Transgênicos , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/fisiopatologia , NF-kappa B/genética , Tecido Parenquimatoso/fisiopatologia
12.
Brain Stimul ; 14(4): 861-872, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34022430

RESUMO

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.


Assuntos
Núcleos Cerebelares , Epilepsia Tipo Ausência , Animais , Córtex Cerebral , Epilepsia Tipo Ausência/genética , Camundongos , Neurônios , Núcleos Talâmicos , Tálamo
13.
J Neurosci ; 41(3): 524-537, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33234612

RESUMO

Dravet syndrome (DS) is an epileptic encephalopathy that still lacks biomarkers for epileptogenesis and its treatment. Dysfunction of NaV1.1 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 NaV1.1 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.


Assuntos
Epilepsias Mioclônicas/fisiopatologia , Epilepsia/fisiopatologia , Ritmo Gama , Convulsões/fisiopatologia , Ritmo Teta , Animais , Anticonvulsivantes/uso terapêutico , Biomarcadores , Canabidiol/uso terapêutico , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Simulação por Computador , Eletroencefalografia , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsia/tratamento farmacológico , Feminino , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Interneurônios/metabolismo , Masculino , Camundongos , Camundongos Knockout , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Convulsões/tratamento farmacológico
14.
Eur J Neurosci ; 53(5): 1672-1686, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33170971

RESUMO

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 α1A subunit of voltage-gated CaV 2.1 Ca2+ 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.


Assuntos
Enxaqueca com Aura , Animais , Canais de Cálcio Tipo N , Modelos Animais de Doenças , Potenciais Evocados Visuais , Humanos , Camundongos , Camundongos Transgênicos
15.
Epilepsia ; 61(4): e30-e36, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32190912

RESUMO

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 NaV 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 NaV 1.1 channels decreased the threshold for hyperthermia-induced seizures. However, the effect of ablation of NaV 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 NaV 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 NaV 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.


Assuntos
Córtex Cerebral/fisiopatologia , Hipocampo/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Convulsões/genética , Convulsões/fisiopatologia , Animais , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
16.
Cephalalgia ; 40(9): 913-923, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32188264

RESUMO

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 (p = 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.


Assuntos
Córtex Cerebral/fisiopatologia , Potenciais Evocados Visuais/fisiologia , Transtornos de Enxaqueca/fisiopatologia , Adulto , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa
17.
Ann Clin Transl Neurol ; 7(1): 132-138, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31880072

RESUMO

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 NaV 1.1 sodium channels (Scn1aL263V ). 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.


Assuntos
Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Transtornos de Enxaqueca/fisiopatologia , Córtex Motor/fisiopatologia , Córtex Visual/fisiopatologia , Animais , Modelos Animais de Doenças , Eletroencefalografia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Canal de Sódio Disparado por Voltagem NAV1.1/genética
18.
Headache ; 60(2): 396-404, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31876298

RESUMO

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.


Assuntos
Modelos Animais de Doenças , Gastroenteropatias , Motilidade Gastrointestinal , Transtornos de Enxaqueca , Animais , Feminino , Gastroenteropatias/etiologia , Masculino , Camundongos , Camundongos Transgênicos , Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/genética
19.
J Neurosci ; 39(48): 9633-9644, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31628185

RESUMO

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 CaV2.1 Ca2+ 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 vice versa 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.SIGNIFICANCE STATEMENT 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.


Assuntos
Apneia/genética , Tronco Encefálico/fisiologia , Canais de Cálcio Tipo N/genética , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Bulbo/fisiologia , Convulsões/genética , Animais , Apneia/tratamento farmacológico , Apneia/fisiopatologia , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/fisiopatologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Masculino , Bulbo/efeitos dos fármacos , Bulbo/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação de Sentido Incorreto/fisiologia , Convulsões/tratamento farmacológico , Convulsões/fisiopatologia
20.
Lab Chip ; 19(8): 1332-1343, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30869670

RESUMO

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.


Assuntos
Dispositivos Lab-On-A-Chip , Neurotransmissores/metabolismo , Animais , Desenho de Equipamento , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenômenos Ópticos
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