Study Design and Protocol of a Randomized Controlled Trial of the Efficacy of a Smartphone-Based Therapy of Migraine (SMARTGEM).

Background: Digitalization and electronic health (eHealth) offer new treatment approaches for patients with migraine. Current smartphone applications (apps) for migraine patients include a wide spectrum of functions ranging from digital headache diaries to app-based headache treatment by, among others, analysis of the possible triggers, behavioral therapy approaches and prophylactic non-drug treatment methods with relaxation therapy or endurance sport. Additional possibilities arise through the use of modern, location-independent communication methods, such as online consultations. However, there is currently insufficient evidence regarding the benefits and/or risks of these electronic tools for patients. To date, only few randomized controlled trials have assessed eHealth applications. Methods: SMARTGEM is a randomized controlled trial assessing whether the provision of a new digital integrated form of care consisting of the migraine app M-sense in combination with a communication platform (with online consultations and medically moderated patient forum) leads to a reduction in headache frequency in migraine patients, improving quality of life, reducing medical costs and work absenteeism (DRKS-ID: DRKS00016328). Discussion: SMARTGEM constitutes a new integrated approach for migraine treatment, which aims to offer an effective, location-independent, time-saving and cost-saving treatment. The design of the study is an example of how to gather high quality evidence in eHealth. Results are expected to provide insightful information on the efficacy of the use of electronic health technology in improving the quality of life in patients suffering from migraine and reducing resource consumption.

Determining the Evolution of Headache Among Regular Users of a Daily Electronic Diary via a Smartphone App: Observational Study.

BACKGROUND: Smartphone-based apps represent a major development in health care management. Specifically in headache care, the use of electronic headache diaries via apps has become increasingly popular. In contrast to the soaring volume of available data, scientific use of these data resources is sparse. OBJECTIVE: In this analysis, we aimed to assess changes in headache and migraine frequency, headache and migraine intensity, and use of acute medication among people who showed daily use of the headache diary as implemented in the freely available basic version of the German commercial app, M-sense. METHODS: The basic version of M-sense comprises an electronic headache diary, documentation of lifestyle factors with a possible impact on headaches, and evaluation of headache patterns. This analysis included all M-sense users who had entered data into the app on a daily basis for at least 7 months. RESULTS: We analyzed data from 1545 users. Mean MHD decreased from 9.42 (SD 5.81) at baseline to 6.39 (SD 5.09) after 6 months (P<.001; 95% CI 2.80-3.25). MMD, AMD, and migraine intensity were also significantly reduced. Similar results were found in 985 users with episodic migraine and in 126 users with chronic migraine. CONCLUSIONS: Among regular users of an electronic headache diary, headache and migraine frequency, in addition to other headache characteristics, improved over time. The use of an electronic headache diary may support standard headache care.

Validation of an algorithm for automated classification of migraine and tension-type headache attacks in an electronic headache diary.

BACKGROUND: This study evaluates the accuracy of an automated classification tool of single attacks of the two major primary headache disorders migraine and tension-type headache used in an electronic headache diary. METHODS: One hundred two randomly selected reported headache attacks from an electronic headache-diary of patients using the medical app M-sense were classified by both a neurologist with specialisation in headache medicine and an algorithm, constructed based on the ICHD-3 criteria for migraine and tension-type headache. The level of agreement between the headache specialist and the algorithm was compared by using a kappa statistic. Cases of disagreement were analysed in a disagreement validity assessment. RESULT: The neurologist and the algorithm classified migraines with aura (MA), migraines without aura (MO), tension-type headaches (TTH) and non-migraine or non-TTH events. Of the 102 headache reports, 86 cases were fully agreed on, and 16 cases not, making the level of agreement unweighted kappa 0.74 and representing a substantial level of agreement. Most cases of disagreement (12 out of 16) were due to inadvertent mistakes of the neurologist identified in the disagreement validity assessment. The second most common reason (3 out of 16) was insufficient information for classification by the neurologist. CONCLUSIONS: The substantial level of agreement indicates that the classification tool is a valuable instrument for automated evaluation of electronic headache diaries, which can thereby support the diagnostic and therapeutic clinical processes. Based on this study's results, additional diagnostic functionalities of primary headache management apps can be implemented. Finally, future research can use this classification algorithm for large scale database analysis for epidemiological studies.

