Attacks of migraine with aura represent a phenomenon in which abnormal neuronal activity in the cortex produces sensory disturbances (aura) some 20-40 min before the onset of headache. The purpose of ...this study was to determine whether cortical spreading depression (CSD)--an event believed to underlie visual aura--can give rise to activation of nociceptors that innervate the meninges--an event believed to set off migraine headache. CSD was induced in anesthetized male rats by stimulation of the visual cortex with electrical pulses, pin prick, or KCl; single-unit activity of meningeal nociceptors was monitored in vivo in the rat before and after CSD. Regardless of the method of cortical stimulation, induction of CSD was recorded in 64 trials. In 31 of those trials, CSD induced a twofold increase in meningeal nociceptor firing rate that persisted for 37.0 +/- 4.6 min in trials in which activity returned to baseline, or >68 min in trials in which activity remained heightened at the time recording was interrupted. In two-thirds of the trials, onset of long-lasting neuronal activation began approximately 14 min after the wave of CSD. The findings demonstrates for the first time that induction of CSD by focal stimulation of the rat visual cortex can lead to long-lasting activation of nociceptors that innervate the meninges. We suggest that migraine with aura is initiated by waves of CSD that lead up to delayed activation of the trigeminovascular pathway.
Scientific evidence supports the notion that migraine pathophysiology involves inherited alteration of brain excitability, intracranial arterial dilatation, recurrent activation, and sensitization of ...the trigeminovascular pathway, and consequential structural and functional changes in genetically susceptible individuals. Evidence of altered brain excitability emerged from clinical and preclinical investigation of sensory auras, ictal and interictal hypersensitivity to visual, auditory, and olfactory stimulation, and reduced activation of descending inhibitory pain pathways. Data supporting the activation and sensitization of the trigeminovascular system include the progressive development of cephalic and whole-body cutaneous allodynia during a migraine attack. In addition, structural and functional alterations include the presence of subcortical white mater lesions, thickening of cortical areas involved in processing sensory information, and cortical neuroplastic changes induced by cortical spreading depression. Here, we review recent anatomical data on the trigeminovascular pathway and its activation by cortical spreading depression, a novel understanding of the neural substrate of migraine-type photophobia, and modulation of the trigeminovascular pathway by the brainstem, hypothalamus and cortex.
Migraine is a common, multifactorial, disabling, recurrent, hereditary neurovascular headache disorder. It usually strikes sufferers a few times per year in childhood and then progresses to a few ...times per week in adulthood, particularly in females. Attacks often begin with warning signs (prodromes) and aura (transient focal neurological symptoms) whose origin is thought to involve the hypothalamus, brainstem, and cortex. Once the headache develops, it typically throbs, intensifies with an increase in intracranial pressure, and presents itself in association with nausea, vomiting, and abnormal sensitivity to light, noise, and smell. It can also be accompanied by abnormal skin sensitivity (allodynia) and muscle tenderness. Collectively, the symptoms that accompany migraine from the prodromal stage through the headache phase suggest that multiple neuronal systems function abnormally. As a consequence of the disease itself or its genetic underpinnings, the migraine brain is altered structurally and functionally. These molecular, anatomical, and functional abnormalities provide a neuronal substrate for an extreme sensitivity to fluctuations in homeostasis, a decreased ability to adapt, and the recurrence of headache. Advances in understanding the genetic predisposition to migraine, and the discovery of multiple susceptible gene variants (many of which encode proteins that participate in the regulation of glutamate neurotransmission and proper formation of synaptic plasticity) define the most compelling hypothesis for the generalized neuronal hyperexcitability and the anatomical alterations seen in the migraine brain. Regarding the headache pain itself, attempts to understand its unique qualities point to activation of the trigeminovascular pathway as a prerequisite for explaining why the pain is restricted to the head, often affecting the periorbital area and the eye, and intensifies when intracranial pressure increases.
This study analysed the organization of central nervous system networks involved in the processing of meningeal inputs in the male, Sprague-Dawley rat. We injected the anterograde tracer, biotin ...dextran, into areas of the medullary trigeminal nucleus caudalis (Sp5C), which receive inputs from the ophthalmic division of the trigeminal nerve. Double-labelling immunohistochemical studies were then performed to compare calcitonin gene-related peptide (CGRP) or serotonin 1D (5HT1D) receptor distributions in the areas innervated by Sp5C neurons. Dense, topographically organized intratrigeminal connections were observed. Sp5C neurons projected to the commissural subnucleus of the solitary tract, A5 cell group region/superior salivatory nucleus, lateral periaqueductal grey matter, inferior colliculus and parabrachial nuclei. Trigeminothalamic afferents were restricted to the posterior group and ventroposteromedial thalamic nuclei. Some of these areas are also immunoreactive for 5HT1D and CGRP and thus remain potential central targets of triptan molecules and other antimigraine drugs.
