Propagation Of Spreading Depression Research Articles

A computational study on the role of glutamate and NMDA receptors on cortical spreading depression using a multidomain electrodiffusion model.

Cortical spreading depression (SD) is a spreading disruption of ionic homeostasis in the brain during which neurons experience complete and prolonged depolarizations. SD is the basis of migraine aura and is increasingly associated with many other brain pathologies. Here, we study the role of glutamate and NMDA receptor dynamics in the context of an ionic electrodiffusion model. We perform simulations in one (1D) and two (2D) spatial dimension. Our 1D simulations reproduce the "inverted saddle" shape of the extracellular voltage signal for the first time. Our simulations suggest that SD propagation depends on two overlapping mechanisms; one dependent on extracellular glutamate diffusion and NMDA receptors and the other dependent on extracellular potassium diffusion and persistent sodium channel conductance. In 2D simulations, we study the dynamics of spiral waves. We study the properties of the spiral waves in relation to the planar 1D wave, and also compute the energy expenditure associated with the recurrent SD spirals.

In Vivo Monitoring of Oxygen Fluctuation Simultaneously at Multiple Sites of Rat Cortex during Spreading Depression

Spreading depression (SD) is a common pathological process in the brain shown as propagating neuronal depolarization followed by activity depression over the brain, and it is closely related to migraines and epilepsy. Although O2 is known to fluctuate during SD, the difference of O2 responses at different sites in the same brain region remains unknown. In this study, we develop an in vivo electrochemical method with microelectrode arrays (MEAs) to monitor, in real time, O2 fluctuation at multiple sites of rat cortex during SD with high spatial/temporal resolution. Platinum nanoparticles are electrochemically deposited on the multiplexed electrodes of the MEAs to monitor O2 fluctuation simultaneously and selectively via a four-electron reduction process. Configuration of electrode arrays is designed rationally to exclude the probable crosstalk between neighbor recording electrodes during simultaneous measurements. With the MEAs, we find both the basal O2 levels and O2 fluctuations at different sites of the cortex during SD exhibit significant differences, indicating the intensity of energy metabolism and oxidative stress vary at different sites even in the same brain region. Further studies prove that O2 fluctuation is mostly caused by the increase of brain blood flow and the consumption of neuronal O2 during SD. Our study reveals that energy metabolism varies at different sites in brain cortex during SD propagation, which may provide new understanding for SD-related pathological processes.

Control of Spreading Depression with Electrical Fields

Spreading depression or depolarization is a large-scale pathological brain phenomenon related to migraine, stroke, hemorrhage and traumatic brain injury. Once initiated, spreading depression propagates across gray matter extruding potassium and other active molecules, collapsing the resting membrane electro-chemical gradient of cells leading to spike inactivation and cellular swelling, and propagates independently of synaptic transmission. We demonstrate the modulation, suppression and prevention of spreading depression utilizing applied transcortical DC electric fields in brain slices, measured with intrinsic optical imaging and potassium dye epifluorescence. We experimentally observe a surface-positive electric field induced forcing of spreading depression propagation to locations in cortex deeper than the unmodulated propagation path, whereby further propagation is confined and arrested even after field termination. The opposite surface-negative electric field polarity produces an increase in propagation velocity and a confinement of the wave to more superficial layers of cortex than the unmodulated propagation path. These field polarities are of opposite sign to the polarity that blocks neuronal spiking and seizures, and are consistent with biophysical models of spreading depression. The results demonstrate the potential feasibility of electrical control and prevention of spreading depression.

Physical exercise counteracts the increase in velocity of propagation of cortical spreading depression imposed by early over-nutrition in rats