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.

Simulation of spreading depolarization trajectories in cerebral cortex: Correlation of velocity and susceptibility in patients with aneurysmal subarachnoid hemorrhage.

In many cerebral grey matter structures including the neocortex, spreading depolarization (SD) is the principal mechanism of the near-complete breakdown of the transcellular ion gradients with abrupt water influx into neurons. Accordingly, SDs are abundantly recorded in patients with traumatic brain injury, spontaneous intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage (aSAH) and malignant hemispheric stroke using subdural electrode strips. SD is observed as a large slow potential change, spreading in the cortex at velocities between 2 and 9 mm/min. Velocity and SD susceptibility typically correlate positively in various animal models. In patients monitored in neurocritical care, the Co-Operative Studies on Brain Injury Depolarizations (COSBID) recommends several variables to quantify SD occurrence and susceptibility, although accurate measures of SD velocity have not been possible. Therefore, we developed an algorithm to estimate SD velocities based on reconstructing SD trajectories of the wave-front's curvature center from magnetic resonance imaging scans and time-of-SD-arrival-differences between subdural electrode pairs. We then correlated variables indicating SD susceptibility with algorithm-estimated SD velocities in twelve aSAH patients. Highly significant correlations supported the algorithm's validity. The trajectory search failed significantly more often for SDs recorded directly over emerging focal brain lesions suggesting in humans similar to animals that the complexity of SD propagation paths increase in tissue undergoing injury.

Heterogeneous propagation of spreading depolarizations in the lissencephalic and gyrencephalic brain.

In the recently published article, "Heterogeneous incidence and propagation of spreading depolarizations," it is shown, in vivo and in vitro, how KCl-induced spreading depolarizations in mouse and rat brains can be highly variable, and that they are not limited, as once thought, to a concentric, isotropic, or homogenous depolarization wave in space or in time. The reported results serve as a link between the different species, and this paper contributes to changing the way in which SD expansion is viewed in the lissencephalic brain. Here, we discuss their results with our previous observations made in the gyrencephalic swine brain, in computer simulations, and in the human brain.

The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão's legacy.

A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leão's historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema. These persistent changes are diagnosed as diffusion restriction in magnetic resonance imaging and define the ischemic core. In delayed lesion growth, transient spreading depolarizations arise spontaneously in the ischemic penumbra and induce further persistent depolarization and excitotoxic damage, progressively expanding the ischemic core. The causal role of these waves in lesion development has been proven by real-time monitoring of electrophysiology, blood flow, and cytotoxic edema. The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development. These pathophysiologic concepts establish a working hypothesis for translation to human disease, where complex patterns of depolarizations are observed in acute brain injury and appear to mediate and signal ongoing secondary damage.

The Role of Cell Volume in the Dynamics of Seizure, Spreading Depression, and Anoxic Depolarization.

Cell volume changes are ubiquitous in normal and pathological activity of the brain. Nevertheless, we know little of how cell volume affects neuronal dynamics. We here performed the first detailed study of the effects of cell volume on neuronal dynamics. By incorporating cell swelling together with dynamic ion concentrations and oxygen supply into Hodgkin-Huxley type spiking dynamics, we demonstrate the spontaneous transition between epileptic seizure and spreading depression states as the cell swells and contracts in response to changes in osmotic pressure. Our use of volume as an order parameter further revealed a dynamical definition for the experimentally described physiological ceiling that separates seizure from spreading depression, as well as predicted a second ceiling that demarcates spreading depression from anoxic depolarization. Our model highlights the neuroprotective role of glial K buffering against seizures and spreading depression, and provides novel insights into anoxic depolarization and the relevant cell swelling during ischemia. We argue that the dynamics of seizures, spreading depression, and anoxic depolarization lie along a continuum of the repertoire of the neuron membrane that can be understood only when the dynamic ion concentrations, oxygen homeostasis,and cell swelling in response to osmotic pressure are taken into consideration. Our results demonstrate the feasibility of a unified framework for a wide range of neuronal behaviors that may be of substantial importance in the understanding of and potentially developing universal intervention strategies for these pathological states.