Objective:
Cortical spreading depression (CSD) has long been implicated in migraine attacks that begin with visual aura. Having shown that a wave of CSD can trigger long‐lasting activation of ...meningeal nociceptors—the first‐order neurons of the trigeminovascular pathway thought to underlie migraine headache—we now report that CSD can activate central trigeminovascular neurons in the spinal trigeminal nucleus (C1–2).
Methods:
Stimulation of the cortex with pinprick or KCl granule was used to induce CSD in anesthetized rats. Neuronal activity was monitored in C1–2 using single‐unit recording.
Results:
In 25 trigeminovascular neurons activated by CSD, mean firing rate (spikes/s) increased from 3.6 ± 1.2 before CSD (baseline) to 6.1 ± 1.8 after CSD (p < 0.0001) for a period >13 minutes. Neuronal activity returned to baseline level after 30.0 ± 3.1 minutes in 14 units, and remained elevated for 66.0 ± 8.3 (22–108) minutes through the entire recording period in the other 11 units. Neuronal activation began within 0.9 ± 0.4 (0–2.5) minutes after CSD in 7 neurons located in laminae I–II, or after a latency of 25.1 ± 4.0 (7–75) minutes in 9 neurons located in laminae I–II, and 9 neurons located in laminae III–V. In 27 trigeminovascular neurons not activated by CSD, mean firing rate was 2.0 ± 0.7 at baseline and 1.8 ± 0.7 after CSD.
Interpretation:
We propose that CSD constitutes a nociceptive stimulus capable of activating peripheral and central trigeminovascular neurons that underlie the headache of migraine with aura. ANN NEUROL 2011;
Historically, photophobia was studied in patients and attempts to explain the underlying mechanisms have been speculative. Efforts to understand better the neural substrate of photophobia paved a way ...to the development of different animal models and the publication of several articles (all in 2010) on the mechanism by which light exacerbates migraine headache.
Observations made in blind migraine patients devoid of any visual perception and blind migraine patients capable of detecting light have led to the discovery of a novel retino-thalamo-cortical pathway that carries photic signal from the retina to thalamic trigeminovascular neurons believed to play a critical role in the perception of headache intensity during migraine. Evidence for modulation of the trigeminovascular pathway by light and identification of the pathway through which photic signals converge on the nociceptive pathway that mediates migraine headache provide first set of scientific data on the mechanism by which light intensifies migraine headache.
The findings provide a neural substrate for migraine-type photophobia. This may lead to identification and development of molecular targets for selective prevention of photophobia during migraine.
Dynamic thalamic regulation of sensory signals allows the cortex to adjust better to rapidly changing behavioral, physiological and environmental demands. To fulfill this role, thalamic neurons must ...themselves be subjected to constantly changing modulatory inputs that originate in multiple neurochemical pathways involved in autonomic, affective and cognitive functions. Our overall goal is to define an anatomical framework for conceptualizing how a 'decision' is made on whether a trigeminovascular thalamic neuron fires, for how long, and at what frequency. To begin answering this question, we determine which neuropeptides/neurotransmitters are in a position to modulate thalamic trigeminovascular neurons. Using a combination of in-vivo single-unit recording, juxtacellular labeling with tetramethylrhodamine dextran (TMR) and in-vitro immunohistochemistry, we found that thalamic trigeminovascular neurons were surrounded by high density of axons containing biomarkers of glutamate, GABA, dopamine and serotonin; moderate density of axons containing noradrenaline and histamine; low density of axons containing orexin and melanin concentrating hormone (MCH); but not axons containing CGRP, serotonin 1D receptor, oxytocin or vasopressin. In the context of migraine, the findings suggest that the transmission of headache-related nociceptive signals from the thalamus to the cortex may be modulated by opposing forces (i.e., facilitatory, inhibitory) that are governed by continuous adjustments needed to keep physiological, behavioral, cognitive and emotional homeostasis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The authors studied the landscape components that favour the occurrence of anthrax in the Flooding Pampa grasslands (Buenos Aires province, Argentina). They made spatial locations of anthrax ...outbreaks diagnosed by registered veterinary laboratories in the study area's zone of influence. As variables for study, they differentiated areas that are flooded for 20% of the time or more from primary and secondary runoff channels. They also identified areas with low-productivity pasture. Logistic regression analysis of farm populations revealed that landscape components favouring the occurrence of anthrax outbreaks are shared runoff channels (odds ratio (OR) = 2.3; confidence interval (CI) = 1.2; 4.7) and > or = 40% low-productivity pasture (OR = 5.4; CI = 3.5; 8.3). Contrary to initial assumptions, susceptibility to flooding was not a significant variable (OR = 1.1; CI = 0.5; 2.1). The authors concluded that the first step in decision-making and ensuring more efficient implementation of future anthrax control and eradication plans was to identify risk variables.
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