Objectives: This investigation studied whether physical exercise could modulate cortical spreading depression (CSD) propagation velocity in adult rat offspring from dams that had received a high-fat (HF) diet during lactation. Methods: Wistar male rats suckled by dams fed either control (C) or HF diet ad libitum. After weaning, pups received standard laboratory chow. From 40 to 60 days of life, half of the animals exercised on a treadmill (group E); the other half remained sedentary (group S). Two additional HF groups (E and S) received fluoxetine (F; 10 mg/kg/day, orogastrically) from 40 to 60 days of life (groups HF/EF and HF/F). Results: At 40 days of life, rats from the maternal HF diet presented higher weight, thoracic circumference, and Lee Index than C animals and remained heavier at 60 days of life. Physical exercise decreased abdominal circumference. HF diet increased CSD propagation velocity (mean ± SD; mm/min) in sedentaries (HF/S 3.47 ± 0.31 versus C/S 3.24 ± 0.26). Treadmill exercise decelerated CSD propagation in both groups C/E (2.94 ± 0.28) and HF/E (2.97 ± 0.40). Fluoxetine alone decreased CSD propagation (HF/F 2.88 ± 0.45) compared with HF/S group. The combination of fluoxetine + exercise under HF condition (2.98 ± 0.27) was similar to HF/E group. Discussion: Physical exercise is able to reduce CSD propagation velocity in rat adult brains even when they have suffered over-nourishing during lactation. The effects of exercise alone or fluoxetine alone on CSD were similar to the effects of fluoxetine + exercise, under the HF condition. Data reinforce malnutrition during lactation modifies cortical electrophysiology even when the HF condition no longer exists.

Evidence of an inverse correlation between serotonergic activity and spreading depression propagation in the rat cortex

Various neurological and psychiatric diseases lead to alterations in cortical serotonergic activity as one of their underlying processes. However, the electrophysiological implication of changes in serotonergic activity remains a matter of investigation. In this study, we investigated whether brain serotonergic activity influences the excitability-related phenomenon known as cortical spreading depression (CSD). CSD parameters (propagation velocity, and amplitude and duration of the DC-shift) was evaluated in rats that received two treatments that increased cortical serotonergic activity, electrical stimulation of the raphe nuclei and subcutaneous injection of a selective serotonin reuptake inhibitor, sumatriptan. A third group of rats was tested on a low-tryptophan diet rat model of serotonin depletion. Control rats for these three groups received, respectively, sham raphe stimulation, saline injection, and a tryptophan-supplemented diet. Compared to controls, electrical stimulation of the raphe nuclei and sumatriptan administration decelerated CSD and increased the duration of the negative DC-shift of CSD, whereas the low-tryptophan diet was associated with significantly accelerated CSD propagation and shortened DC-shift of CSD (p<0.05). We concluded that serotonergic neurons are very important for stabilizing the delicate equilibrium between excitatory and inhibitory neuronal influences that determines cortical excitability and CSD propagation. Our pharmacological, electrophysiological and dietary data suggest that cortical serotonergic activity negatively modulates CSD propagation in the rat cortex. Reduced central serotonergic activity, as can be observed in several neurological and psychiatric diseases, may constitute a pathological factor for increased sensitivity to CSD.

A computational multiscale model of cortical spreading depression propagation

Cortical Spreading Depression (CSD) is a disruption of the brain homeostasis that, originating in the visual cortex and traveling towards the frontal lobe, temporarily impairs the normal functioning of neurons. Although, as of today, little is known about the mechanisms that can trigger or stop such phenomenon, CSD is commonly accepted as a correlate of migraine visual aura. In this paper, we introduce a multiscale PDE-ODE model that couples the propagation of the depolarization wave associated to CSD with a detailed electrophysiological model for the neuronal activity to capture both macroscopic and microscopic dynamics.

In vivo imaging reveals that pregabalin inhibits cortical spreading depression and propagation to subcortical brain structures

Migraine is characterized by severe headaches that can be preceded by an aura likely caused by cortical spreading depression (SD). The antiepileptic pregabalin (Lyrica) shows clinical promise for migraine therapy, although its efficacy and mechanism of action are unclear. As detected by diffusion-weighted MRI (DW-MRI) in wild-type (WT) mice, the acute systemic administration of pregabalin increased the threshold for SD initiation in vivo. In familial hemiplegic migraine type 1 mutant mice expressing human mutations (R192Q and S218L) in the CaV2.1 (P/Q-type) calcium channel subunit, pregabalin slowed the speed of SD propagation in vivo. Acute systemic administration of pregabalin in vivo also selectively prevented the migration of SD into subcortical striatal and hippocampal regions in the R192Q strain that exhibits a milder phenotype and gain of CaV2.1 channel function. At the cellular level, pregabalin inhibited glutamatergic synaptic transmission differentially in WT, R192Q, and S218L mice. The study describes a DW-MRI analysis method for tracking the progression of SD and provides support and a mechanism of action for pregabalin as a possible effective therapy in the treatment of migraine.

