Thalamo-cortical network activity between migraine attacks. Insights from MRI-based microstructural and functional resting-state network correlation analysis

BACKGROUND: Resting state magnetic resonance imaging allows studying functionally interconnected brain networks. Here we were aimed to verify functional connectivity between brain networks at rest and its relationship with thalamic microstructure in migraine without aura (MO) patients between attacks. METHODS: Eighteen patients with untreated MO underwent 3 T MRI scans and were compared to a group of 19 healthy volunteers (HV). We used MRI to collect resting state data among two selected resting state networks, identified using group independent component (IC) analysis. Fractional anisotropy (FA) and mean diffusivity (MD) values of bilateral thalami were retrieved from a previous diffusion tensor imaging study on the same subjects and correlated with resting state ICs Z-scores. RESULTS: In comparison to HV, in MO we found significant reduced functional connectivity between the default mode network and the visuo-spatial system. Both HV and migraine patients selected ICs Z-scores correlated negatively with FA values of the thalamus bilaterally. CONCLUSIONS: The present results are the first evidence supporting the hypothesis that an abnormal resting within networks connectivity associated with significant differences in baseline thalamic microstructure could contribute to interictal migraine pathophysiology

Altered processing of sensory stimuli in patients with migraine

Migraine is a cyclic disorder, in which functional and morphological brain changes fluctuate over time, culminating periodically in an attack. In the migrainous brain, temporal processing of external stimuli and sequential recruitment of neuronal networks are often dysfunctional. These changes reflect complex CNS dysfunction patterns. Assessment of multimodal evoked potentials and nociceptive reflex responses can reveal altered patterns of the brain's electrophysiological activity, thereby aiding our understanding of the pathophysiology of migraine. In this Review, we summarize the most important findings on temporal processing of evoked and reflex responses in migraine. Considering these data, we propose that thalamocortical dysrhythmia may be responsible for the altered synchronicity in migraine. To test this hypothesis in future research, electrophysiological recordings should be combined with neuroimaging studies so that the temporal patterns of sensory processing in patients with migraine can be correlated with the accompanying anatomical and functional changes

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 a ghost 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 subforms. We suggest a congruence between the prevalence of MO and MA with the statistical properties of the traveling waves' forms, according to which (i) activation of nociceptive mechanisms relevant for headache is dependent upon a sufficiently large instantaneous affected cortical area anti-correlated to both SD duration and total affected cortical area such that headache would be less severe in MA than in MO (ii) the incidence of MA is reflected in the distance to the saddle-node bifurcation, and (iii) 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.Comment: 14 pages, 11 figure

Resting-state EEG power and coherence vary between migraine phases

© 2016, The Author(s). Background: Migraine is characterized by a series of phases (inter-ictal, pre-ictal, ictal, and post-ictal). It is of great interest whether resting-state electroencephalography (EEG) is differentiable between these phases. Methods: We compared resting-state EEG energy intensity and effective connectivity in different migraine phases using EEG power and coherence analyses in patients with migraine without aura as compared with healthy controls (HCs). EEG power and isolated effective coherence of delta (1–3.5 Hz), theta (4–7.5 Hz), alpha (8–12.5 Hz), and beta (13–30 Hz) bands were calculated in the frontal, central, temporal, parietal, and occipital regions. Results: Fifty patients with episodic migraine (1–5 headache days/month) and 20 HCs completed the study. Patients were classified into inter-ictal, pre-ictal, ictal, and post-ictal phases (n = 22, 12, 8, 8, respectively), using 36-h criteria. Compared to HCs, inter-ictal and ictal patients, but not pre- or post-ictal patients, had lower EEG power and coherence, except for a higher effective connectivity in fronto-occipital network in inter-ictal patients (p <.05). Compared to data obtained from the inter-ictal group, EEG power and coherence were increased in the pre-ictal group, with the exception of a lower effective connectivity in fronto-occipital network (p <.05). Inter-ictal and ictal patients had decreased EEG power and coherence relative to HCs, which were “normalized” in the pre-ictal or post-ictal groups. Conclusion: Resting-state EEG power density and effective connectivity differ between migraine phases and provide an insight into the complex neurophysiology of migraine

Two-dimensional wave patterns of spreading depolarization: retracting, re-entrant, and stationary waves

We present spatio-temporal characteristics of spreading depolarizations (SD) in two experimental systems: retracting SD wave segments observed with intrinsic optical signals in chicken retina, and spontaneously occurring re-entrant SD waves that repeatedly spread across gyrencephalic feline cortex observed by laser speckle flowmetry. A mathematical framework of reaction-diffusion systems with augmented transmission capabilities is developed to explain the emergence and transitions between these patterns. Our prediction is that the observed patterns are reaction-diffusion patterns controlled and modulated by weak nonlocal coupling. The described spatio-temporal characteristics of SD are of important clinical relevance under conditions of migraine and stroke. In stroke, the emergence of re-entrant SD waves is believed to worsen outcome. In migraine, retracting SD wave segments cause neurological symptoms and transitions to stationary SD wave patterns may cause persistent symptoms without evidence from noninvasive imaging of infarction

