Spreading Depolarization

Spreading depolarizations are implicated in a diverse set of neurologic diseases. They are unusual forms of nervous system activity in that they propagate very slowly and approximately concentrically, apparently not respecting the anatomic, synaptic, functional, or vascular architecture of the brain. However, there is evidence that spreading depolarizations are not truly concentric, isotropic, or homogeneous, either in space or in time. Here we present evidence from KCl-induced spreading depolarizations, in mouse and rat, in vivo and in vitro, showing the great variability that these depolarizations can exhibit. This variability can help inform the mechanistic understanding of spreading depolarizations, and it has implications for their phenomenology in neurologic disease.

Growing clinical evidence suggests critical involvement of spreading depolarizations (SDs) in the pathophysiology of neurological disorders such as migraine and stroke. MRI provides powerful tools to detect and assess co-occurring cerebral hemodynamic and cellular changes during SDs. This study reports the feasibility and advantages of two MRI scans, based on balanced steady-state free precession (b-SSFP) and diffusion-weighted multi-spin-echo (DT2), heretofore unexplored for monitoring SDs. These were compared with gradient-echo MRI. SDs were induced by KCl application in rat brain. Known for high SNR, the T 2-and T 1-based b-SSFP contrast was hypothesized to provide higher spatiotemporal specificity than T Ã 2-based gradient-echo scanning. DT2 scanning was designed to provide simultaneous T 2 and apparent diffusion coefficient (ADC) measurements, thus enabling combined quantitative assessment of hemodynamic and cellular changes during SDs. Procedures were developed to automate identification of SD-induced responses in all the scans. These responses were analyzed to determine detection sensitivity and temporal characteristics of signals from each scanning method. Cluster analysis was performed to elucidate unique temporal patterns for each contrast. All scans allowed detection of SD-induced responses. b-SSFP scans showed significantly larger relative intensity changes, narrower peak widths and greater spatial specificity compared with gradient-echo MRI. SD-induced effects on ADC, calculated from DT2 scans, showed the most pronounced signal changes, displaying about 20% decrease, as against 10-15% signal increases observed with b-SSFP and gradient-echo scanning. Cluster analysis revealed additional temporal sub-patterns, such as an initial dip on gradient-echo scans and temporally shifted T 2 and proton density changes in DT2 data. To summarize, b-SSFP and DT2 scanning provide distinct information on SDs compared with gradient-echo MRI. DT2 scanning, with its potential to simultaneously provide cellular and hemodynamic information, can offer unique information on the interrelationship between these processes in pathologic brain, which may improve monitoring of spreading depolarizations in (pre)clinical settings.

