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Migraine Disorders: HELP
Articles by Rami Burstein
Based on 64 articles published since 2008
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Between 2008 and 2019, R. Burstein wrote the following 64 articles about Migraine Disorders.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial The enigma of the dorsolateral pons as a migraine generator. 2012

Borsook, D / Burstein, R. · ·Cephalalgia · Pubmed #22798640.

ABSTRACT: In this editorial, we integrate improved understanding of functional and structural brain stem anatomy with lessons learned from other disciplines on brainstem function to provide an alternative interpretation to the data used to support the brainstem migraine generator theory.

2 Editorial The vascular theory of migraine: leave it or love it? 2011

Levy, Dan / Burstein, Rami. · ·Ann Neurol · Pubmed #21520229.

ABSTRACT: -- No abstract --

3 Editorial Almotriptan efficacy in migraine with allodynia: a critique of Schoenen et al. 2009

Burstein, R / Jakubowski, M. · ·Cephalalgia · Pubmed #19366354.

ABSTRACT: -- No abstract --

4 Review Neuropeptides and Neurotransmitters That Modulate Thalamo-Cortical Pathways Relevant to Migraine Headache. 2017

Noseda, Rodrigo / Borsook, David / Burstein, Rami. ·Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. · Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. ·Headache · Pubmed #28485844.

ABSTRACT: 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. This review defines a chemical framework for thinking about the complexity of factors that modulate the response properties of relay trigeminovascular thalamic neurons. Following the presentation of scientific evidence for monosynaptic connections between thalamic trigeminovascular neurons and axons containing glutamate, GABA, dopamine, noradrenaline, serotonin, histamine, orexin, and melanin-concentrating hormone, this review synthesizes a large body of data to propose that the transmission of headache-related nociceptive signals from the thalamus to the cortex is modulated by potentially opposing forces and that the so-called 'decision' of which system (neuropeptide/neurotransmitter) will dominate the firing of a trigeminovascular thalamic neuron at any given time is determined by the constantly changing physiological (sleep, wakefulness, food intake, body temperature, heart rate, blood pressure), behavioral (addiction, isolation), cognitive (attention, learning, memory use), and affective (stress, anxiety, depression, anger) adjustment needed to keep homeostasis.

5 Review Extracranial origin of headache. 2017

Burstein, Rami / Blake, Pamela / Schain, Aaron / Perry, Carlton. ·aDepartment of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center bDepartment of Anesthesia, Harvard Medical School, Boston, Massachusetts cHeadache Center of Greater Heights, Memorial Hermann Medical Group dRiver Oaks Plastic Surgery Center, Houston, Texas, USA. ·Curr Opin Neurol · Pubmed #28248698.

ABSTRACT: PURPOSE OF REVIEW: To summarize recent clinical and preclinical studies on extracranial pathophysiologies in migraine. It challenges the opinion-based notion that the headache phase of migraine occurs without input from peripheral nociceptors or is caused solely by activation of intracranial nociceptors supplying dural and cerebral vasculature. RECENT FINDINGS: Data that support a scenario by which migraine can originate extracranially include the perception of imploding headache that hurts outside the cranium, the existence of a network of sensory fibers that bifurcate from parent axons of intracranial meningeal nociceptors and reach extracranial tissues such as periosteum and pericranial muscles by crossing the calvarial bones through the sutures, the discovery of proinflammatory genes that are upregulated and anti-inflammatory genes that are down regulated in extracranial tissue of chronic migraine patients, and evidence that administration of OnabotulinumtoxinA to peripheral tissues outside the calvaria reduces frequency of migraine headache. SUMMARY: These findings seeks to shift clinical practice from prophylactically treating chronic migraine solely with medications that reduce neuronal excitability to treating irritated nociceptors or affected tissues. The findings also seeks to shift current research from focusing solely on central nervous system alterations and activation of meningeal nociceptors as a prerequisite for studying migraine.