Effects of Glia in a Triphasic Continuum Model of Cortical Spreading Depression

Cortical spreading depression (SD) is a spreading disruption in brain ionic homeostasis during which neurons experience complete and prolonged depolarizations. SD is generally believed to be the physiological substrate of migraine aura and is associated with many other brain pathologies. Here, we perform simulations with a model of SD treating brain tissue as a triphasic continuum of neurons, glia and the extracellular space. A thermodynamically consistent incorporation of the major biophysical effects, including ionic electrodiffusion and osmotic water flow, allows for the computation of important physiological variables including the extracellular voltage (DC) shift. A systematic parameter study reveals that glia can act as both a disperser and buffer of potassium in SD propagation. Furthermore, we show that the timing of the DC shift with respect to extracellular [Formula: see text] rise is highly dependent on glial parameters, a result with implications for the identification of the propagating mechanism of SD.

Modulation of the glial response via the platelet-derived growth factor receptors (PDGFR) on the diencephalic dopaminergic neurons in zebrafish larvae

s / Parkinsonism and Related Disorders 22 (2016) e149ee192 e180 P 6.017. MODULATION OF THE GLIAL RESPONSE VIA THE PLATELET-DERIVED GROWTH FACTOR RECEPTORS (PDGFR) ON THE DIENCEPHALIC DOPAMINERGIC NEURONS IN ZEBRAFISH LARVAE Anwar Norazit, David Wong, Nadia Abdul Halim, Suzita Mohd Noor. Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia Objectives: Activated astrocytes express PDGF receptors on their surface. PDGF may have a role in modulating the expression of astrocytes to act as neuroprotectors on the dopaminergic neurons. Methods: Zebrafish larvae were treated with either 0.1% DMSO (vehicle control), Imatinib (PDGFR inhibitor), 0.1 mg/ml MPTP (dopaminergic neurotoxin), or a combination of Imatinib and MPTP at 4 dpf. Solutions were refreshed daily and larvae were maintained till 7 dpf. Behavioural analyses was conducted to measure response to tail touch and posture before and after tail touch. The presence of spinal curvature was also observed. RT-PCR was done to determine the expression levels of th (dopaminergic neurons) and gfap (astrocytes). Results: Behaviour analyses revealed marked slow responses in larvae treated with MPTP, Imatinib and Imatinib in combination with MPTP. Furthermore, a significant (p<0.05) number of Imatinib-treated larvae and larvae treated in combination with Imatinib and MPTP exhibited spinal curvatures compared to other treatment groups. Despite the behavioural changes, gene expression analysis did not show any qualitative change for all treated groups. Conclusion: These findings suggest PDGF may have a role in modulating astrocytes' neuroprotective response via the PDGF receptors. The changes in behavioural indices needs to be confirmed by qRT-PCR and wholemount in situ immunofluorescence. P 6.018. INTEGRATION OF CORTICAL AND BASAL GANGLIA INPUTS IN MOTOR THALAMUS OF PARKINSONIAN ANIMAL MODELS Gerg Orban, Wei Song, Alain Kaelin-Lang, Salvatore Galati. Neurocenter of Southern Switzerland, Lugano, Switzerland Objectives: Pathological erratic motor thalamus (MTh) activity has been considered to contribute to the generation of Parkinson's disease (PD) symptoms. Basal ganglia (BG) structures afferent to MTh shown synchronized oscillatory activity in dopamine (DA) -depleted BG reflecting underlying pathophysiological mechanisms of Parkinsonism. Acute or chronic DA depletion, drives pathological cortical-substantia nigra pars reticulata (SNr) coherences in urethane-anesthetized rats. Since SNr exerts direct control on the BG-receiving MTh relaying information to the cortex, its disorganized patterns of activity may have a strong influence on the activity of the downstream thalamocortical relay. We aim to characterized the impact of these changes on MTh. Methods: We investigate the firing properties of MTh cells following i) chronic DA depletion in 6-hydroxydopamine (6-OHDA) animal models of PD and ii) in acute DA depleted animals after tetrodotoxin (TTX)-mediated blockade of the nigro-striatal pathway. Results: MTh neurons showed a firing reduction in 6-OHDA animals. In TTX group we observed a time-looked inhibition of MTh cells (Figure1). Conclusions: The MTh is a structure strategically situated between BG and cortex whose activity was conjectured to play a crucial role in PD. Our preliminary data are in agreement with the classical basal ganglia scheme. P 6.019. SPREADING DEPRESSION SUSCEPTIBILITY IS REDUCED IN PARKINSON RAT MODEL Mahmoud Lotfinia. Shefa Neuroscience Research Center, Tehran, Islamic Republic of Iran Objectives: To evaluate whether administration of 6-hydroxydopamine in the medial forebrain bundle and creating a Parkinson rat model, can have an effect on Spreading depression Susceptibility or not? Parkinson disease (PD) is known by amajor loss of dopaminergic nigrostriatal neurons and by an increased turnover of neurotransmitter by surviving neurons of the nigrostriatal tract. The clinical diagnosis of PD is based on the identification of some combination of the cardinal motor signs of bradykinesia, rigidity, tremor, and postural instability. Spreading depression (SD) known as an evoked neuronal activity and changes in ionic, metabolic and hemodynamic characteristics of the brain. Pronounced release of dopamine during SD and the probable role of dopamine in SD process suggests that disruption of dopaminergic pathway in PD may cause SD to behave differently. Methods: To test this possibility, we induced dopaminergic lesion by bilateral intracerebral stereotactic injection of 6 mL of 6-hydroxydopamine in the medial forebrain bundle (MFB). After 4 days, SD was induced by the injection of 3M KCl and SD propagation was followed using two ion-sensitive microelectrodes placed in the parietal and occipital cortex. Results: Eliciting SD in ratmodel was associatedwith a significant increase in the threshold of SD and a decrease in the propagation velocity and duration of accompanying extracellular DC changes. Conclusions: The present data show that rat model of Parkinson's disease are less prone to SD.