Cortical hot spots and labyrinths: why cortical neuromodulation for episodic migraine with aura should be personalized.

Stimulation protocols for medical devices should be rationally designed. For episodic migraine with aura we outline model-based design strategies toward preventive and acute therapies using stereotactic cortical neuromodulation. To this end, we regard a localized spreading depression (SD) wave segment as a central element in migraine pathophysiology. To describe nucleation and propagation features of the SD wave segment, we define the new concepts of cortical hot spots and labyrinths, respectively. In particular, we firstly focus exclusively on curvature-induced dynamical properties by studying a generic reaction-diffusion model of SD on the folded cortical surface. This surface is described with increasing level of details, including finally personalized simulations using patient's magnetic resonance imaging (MRI) scanner readings. At this stage, the only relevant factor that can modulate nucleation and propagation paths is the Gaussian curvature, which has the advantage of being rather readily accessible by MRI. We conclude with discussing further anatomical factors, such as areal, laminar, and cellular heterogeneity, that in addition to and in relation to Gaussian curvature determine the generalized concept of cortical hot spots and labyrinths as target structures for neuromodulation. Our numerical simulations suggest that these target structures are like fingerprints, they are individual features of each migraine sufferer. The goal in the future will be to provide individualized neural tissue simulations. These simulations should predict the clinical data and therefore can also serve as a test bed for exploring stereotactic cortical neuromodulation.

Analyzing critical propagation in a reaction-diffusion-advection model using unstable slow waves.

The effect of advection on the propagation and in particular on the critical minimal speed of traveling waves in a reaction-diffusion model is studied. Previous theoretical studies estimated this effect on the velocity of stable fast waves and predicted the existence of a critical advection strength below which propagating waves are not supported anymore. In this paper, an analytical expression for the advection-velocity relation of the unstable slow wave is derived. In addition, the critical advection strength is calculated taking into account the unstable slow wave solution. We also analyze a two-variable reaction-diffusion-advection model numerically in a wide parameter range. Due to the new control parameter (advection) we can find stable wave propagation in the otherwise non-excitable parameter regime, if the advection strength exceeds a critical value. Comparing theoretical predictions to numerical results, we find that they are in good agreement. Theory provides an explanation for the observed behaviour.

How does spreading depression spread? Physiology and modeling.

Spreading depression (SD) is a wave phenomenon in gray matter tissue. Locally, it is characterized by massive redistribution of ions across cell membranes. As a consequence, there is sustained membrane depolarization and tissue polarization that depress any normal electrical activity. Despite these dramatic events, SD remains difficult to observe in humans noninvasively, which, for long, has slowed advances in this field. The growing appreciation of its clinical importance in migraine and stroke is therefore consistent with an increasing need for computational methods that tackle the complexity of the problem at multiple levels. In this review, we focus on mathematical tools to investigate the question of spread and its two complementary aspects: What are the physiological mechanisms and what is the spatial extent of SD in the cortex? This review discusses two types of models used to study these two questions, namely, Hodgkin-Huxley type and generic activator-inhibitor models, and the recent advances in techniques to link them.

Understanding migraine using dynamic network biomarkers.

BACKGROUND: Mathematical modeling approaches are becoming ever more established in clinical neuroscience. They provide insight that is key to understanding complex interactions of network phenomena, in general, and interactions within the migraine-generator network, in particular. PURPOSE: In this study, two recent modeling studies on migraine are set in the context of premonitory symptoms that are easy to confuse for trigger factors. This causality confusion is explained, if migraine attacks are initiated by a transition caused by a tipping point. CONCLUSION: We need to characterize the involved neuronal and autonomic subnetworks and their connections during all parts of the migraine cycle if we are ever to understand migraine. We predict that mathematical models have the potential to dismantle large and correlated fluctuations in such subnetworks as a dynamic network biomarker of migraine.

Dynamics from seconds to hours in Hodgkin-Huxley model with time-dependent ion concentrations and buffer reservoirs.