6 Review The Insula: A "Hub of Activity" in Migraine. 2016

Borsook, David / Veggeberg, Rosanna / Erpelding, Nathalie / Borra, Ronald / Linnman, Clas / Burstein, Rami / Becerra, Lino. ·Pain/Analgesia Imaging Neuroscience (P.A.I.N.) Group, Department of Anesthesia, Boston Children's Hospital, Center for Pain and the Brain, Harvard Medical School, Waltham, MA, USA david.borsook@childrens.harvard.edu. · Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA. · Departments of Psychiatry and Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. · Pain/Analgesia Imaging Neuroscience (P.A.I.N.) Group, Department of Anesthesia, Boston Children's Hospital, Center for Pain and the Brain, Harvard Medical School, Waltham, MA, USA. · Department of Anesthesia, Beth Israel Deaconess Hospital, Harvard Medical School, Boston, MA, USA. ·Neuroscientist · Pubmed #26290446.

ABSTRACT: The insula, a "cortical hub" buried within the lateral sulcus, is involved in a number of processes including goal-directed cognition, conscious awareness, autonomic regulation, interoception, and somatosensation. While some of these processes are well known in the clinical presentation of migraine (i.e., autonomic and somatosensory alterations), other more complex behaviors in migraine, such as conscious awareness and error detection, are less well described. Since the insula processes and relays afferent inputs from brain areas involved in these functions to areas involved in higher cortical function such as frontal, temporal, and parietal regions, it may be implicated as a brain region that translates the signals of altered internal milieu in migraine, along with other chronic pain conditions, through the insula into complex behaviors. Here we review how the insula function and structure is altered in migraine. As a brain region of a number of brain functions, it may serve as a model to study new potential clinical perspectives for migraine treatment.

7 Review Migraine: multiple processes, complex pathophysiology. 2015

Burstein, Rami / Noseda, Rodrigo / Borsook, David. ·Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, Harvard Medical School, Boston, Massachusetts 02115 rburstei@bidmc.harvard.edu. · Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, Harvard Medical School, Boston, Massachusetts 02115. · Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, and Harvard Medical School, Boston, Massachusetts 02115. ·J Neurosci · Pubmed #25926442.

ABSTRACT: 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.

8 Review Sex and the migraine brain. 2014

Borsook, D / Erpelding, N / Lebel, A / Linnman, C / Veggeberg, R / Grant, P E / Buettner, C / Becerra, L / Burstein, R. ·Boston Children's Hospital P.A.I.N. Group, Boston Children's Hospital, USA; Massachusestts General Hospital, Boston Children's Hospital, USA; Harvard Medical School, USA. Electronic address: david.borsook@childrens.harvard.edu. · Boston Children's Hospital P.A.I.N. Group, Boston Children's Hospital, USA; Harvard Medical School, USA. · Boston Children's Hospital P.A.I.N. Group, Boston Children's Hospital, USA; Headache Clinic, Boston Children's Hospital, USA; Harvard Medical School, USA. · Boston Children's Hospital P.A.I.N. Group, Boston Children's Hospital, USA; Massachusestts General Hospital, Boston Children's Hospital, USA; Harvard Medical School, USA. · Fetal-Neonatal Neuroimaging and Developmental Science Center (FNNDSC), Boston Children's Hospital, USA; Harvard Medical School, USA. · Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, USA; Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, USA; Harvard Medical School, USA. · Harvard Medical School, USA. ·Neurobiol Dis · Pubmed #24662368.

ABSTRACT: The brain responds differently to environmental and internal signals that relate to the stage of development of neural systems. While genetic and epigenetic factors contribute to a premorbid state, hormonal fluctuations in women may alter the set point of migraine. The cyclic surges of gonadal hormones may directly alter neuronal, glial and astrocyte function throughout the brain. Estrogen is mainly excitatory and progesterone inhibitory on brain neuronal systems. These changes contribute to the allostatic load of the migraine condition that most notably starts at puberty in girls.

9 Review Migraine Mistakes: Error Awareness. 2014

Borsook, David / Aasted, Christopher M / Burstein, Rami / Becerra, Lino. ·Center for Pain and the Brain and PAIN Group (Boston Children's Hospital, Massachusetts General Hospital, and McLean Hospital), Harvard Medical School, Boston, MA, USA dborsook@partners.org. · Center for Pain and the Brain and PAIN Group (Boston Children's Hospital, Massachusetts General Hospital, and McLean Hospital), Harvard Medical School, Boston, MA, USA. · Beth Israel Deaconess Hospital, Harvard Medical School, Boston, MA, USA. ·Neuroscientist · Pubmed #24047609.