Although migraine and stroke are dis nct diseases, there is increasing evidence for comorbidity and overlapping pathology. 1,2 Epidemiological studies have suggested that the link is more pronounced for migraine with aura, 3 a migraine subtype in which the headache is preceded by transient focal neurological symptoms ("aura"). 4 Human imaging and animal studies have indicated that cor cal spreading depolariza on (CSD), a wave of massive depolariza on of neurons and glial cells that is accompanied by vasodilata on due to neurovascular coupling, 1 is the mechanism underlying the migraine aura. 5,6 Waves with similar characteris cs also occur in ischemic stroke, where they are referred to as peri-infarct depolariza ons (PIDs). 7,8 PIDs circle around the ischemic core, into the border zone ("penumbra") thereby increasing the ischemic territory with each wave, due to, amongst others, paradoxical vasoconstric on and accompanying supply-demand mismatch. 7,8 It has therefore been postulated that spreading depolariza on (SD), with involvement of neuronal and vascular mechanisms, may explain the link between migraine and stroke. 1 The rela on between migraine and stroke is also refl ected in the clinical spectrum of various monogenic diseases. 9 We envisaged that inves ga ng transgenic mouse models for such disorders, and comparing measures of migraine (i.e. CSD) and stroke (i.e. ischemia a er transient middle cerebral artery occlusion (MCAO)) in them, may shed light on the mechanisms relevant to migraine and stroke. Here we used mouse models for three disorders for which the rela on between migraine and stroke (in pa ents and/or in animal studies) is most pronounced: Familial Hemiplegic Migraine type 1 (FHM1), 10 Cerebral Autosomal Dominant Arteriopathy with Subcor cal Infarcts and Leukoencephalopathy (CADASIL), 11 and Re nal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifesta ons (RVCL-S). 12 FHM1 is a monogenic form of migraine caused by specifi c missense muta ons in CACNA1A that result in a acks of headache accompanied by an aura with hemiparesis. 4,13 FHM1 exhibits a neuronal phenotype as shown by the enhanced neurotransmission and increased suscep bility to CSD in FHM1 mutant mice. 14-16 FHM1 mice, either with the R192Q or the S218L muta on, were shown to also have an increased vulnerability to ischemic stroke, as evidenced by the increased infarct volume and decreased anoxic depolariza on (AD) latency. 17 Of note, a follow-up study only confi rmed the infarct volume phenotype in the severer S218L mutant mice. 18 CADASIL is a progressive small vessel disease caused by muta ons involving cysteines in NOTCH3 that result in ischemic strokes and (vascular) demen a. 19,20 Notably, the presen ng symptom of CADASIL in 40% of pa ents is migraine with aura. 21,22 CADASIL exhibits a vascular phenotype as evidenced by an accumula on of mutant protein in vascular smooth muscle cells in a transgenic overexpressor mouse model for CADASIL. 23,24 Of note, another CADASIL mouse model expressing a diff erent NOTCH3 muta on also showed hallmarks of CADASIL, and interes ngly, also an increased suscep bility for CSDs. 25 Finally, RVCL-S, which is caused by C-terminal trunca ng muta ons in TREX1 that cause systemic microvascular vasculopathy with white ma er lesions. 26 Many pa ents with RVCL-S also have migraine. 26 RVCL-S exhibits a vascular (endothelial) phenotype but the exact mechanism that results in pathology is not known. An unpublished knock-in (KI) mouse model that expresses truncated Trex1 protein was generated and analyzed in the present study. Given that disease onset in pa ents with CADASIL 27-29 and with RVCL-S 12 typically occurs at middle age, but at rela vely young age in pa ents with FHM, 10 we compared readouts for migraine and ischemic stroke in young (3-to 6-month-old; both CSD and ischemic stroke) and old (12-to 14-month old; only ischemic stroke) FHM1, CADASIL and RVCL-S mice and the

A BS TRACT: Objective: Spreading depolarization (SD) is a transient self-propagating wave of neuronal and glial depolarization coupled with large membrane ionic changes and a subsequent depression of neuronal activity. Spreading depolarization in the cortex is implicated in migraine, stroke, and epilepsy. Conversely, spreading depolarization in the striatum, a brain structure deeply involved in motor control and in Parkinson's disease (PD) pathophysiology, has been poorly investigated. Methods: We characterized the participation of glutamatergic and dopaminergic transmission in the induction of striatal spreading depolarization by using a novel approach combining optical imaging, measurements of endogenous DA levels, and pharmacological and molecular analyses. Results: We found that striatal spreading depolarization requires the concomitant activation of D1-like DA and Nmethyl-D-aspartate receptors, and it is reduced in experimental PD. Chronic L-dopa treatment, inducing dyskinesia in the parkinsonian condition, increases the occurrence and speed of propagation of striatal spreading depolarization, which has a direct impact on one of the signaling pathways downstream from the activation of D1 receptors. Conclusion: Striatal spreading depolarization might contribute to abnormal basal ganglia activity in the dyskinetic condition and represents a possible therapeutic target.

Spreading depolarizations are implicated in a diverse set of neurologic diseases. They are unusual forms of nervous system activity in that they propagate very slowly and approximately concentrically, apparently not respecting the anatomic, synaptic, functional, or vascular architecture of the brain. However, there is evidence that spreading depolarizations are not truly concentric, isotropic, or homogeneous, either in space or in time. Here we present evidence from KCl-induced spreading depolarizations, in mouse and rat, in vivo and in vitro, showing the great variability that these depolarizations can exhibit. This variability can help inform the mechanistic understanding of spreading depolarizations, and it has implications for their phenomenology in neurologic disease.