Cell swelling increases the severity of spreading depression in Locusta migratoria.

Progressive accumulation of extracellular potassium ions can trigger propagating waves of spreading depression (SD), which are associated with dramatic increases in extracellular potassium levels ([K(+)]o) and arrest in neural activity. In the central nervous system the restricted nature of the extracellular compartment creates an environment that is vulnerable to disturbances in ionic homeostasis. Here we investigate how changes in the size of the extracellular space induced by alterations in extracellular osmolarity affect locust SD. We found that hypotonic exposure increased susceptibility to experimentally induced SD evidenced by a decrease in the latency to onset and period between individual events. Hypertonic exposure was observed to delay the onset of SD or prevent the occurrence altogether. Additionally, the magnitude of extracellular K(+) concentration ([K(+)]o) disturbance during individual SD events was significantly greater and they were observed to propagate more quickly under hypotonic conditions compared with hypertonic conditions. Our results are consistent with a conclusion that hypotonic exposure reduced the size of the extracellular compartment by causing cell swelling and thus facilitated the accumulation of K(+) ions. Lastly, we found that pharmacologically reducing the accumulation of extracellular K(+) using the K(+) channel blocker tetraethylammonium slowed the rate of SD propagation while increasing [K(+)]o through inhibition of the Na-K-2Cl cotransporter increased propagation rates. Overall our findings indicate that treatments or conditions that act to reduce the accumulation of extracellular K(+) help to protect against the development of SD and attenuate the spread of ionic disturbance adding to the evidence that diffusion of K(+) is a leading event during locust SD.

Identification of the extent of cortical spreading depression propagation by Npas4 mRNA expression

Cortical spreading depression (CSD) is a phenomenon associated with a propagating large shift in direct current (DC) potential followed by suppression of electrophysiological activity. For temporal analysis of CSD propagation, electrophysiological recording is the most reliable tool. However, it is difficult to completely identify the spatial area of the brain influenced by CSD, because recording sites are technically limited. Histological post hoc identification of activated neurons by labeling the induction of an immediate early gene (IEG) could determine areas of CSD propagation. We found that cortical application of potassium chloride induced expression of Npas4 IEG mRNA in the ipsilateral dorsal cortex. Interestingly, induction of Npas4 was never observed in the ipsilateral hippocampus and there was a clear boundary to the area of Npas4 expression. To determine whether the boundary of the area of Npas4 mRNA expression was the limit of CSD propagation, we recorded local field potentials from multiple sites that crossed the boundary of Npas4 expression. We found that the area of Npas4 mRNA expression coincided with the area of DC-potential shift propagation. We propose that induction of Npas4 identifies the area influenced by CSD propagation.

