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,... Show moreMigraine 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 alpha(1A) subunit of voltage-gated Ca(V)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. Show less
Perenboom, M.J.L.; Ruit, M. van de; Zielman, R.; Maagdenberg, A.M.J.M. van den; Ferrari, M.D.; Carpay, J.A.; Tolner, E.A. 2020
BackgroundMigraine is associated with altered sensory processing and cortical responsivity that may contribute to susceptibility to attacks by changing brain network excitability dynamics. To gain... Show moreBackgroundMigraine 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.MethodsEEG 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.ResultsResponses 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.ConclusionsWe 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. Show less
Familial hemiplegic migraine type 1 (FHM1) is a rare monogenic subtype of migraine with aura caused by mutations in CACNA1A that encodes the alpha(1A) subunit of voltage-gated Ca(V)2.1 calcium... Show moreFamilial hemiplegic migraine type 1 (FHM1) is a rare monogenic subtype of migraine with aura caused by mutations in CACNA1A that encodes the alpha(1A) subunit of voltage-gated Ca(V)2.1 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. Show less
Shyti, R.; Kohler, I.; Schoenmaker, B.; Derks, R.J.E.; Ferrari, M.D.; Tolner, E.A.; ... ; Maagdenberg, A.M.J.M. van den 2015
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... Show moreMigraine 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. Show less
Tolner, E.A.; Houben, T.; Terwindt, G.M.; Vries, B. de; Ferrari, M.D.; Maagdenberg, A.M.J.M. van den 2015