The classical Hodgkin-Huxley (HH) model neglects the time-dependence of ion concentrations in spiking dynamics. The dynamics is therefore limited to a time scale of milliseconds, which is determined by the membrane capacitance multiplied by the resistance of the ion channels, and by the gating time constants. We study slow dynamics in an extended HH framework that includes time-dependent ion concentrations, pumps, and buffers. Fluxes across the neuronal membrane change intra- and extracellular ion concentrations, whereby the latter can also change through contact to reservoirs in the surroundings. Ion gain and loss of the system is identified as a bifurcation parameter whose essential importance was not realized in earlier studies. Our systematic study of the bifurcation structure and thus the phase space structure helps to understand activation and inhibition of a new excitability in ion homeostasis which emerges in such extended models. Also modulatory mechanisms that regulate the spiking rate can be explained by bifurcations. The dynamics on three distinct slow times scales is determined by the cell volume-to-surface-area ratio and the membrane permeability (seconds), the buffer time constants (tens of seconds), and the slower backward buffering (minutes to hours). The modulatory dynamics and the newly emerging excitable dynamics corresponds to pathological conditions observed in epileptiform burst activity, and spreading depression in migraine aura and stroke, respectively.

Linking a genetic defect in migraine to spreading depression in a computational model.

Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura. A mutation causing FHM type 3 (FHM3) has been identified in SCN1A encoding the Nav1.1 Na(+) channel. This genetic defect affects the inactivation gate. While the Na(+) tail currents following voltage steps are consistent with both hyperexcitability and hypoexcitability, in this computational study, we investigate functional consequences beyond these isolated events. Our extended Hodgkin-Huxley framework establishes a connection between genotype and cellular phenotype, i.e., the pathophysiological dynamics that spans over multiple time scales and is relevant to migraine with aura. In particular, we investigate the dynamical repertoire from normal spiking (milliseconds) to spreading depression and anoxic depolarization (tens of seconds) and show that FHM3 mutations render gray matter tissue more vulnerable to spreading depression despite opposing effects associated with action potential generation. We conclude that the classification in terms of hypoexcitability vs. hyperexcitability is too simple a scheme. Our mathematical analysis provides further basic insight into also previously discussed criticisms against this scheme based on psychophysical and clinical data.

Radial, spiral and reverberating waves of spreading depolarization occur in the gyrencephalic brain.

OBJECTIVES: The detection of the hemodynamic and propagation patterns of spreading depolarizations (SDs) in the gyrencephalic brain using intrinsic optical signal imaging (IOS). METHODS: The convexity of the brain surface was surgically exposed in fourteen male swine. Within the boundaries of this window, brains were immersed and preconditioned with an elevated K(+) concentration (7 mmol/l) in the standard Ringer lactate solution for 30-40 min. SDs were triggered using 3-5 µl of 1 mol/l KCl solution. Changes in tissue absorbency or reflection were registered with a CCD camera at a wavelength of 564 nm (14 nm FWHM), which was mounted 25 cm above the exposed cortex. Additional monitoring by electrocorticography and laser-Doppler was used in a subset of animals (n=7) to validate the detection of SD. RESULTS: Of 198 SDs quantified in all of the experiments, 187 SDs appeared as radial waves that developed semi-planar fronts. The morphology was affected by the surface of the gyri, the sulci and the pial vessels. Other SD patterns such as spirals and reverberating waves, which have not been described before in gyrencephalic brains, were also observed. Diffusion gradients created in the cortex surface (i.e., KCl concentrations), sulci, vessels and SD-SD interactions make the gyrencephalic brain prone to the appearance of irregular SD waves. CONCLUSION: The gyrencephalic brain is capable of irregular SD propagation patterns. The irregularities of the gyrencephalic brain cortex may promote the presence of re-entrance waves, such as spirals and reverberating waves.

Bistable dynamics underlying excitability of ion homeostasis in neuron models.