GABAA receptor α2 subtype activation suppresses retinal spreading depression

Cortical spreading depression (SD) is a transient propagating neuronal excitation followed by depression, which is generally accepted as the underlying cause of migraine. The inhibitory γ-aminobutyric acid type A (GABAA) receptor activation not only reduces cortical SD frequency and propagation, but also relieves migraine headache. This study aims to determine the role of major α subtypes of GABAA receptor in mediating SD genesis and propagation using an efficient in vitro chick retinal model. We firstly demonstrated that abundant α2, and to a lesser extent, α5 of GABAA receptor expression in the chick retina, enabled the tissue useful for studying GABAA receptor pharmacology and SD. Marked suppression of SD by SL651498 and TPA023 was observed at 10μmolL−1 and 50μmolL−1, respectively, suggesting a critical role of GABAA receptor α subtypes, in particular α2, in modulating retinal SD elicitation and propagation. The negative data on NS11394 at 3μmolL−1 on SD and the little positive selectivity of TPA023 for α5 did not support that α5 subtype is involved in SD genesis and propagation. Our data provide strong evidence that α2, but not α5 is involved in the early stage of migraine, indicating that α2 subtype is a possible drug target related to migraine with aura.

Cytoarchitecture-Dependent Decrease in Propagation Velocity of Cortical Spreading Depression in the Rat Insular Cortex Revealed by Optical Imaging.

Cortical spreading depression (SD) is a self-propagating wave of depolarization accompanied by a substantial disturbance of the ionic distribution between the intra- and extracellular compartments. Glial cells, including astrocytes, play critical roles in maintenance of the extracellular environment, including ionic distribution. Therefore, SD propagation in the cerebral cortex may depend on the density of astrocytes. The present study aimed to examine the profile of SD propagation in the insular cortex (IC), which is located between the neocortex and paleocortex and is where the density of astrocytes gradually changes. The velocity of SD propagation in the neocortex, including the somatosensory, motor, and granular insular cortices (5.7 mm/min), was higher than that (2.8 mm/min) in the paleocortex (agranular insular and piriform cortices). Around thick vessels, including the middle cerebral artery, SD propagation was frequently delayed and sometimes disappeared. Immunohistological analysis of glial fibrillary acidic protein (GFAP) demonstrated the sparse distribution of astrocytes in the somatosensory cortex and the IC dorsal to the rhinal fissure, whereas the ventral IC showed a higher density of astrocytes. These results suggest that cortical cytoarchitectonic features, which possibly involve the distribution of astrocytes, are crucial for regulating the velocity of SD propagation in the cerebral cortex.

EHMTI-0094. Effect of nifedipine on memory impairment induced by repetitive spreading depression

Spreading depression (SD) is known by transient loss of spontaneous and evoked neuronal activity and changes in ionic, metabolic and hemodynamic characteristics of the brain. It has been shown that repetitive SD produced memory deficits in juvenile rats. Furthermore, the role of Ca2+channels on induction and propagation of SD was investigated by several scientists. The aim of the present study was to study the role of a Ca2+channel-blocker, nifedipine, on memory deficits induced by repetitive SD.

Propagation of Spreading Depression: A Review of Different Hypothesis

Propagation of Spreading Depression: A Review of Different Hypothesis

Familial hemiplegic migraine and spreading depression.

Familial hemiplegic migraine (FHM) is an autosomal dominantly inherited subtype of migraine with aura, characterized by transient neurological signs and symptoms. Typical hemiplegic migraine attacks start in the first or second decade of life. Some patients with FHM suffer from daily recurrent attacks since childhood. Results from extensive studies of cellular and animal models have indicated that gene mutations in FHM increase neuronal excitability and reduce the threshold for spreading depression (SD). SD is a transient wave of profound neuronal and glial depolarization that slowly propagates throughout the brain tissue and is characterized by a high amplitude negative DC shift. After induction of SD, S218L mutant mice exhibited neurological signs highly reminiscent of clinical attacks in FHM type 1 patients carrying this mutation. FHM1 with ataxia is attributable to specific mutations that differ from mutations that cause pure FHM1 and have peculiar consequences on cerebellar Cav2.1 currents that lead to profound Purkinje cell dysfunction and neuronal loss with atrophy. SD in juvenile rats produced neuronal injury and death. Hormonal factors involved in FHM affect SD initiation and propagation. The data identify SD as a possible target of treatment of FHM. In addition, FHM is a useful model to explore the mechanisms of more common types of migraine.