Cortical spreading depression (CSD) is a pathologic mechanism of migraine. We have identified a novel neocortex-specific mechanism of CSD initiation and a novel pathological role of GABAergic neurons. Mutations of the NaV1.1 sodium channel (the SCN1A gene), which is particularly important for GABAergic neurons’ excitability, cause Familial Hemiplegic Migraine type-3 (FHM3), a subtype of migraine with aura. They induce gain-of-function of NaV1.1 and hyperexcitability of GABAergic interneurons in culture. However, the mechanism linking these dysfunctions to CSD and FHM3 has not been elucidated. Here, we show that NaV1.1 gain-of-function, induced by the specific activator Hm1a, or mimicked by optogenetic-induced hyperactivity of cortical GABAergic neurons, is sufficient to ignite CSD by spiking-generated extracellular K+ build-up. This mechanism is neocortex specific because, with these approaches, CSD was not generated in other brain areas. GABAergic and glutamatergic synaptic transmi...

Laser speckle contrast imaging (LSCI) is a real-time imaging modality reflecting microvascular perfusion. We report on the application of the motion history image (MHI) method on LSCI data obtained from the two hemispheres of a mouse. Through the generation of a single image, MHI stresses the microvascular perfusion changes. Our experimental results performed during a pinprick-triggered spreading depolarization demonstrate the effectiveness of MHI: MHI allows the visualization of perfusion changes without loss of resolution and definition. Moreover, MHI provides close results to the ones given by the generalized differences (GD) algorithm. However, MHI has the advantage of giving information on the temporal evolution of the perfusion variations, which GD does not.

Spreading depolarizations are implicated in a diverse set of neurologic diseases. They are unusual forms of nervous system activity in that they propagate very slowly and approximately concentrically, apparently not respecting the anatomic, synaptic, functional, or vascular architecture of the brain. However, there is evidence that spreading depolarizations are not truly concentric, isotropic, or homogeneous, either in space or in time. Here we present evidence from KCl-induced spreading depolarizations, in mouse and rat, in vivo and in vitro, showing the great variability that these depolarizations can exhibit. This variability can help inform the mechanistic understanding of spreading depolarizations, and it has implications for their phenomenology in neurologic disease.

Laser speckle contrast imaging (LSCI) is a real-time imaging modality reflecting microvascular perfusion. We report on the application of the motion history image (MHI) method on LSCI data obtained from the two hemispheres of a mouse. Through the generation of a single image, MHI stresses the microvascular perfusion changes. Our experimental results performed during a pinprick-triggered spreading depolarization demonstrate the effectiveness of MHI: MHI allows the visualization of perfusion changes without loss of resolution and definition. Moreover, MHI provides close results to the ones given by the generalized differences (GD) algorithm. However, MHI has the advantage of giving information on the temporal evolution of the perfusion variations, which GD does not.

Waves of spreading depolarization (SD) have been implicated in the progressive expansion of acute brain injuries. SD can persist over several days, coincident with the time course of astrocyte activation, but little is known about how astrocyte activation may influence SD susceptibility. We examined whether activation of astrocytes modified SD threshold in hippocampal slices. Injection of a lentiviral vector encoding Ciliary neurotrophic factor (CNTF) into the hippocampus in vivo,

Spreading depolarization (SD) is a transient self-propagating wave of neuronal and glial depolarization coupled with large membrane ionic changes and a subsequent depression of neuronal activity. Spreading depolarization in the cortex is implicated in migraine, stroke, and epilepsy. Conversely, spreading depolarization in the striatum, a brain structure deeply involved in motor control and in Parkinson's disease (PD) pathophysiology, has been poorly investigated. Methods: We characterized the participation of glutama-tergic and dopaminergic transmission in the induction of striatal spreading depolarization by using a novel approach combining optical imaging, measurements of endogenous DA levels, and pharmacological and molecular analyses. Results: We found that striatal spreading depolarization requires the concomitant activation of D1-like DA and N-methyl-D-aspartate receptors, and it is reduced in experimental PD. Chronic Ldopa treatment, inducing dyskinesia in the parkinsonian condition, increases the occurrence and speed of propagation of striatal spreading depolarization, which has a direct impact on one of the signaling pathways downstream from the activation of D1 receptors. Conclusion: Striatal spreading depolarization might contribute to abnormal basal ganglia activity in the dyskinetic condition and represents a possible therapeutic target.