When neurons fire action potentials, dissipation of free energy is usually not directly considered, because the change in free energy is often negligible compared to the immense reservoir stored in neural transmembrane ion gradients and the long-term energy requirements are met through chemical energy, i.e., metabolism. However, these gradients can temporarily nearly vanish in neurological diseases, such as migraine and stroke, and in traumatic brain injury from concussions to severe injuries. We study biophysical neuron models based on the Hodgkin-Huxley (HH) formalism extended to include time-dependent ion concentrations inside and outside the cell and metabolic energy-driven pumps. We reveal the basic mechanism of a state of free energy-starvation (FES) with bifurcation analyses showing that ion dynamics is for a large range of pump rates bistable without contact to an ion bath. This is interpreted as a threshold reduction of a new fundamental mechanism of ionic excitability that causes a long-lasting but transient FES as observed in pathological states. We can in particular conclude that a coupling of extracellular ion concentrations to a large glial-vascular bath can take a role as an inhibitory mechanism crucial in ion homeostasis, while the Na⁺/K⁺ pumps alone are insufficient to recover from FES. Our results provide the missing link between the HH formalism and activator-inhibitor models that have been successfully used for modeling migraine phenotypes, and therefore will allow us to validate the hypothesis that migraine symptoms are explained by disturbed function in ion channel subunits, Na⁺/K⁺ pumps, and other proteins that regulate ion homeostasis.

Towards dynamical network biomarkers in neuromodulation of episodic migraine.

Computational methods have complemented experimental and clinical neurosciences and led to improvements in our understanding of the nervous systems in health and disease. In parallel, neuromodulation in form of electric and magnetic stimulation is gaining increasing acceptance in chronic and intractable diseases. In this paper, we firstly explore the relevant state of the art in fusion of both developments towards translational computational neuroscience. Then, we propose a strategy to employ the new theoretical concept of dynamical network biomarkers (DNB) in episodic manifestations of chronic disorders. In particular, as a first example, we introduce the use of computational models in migraine and illustrate on the basis of this example the potential of DNB as early-warning signals for neuromodulation in episodic migraine.

Transient localized wave patterns and their application to migraine.

Transient dynamics is pervasive in the human brain and poses challenging problems both in mathematical tractability and clinical observability. We investigate statistical properties of transient cortical wave patterns with characteristic forms (shape, size, duration) in a canonical reaction-diffusion model with mean field inhibition. The patterns are formed by ghost behavior near a saddle-node bifurcation in which a stable traveling wave (node) collides with its critical nucleation mass (saddle). Similar patterns have been observed with fMRI in migraine. Our results support the controversial idea that waves of cortical spreading depression (SD) have a causal relationship with the headache phase in migraine and, therefore, occur not only in migraine with aura (MA), but also in migraine without aura (MO), i.e., in the two major migraine subtypes. We suggest a congruence between the prevalence of MO and MA with the statistical properties of the traveling waves' forms according to which two predictions follow: (i) the activation of nociceptive mechanisms relevant for headache is dependent upon a sufficiently large instantaneous affected cortical area; and (ii) the incidence of MA is reflected in the distance to the saddle-node bifurcation. We also observed that the maximal instantaneous affected cortical area is anticorrelated to both SD duration and total affected cortical area, which can explain why the headache is less severe in MA than in MO. Furthermore, the contested notion of MO attacks with silent aura is resolved. We briefly discuss model-based control and means by which neuromodulation techniques may affect pathways of pain formation.

Is spreading depolarization characterized by an abrupt, massive release of gibbs free energy from the human brain cortex?

In the evolution of the cerebral cortex, the sophisticated organization in a steady state far away from thermodynamic equilibrium has produced the side effect of two fundamental pathological network events: ictal epileptic activity and spreading depolarization. Ictal epileptic activity describes the partial disruption, and spreading depolarization describes the near-complete disruption of the physiological double Gibbs-Donnan steady state. The occurrence of ictal epileptic activity in patients has been known for decades. Recently, unequivocal electrophysiological evidence has been found in patients that spreading depolarizations occur abundantly in stroke and brain trauma. The authors propose that the ion changes can be taken to estimate relative changes in Gibbs free energy from state to state. The calculations suggest that in transitions from the physiological state to ictal epileptic activity to spreading depolarization to death, the cortex releases Gibbs free energy in a stepwise fashion. Spreading depolarization thus appears as a twilight state close to death. Consistently, electrocorticographic recordings in the core of focal ischemia or after cardiac arrest display a smooth transition from the initial spreading depolarization component to the later ultraslow negative potential, which is assumed to reflect processes in cellular death.