A Systems Neuroscience Approach to Migraine

Migraine is an extremely common but poorly understood nervous system disorder. We conceptualize migraine as a disorder of sensory network gain and plasticity, and we propose that this framing makes it amenable to the tools of current systems neuroscience

Short-term synaptic plasticity in chronic migraine with medication overuse

The International Classification of Headache Disorders defines medication overuse headache (MOH) as headaches occurring ≥ 15 days per month for a period of at least 3 months as the result of excessive intake of acute medications such as non-steroidal analgesic drugs (NSAIDs) and triptans. Several electrophysiological studies have investigated the pathophysiology of MOH and demonstrated that patients with MOH exhibit characteristic neurophysiological abnormalities. For example, patients with MOH show response sensitisation of the somatosensory cortex in response to different repetitive sensorial stimulations, demonstrated by an initial increase in the amplitude of evoked potentials. Patients with MOH also exhibit impaired amplitude habituation, defined as the absence of a decrease in amplitude in response to repeated stimulation. Since habituation is a basic form of learning, these findings suggested that patients with MOH experience alterations in neural plasticity and learning processes. We recently assessed neural plasticity in the motor cortex of chronic migraineurs with and without medication overuse using low- and high-frequency repetitive transcranial magnetic stimulation (rTMS). We found that, depending on the duration of overuse headache, patients did not show short-term potentiation of motor evoked potentials in response to facilitatory trains of rTMS. In contrast, chronic migraineurs without medication overuse showed normal responses to inhibitory/facilitatory trains of rTMS. These observations led us to hypothesise that medication overuse induces a dysfunctional state of brain plasticity. On this premise, we further speculated that medication-induced alterations in short-term plasticity would normalise after the discontinuation of medication overuse. Withdrawal from acute medication is the first-choice strategy in the management of MOH patients, but the mechanisms involved in clinical improvement after detoxification are not clear, even though numerous structural and functional neuroimaging studies showed that detoxification is associated to normalization of gray matter volume and connectivity of several brain areas involved in pain processing, cognition and planning strategies. The aim of this study was to examine responses of patients with MOH to both low- and high-frequency rTMS over the motor cortex before and after drug withdrawal in comparison to normal subjects in order to understand the characteristics of short-term plasticity dysfunction in MOH. We found that the dysfunctions in short term potentiation mechanisms in MOH are fully reversible after withdrawal, indicating that this strategy may achieve clinical improvement by restoring the physiological brain plasticity. This finding adds to the importance of starting a withdrawal treatment as early as possible in patients with MOH in order to facilitate normalisation of brain plasticity mechanisms