Spreading depression triggers ictaform activity in partially disinhibited neuronal tissues

There is unequivocal electrophysiological evidence that spreading depression (SD) can trigger epileptiform field potentials. In vitro experiments on human brain tissues indicated that γ-aminobutyric acid (GABA)-mediated inhibition prevented this process. Intra- and extracellular recordings of bioelectrical activities were performed in the rodent neocortex, hippocampus and amygdala after perfusion of low concentrations of the GABAA antagonist bicuculline and induction of SD by KCl application. Induction of SD in combined amygdala–hippocampus–cortex slices pre-treated with low concentration of bicuculline triggered epileptiform burst discharges in cortical as well as subcortical brain structures. Propagation of SD significantly depolarized the membrane, decreased the amplitude and duration of action potentials (APs) and after-hyperpolarization as well as the neuronal membrane input resistance and the amplitude of threshold potentials. Ten to twenty minutes after induction of SD, the pattern of APs changed from regular firing to a series of APs riding on an underlying paroxysmal depolarization shift before the appearance of typical ictaform activities. Changes of characteristic features of APs occurred after SD persisted during the appearance of epileptiform activities. These results indicate that SD increases neuronal excitability and facilitates synchronization of neuronal discharges in the presence of partial disinhibition of neuronal tissues. Our findings might explain the occurrence of seizures in neurological disorders with partial impairment of inhibitory tone, such as brain ischemia and epilepsy.

Memory improvement after spreading depression by NMDA blocker as memory destructor

Spreading depression (SD) is transient neural hyperexitablity followed by depolarization wave, which propagates/INS; through the brain and modulate electrical gradient and synaptic activity. Data have shown that SD wave distributes/INS; coincidence between neural activity and behavioral activity/INS;. Neural activity and electrical potential effect on memory retrieval have been demonstrated. Inhibitory effect of NMDA receptors in SD procedure can control memory impairment caused by SD. However, the /INS;negative effect of NMDA receptor blockage on memory has/INS; been proven in previous studies. In the present study the /INS;effect of NMDA receptors blockage (MK801) used to evaluate its efficiency in subsiding of SD negative influence on memory. /INS;Wistar rats/INS; (60–/INS;80 g/INS;) were /INS;randomly chosen in 6 groups and (NMDA blocker0.63–/INS;1 mg/kg) were administrated after 3 mol/L KCl injection for induction of repetitive/INS; SD in rat. The groups were evaluated by T-maze test and SD groups /INS;were compared with control groups, including (NMDA blocker 1–/INS;0.63 mg/kg /INS;controls) and sham group. T-maze data have showed that repeated SD could significantly alter memory/INS; retrieval performance. However, in the second week memory enhancement was/INS; induced by SD induction. Repeated SD induction during other weeks indicated/INS; impairment in memory. Application of NMDA blocker showed significantly enhanced /INS;memory retrieval and/INS; could /INS;potentially control memory impairment after SD. /INS;The studies indicated that NMDA blocker may decrease memory performance/INS;, on the other hand the /INS;effect of MK801 on inhibition of SD propagation may somehow weaken memory improvement due to its memory destruction effects.

Spreading depression and the clinical correlates of migraine

Migraine is the most common neurologic condition. One-third of migraineurs experience transient neurologic symptoms, the so-called aura. There is strong evidence that spreading depression (SD) is the electrophysiologic substrate of migraine aura. SD is an intense pan-depolarization wave that slowly propagates in gray matter by way of contiguity and transiently disrupts neuronal function. When induced subcortically, striatal SD causes hemiparesis, hippocampal SD can trigger seizures and impact cognition, and bilateral thalamic SD can diminish consciousness. Recent data show that transgenic mice expressing familial hemiplegic migraine (FHM) type 1 mutations in voltage-gated Ca2+ channels (Cav2.1) develop mutation-specific aura-like signs after a cortical SD similar to patients with the respective mutation. These signs are associated with facilitated subcortical SD propagation. As in FHM, mice with the R192Q mutation develop pure hemiplegia associated with cortical SDs propagating into caudoputamen. S218L mice display additional signs such as seizures and coma when SD propagates into hippocampus and thalamus. In hyperexcitable FHM brains, SD may propagate between cortex and subcortical structures via permissive gray matter bridges, or originate de novo in subcortical structures, to explain unusual and severe aura signs and symptoms. Reciprocal spread and reverberating waves can explain protracted attacks.

Preferential susceptibility and propagation of spreading depression in superficial cortical layers

Preferential susceptibility and propagation of spreading depression in superficial cortical layers