Spreading depolarizations are implicated in a diverse set of neurologic diseases. They are unusual forms of nervous system activity in that they propagate very slowly and approximately concentrically, apparently not respecting the anatomic, synaptic, functional, or vascular architecture of the brain. However, there is evidence that spreading depolarizations are not truly concentric, isotropic, or homogeneous, either in space or in time. Here we present evidence from KCl-induced spreading depolarizations, in mouse and rat, in vivo and in vitro, showing the great variability that these depolarizations can exhibit. This variability can help inform the mechanistic understanding of spreading depolarizations, and it has implications for their phenomenology in neurologic disease.

This paper presents the design, testing and quantitative evaluation of a highperformance, low-power, portable multi-instrument (107x79mm 2), capable of recording important biosignals accurately and in real-time. This highly versatile system has the ability to transmit the captured bio-data back to the user either in a wired (HDMI cable) or wireless (ZigBee protocol) manner, depending on the targeted application. The biological information that can be recorded by the proposed instrument spans a wide range of bio-potentials and bio-amperometric signals. The proposed instrument is split into two complementary "sub-instruments", where one is operating as the front-end device, responsible for the accurate, low-noise signal detection and transmission, while the second "sub-instrument" is operating as the "base station", responsible for the collection and further processing of the captured data. For wired transmission (e.g to the user's PC) the front end module can operate independently, however, for wireless transmission both "sub-instruments" are required (transmitterbase station architecture). For wireless transmission, each of the two "subinstruments" is equipped with dedicated 2Mbps ZigBee radio transceivers and both parts are controlled by a small area embedded FPGA module. The frontend device features two distinct sections: (a) a current/voltage to voltage section comprising six potentiometry and two transimpedance amplifier-based amperometry channels. These eight in total analogue channels are converted into digital form by means of a 24bit, voltage input, Analogue-to-Digital Converter (ADC) and (b) a four channel, commercially available switched-capacitor-based ADC Integrated Circuit (IC), which converts input charge to digital data with

Spreading depression (SD) is a propagating wave of depolarization followed by depression of the neuroglial activities and can modulate extracellular dopamine concentrations in the neocortex. It has been shown that the dopaminergic system plays a role in migraine. SD has been suggested as a critical phenomenon in the pathophysiology of migraine. The aim of this study was to investigate the effect of dopamine D2 receptors on the characteristic features of SD in rat neocortical tissues. The effect of dopamine D2 receptor agonist quinpirole and D2 receptor antagonist sulpiride was tested on different characteristic features (amplitude, duration and velocity) of KCl-induced SD in somatosensory neocortical slices of adult rats. The effect of above-mentioned substances on production of long-term potentiation (LTP) in the neocortex was also evaluated. The present data revealed a dose-dependent suppression of the amplitude and duration of SD in the presence of the dopamine D2 receptor antago...

The propagation of depolarization in cardiac muscle is known to be anisotropic in several characteristics: velocity of propagation, waveform of depolarization, and safety factor. Previous models, both 1-D and 2-D , have been able to account for some, but not all of these anisotropies. A new 2-D model is described in this paper, using a "brick wall" form of staggered transverse intercellular connections suggested by the t issue structure. This new propagation model accounts for all three kinds of anisotropic characteristics .

Introduction: Spreading depression (SD) is a propagating wave of depolarization followed by
depression of the neuroglial activities and can modulate extracellular dopamine concentrations
in the neocortex. It has been shown that the dopaminergic system plays a role in migraine. SD
has been suggested as a critical phenomenon in the pathophysiology of migraine. The aim of this
study was to investigate the effect of dopamine D2 receptors on the characteristic features of SD
in rat neocortical tissues.
Methods: The effect of dopamine D2 receptor agonist quinpirole and D2 receptor antagonist
sulpiride was tested on different characteristic features (amplitude, duration and velocity) of
KCl-induced SD in somatosensory neocortical slices of adult rats. The effect of above-mentioned
substances on production of long-term potentiation (LTP) in the neocortex was also evaluated.
Results: The present data revealed a dose-dependent suppression of the amplitude and duration
of SD in the presence of the dopamine D2 receptor antagonist sulpiride in the neocortex. D2
dopamine receptor agonist quinpirole dose-dependently enhanced the amplitude and duration of
the neocortical SD. Furthermore, application of D2 receptor antagonist significantly suppressed
induction of LTP.
Discussion: These results indicate that D2 receptors modulate the initiation of SD in the neocortex.
This finding refers to the potential role of D2 receptor antagonist in treatment of migraine pain.