Unique neural mechanisms of the migraine brain

Whether migraine pathophysiology stems from vascular or centrally-driven origins has been debated for decades. However, facilitated by the development of modern neural imaging techniques and scientific technology, the last century has seen the largest advance in our understanding of migraine. It is now well accepted that sensitization of the trigeminovascular pathway plays a crucial role in the initiation and expression of a migraine. This is supported by experimental human studies that revealed abnormal activity of the trigeminovascular system. This abnormal activity was found particularly in areas of the brainstem, midbrain and hypothalamus during a migraine attack itself and during the interictal period, that is at least 72 hours following and not within 24 hours before a migraine. Research into the premonitory period, the critical 24-hour pain-free period preceding a migraine, is scarce and as a result, there is a gap in our understanding of how and why sensitization occurs. It may be that altered brain function, particularly in brainstem sites, may either trigger a migraine itself or facilitate a peripheral trigger that activates certain pain-processing brain regions, resulting in head pain. As it is impossible to predict when a migraine is imminent, few studies have investigated the premonitory period. Understanding the underlying mechanisms of the migraine cycle has potential to transform the way migraine disorder is treated. The aim of this thesis was to identify functional brain differences throughout the migraine cycle, in particular in the critical 24-hour pain-free period preceding a migraine. The first investigation (Chapter 2) aimed to identify if neural activity within the brainstem and hypothalamus would alter over the migraine cycle. I employed high-resolution functional magnetic imaging (fMRI) to measure ongoing activity patterns reflected through infra-slow oscillations (ISOs) and functional connectivity in the interictal, postdrome and premonitory periods of migraine compared with controls. A comparison between all groups provided evidence of unique activity in the 24-hour period immediately preceding a migraine. Increased ISO activity occurred exclusively in this period in areas of the trigeminovascular system including the spinal trigeminal nucleus (SpV), midbrain periaqueductal gray (PAG), dorsal pons, thalamus and hypothalamus. Remarkably, midbrain and hypothalamic sites were found to display increased functional connectivity and regional homogeneity immediately preceding a migraine suggesting a role for the PAG-hypothalamic interaction in migraine expression. Importantly, interictal and postdrome groups displayed similar activity as control groups, highlighting the unique nature of the premonitory period. It is possible that these increases in ISO power and regional homogeneity result from enhanced amplitude and synchrony of oscillatory gliotransmitter release immediately before a migraine attack, thus supporting the role of astrocytes and gliotransmission in migraine initiation and/or expression. These findings have never been reported in the premonitory period of migraine and reflect altered brainstem and hypothalamic function immediately preceding a migraine. Along with the central nervous system, cerebral vasculature changes have been strongly implicated as critical for migraine initiation. The second investigation (Chapter 3) aimed to build on my previous study by determining whether changes in absolute activity levels, reflected through abnormal cerebral blood flow (CBF), could be identified throughout the migraine cycle. I used pseudocontinuous arterial spin labelling (pcASL) to measure CBF in the interictal, postdrome and premonitory periods of migraine compared with controls. In line with the findings of my first investigation, this analysis revealed distinctive activity in the 24-hour period immediately preceding a migraine with decreased CBF in the hypothalamus, PAG and SpV. In addition, decreased CBF was revealed in higher brain structures such as the visual cortex, orbitofrontal cortex (OFC) and retrosplenial cortex. These findings also reflected alterations in the interictal group with decreases in CBF detected in higher brain structures including the nucleus accumbens, putamen, OFC and ventrolateral prefrontal cortex. Remarkably, decreased CBF in brainstem regions was found only in the period immediately preceding a migraine and these decreases occurred suddenly, as opposed to the decreased CBF found in the higher brain regions which tended to occur gradually throughout the interictal period as the migraine approached. The specialized activity of the brainstem in the period immediately preceding a migraine further emphasizes that brainstem abnormalities are involved in the initiation and/or expression of a migraine. Though many studies have explored CBF during other periods of migraine, this is the first study to measure resting CBF during the 24-hour period immediately preceding a migraine using ASL, and furthermore, to couple ongoing activity patterns (Chapter 2) with absolute brain activity. The first two cross-sectional investigations (Chapters 2 and 3) revealed unique abnormal activity in the 24-hour period immediately preceding a migraine in areas of the brainstem, midbrain and hypothalamus. However, it remains unknown whether similar patterns would be revealed in a longitudinal study when comparing periods throughout an individual’s migraine cycle. To complete this thesis, the third investigation (Chapter 4) aimed to follow the migraine cycle of three migraineurs by imaging them five days a week over four weeks. Due to the cyclic nature of migraine, I expected that when comparing the activity in the 24-hour period immediately preceding a migraine with other periods of migraine within these individuals, the findings would reflect similar patterns as our cross-sectional studies. Indeed, using fMRI I explored resting brainstem activity patterns and found that although resting activity variability was similar in controls and migraineurs on most days, during the period immediately preceding a migraine, brainstem variability increased dramatically. These increases in resting variability were restricted to specific areas of the pain processing pathway including the SpV and dorsal pons. Remarkably, these changes were located in the same brainstem regions which have been shown to be activated during a migraine itself, but again they occurred whilst the individual was not in pain. These increases in brainstem variability were characterised by increased power at ISOs between 0.03-0.06 Hz and they were coupled to increases in resting regional homogeneity directly prior to a migraine. These oscillatory and regional homogeneity changes are consistent with the idea that changes in astrocyte function may precede a migraine and be responsible for its initiation and/or maintenance. These data provide the first evidence of altered brainstem function directly before a migraine throughout the migraine cycle of multiple individuals and provide compelling evidence for the hypothesis that brainstem function is altered immediately before a migraine. Overall, these data reveal that the 24-hour period immediately preceding a migraine possesses unique qualities that may be crucial in the initiation and/or expression of the migraine. My findings reflect abnormal activity of the trigeminovascular system, in particular in areas of the brainstem, midbrain and hypothalamus. I found increases in ongoing activity patterns in the 24-hour period immediately preceding a migraine only, however abnormalities in absolute activity levels were also found in higher brain structures in the interictal period. Finally, when exploring the migraine cycle within three individuals, I found that the 24-hour period immediately preceding a migraine reflected very similar patterns to those revealed in my cross-sectional studies; relatively stable activity until the 24-hour period preceding a migraine, where a sudden over-exaggeration of activity occurred. It seems that migraine is indeed a cyclic disorder with brainstem function oscillating between altered states