ABSTRACT: Error awareness or detection is the conscious and subconscious processing to evaluate physiological signals that are different from a baseline or homeostatic level. Migraine is a unique neurological disorder in which there are repeated attacks interspersed by attack-free periods. These attacks are dynamic and multidimensional in the sense that sensory, affective, autonomic, and cognitive functions are altered and these changes evolve differently before (pre-ictal), during (ictal), and immediately after (post-ictal) an attack. Thus migraine serves as a model disease to understand how the brain monitors and react to the presence of errors.

10 Review Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain. 2013

Noseda, Rodrigo / Burstein, Rami. ·Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address: rnoseda@bidmc.harvard.edu. ·Pain · Pubmed #23891892.

ABSTRACT: 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.

11 Review The science of migraine. 2011

Burstein, Rami / Jakubowski, Moshe / Rauch, Steven D. ·Departments of Anesthesia, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. rburstei@bidmc.harvard.edu ·J Vestib Res · Pubmed #22348935.

ABSTRACT: The cardinal symptom of migraine is headache pain. In this paper we review the neurobiology of this pain as it is currently understood. In recent years, we discovered that the network of neurons that sense pain signals from the dura changes rapidly during the course of a single migraine attack and that the treatment of an attack is a moving target. We found that if the pain is not stopped within 10-20 minutes after it starts, the first set of neurons in the network, those located in the trigeminal ganglion, undergo molecular changes that make them hypersensitive to the changing pressure inside the head, which explains why migraine headache throbs and is worsened by bending over and sneezing. We found that if the pain is not stopped within 60-120 minutes, the second group of neurons in the network, those located in the spinal trigeminal nucleus, undergoes molecular changes that convert them from being dependent on sensory signals they receive from the dura by the first set of neurons, into an independent state in which they themselves become the pain generator of the headache. When this happens, patients notice that brushing their hair, taking a shower, touching their periorbital skin, shaving, wearing earrings, etc become painful, a condition called cutaneous allodynia. Based on this scenario, we showed recently that the success rate of rendering migraine patients pain-free increased dramatically if medication was given before the establishment of cutaneous allodynia and central sensitization. The molecular shift from activity-dependent to activity-independent central sensitization together with our recent conclusion that triptans have the ability to disrupt communications between peripheral and central trigeminovascular neurons (rather than inhibiting directly peripheral or central neurons) explain their clinical effects. Both our clinical and pre-clinical findings of the last five years point to possible short- and long-term advantages in using an early-treatment approach in the treatment of acute migraine attacks.

12 Review A critical view on the role of migraine triggers in the genesis of migraine pain. 2009

Levy, Dan / Strassman, Andrew M / Burstein, Rami. ·Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. ·Headache · Pubmed #19545256.

ABSTRACT: A number of distinct endogenous and exogenous factors have been implicated in migraine precipitation but the exact nature of the triggering process itself and its relationship to the genesis of the headache remains largely speculative. In this article, we examine the potential sites and downstream cascades through which migraine triggers might exert their action to promote the activation of the migraine pain pathway. We further look at the laterality of the headache as a potential indicator for the site of migraine pain initiation and examine the question of triggering factor specificity in relation to the current understanding of migraine pathophysiology.

13 Review Origin of pain in migraine: evidence for peripheral sensitisation. 2009

Olesen, Jes / Burstein, Rami / Ashina, Messoud / Tfelt-Hansen, Peer. ·Danish Headache Center and Department of Neurology, Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, DK-2600 Glostrup, Copenhagen, Denmark. jeol@glo.regionh.dk ·Lancet Neurol · Pubmed #19539239.

ABSTRACT: Migraine is the most common neurological disorder, and much has been learned about its mechanisms in recent years. However, the origin of painful impulses in the trigeminal nerve is still uncertain. Despite the attention paid recently to the role of central sensitisation in migraine pathophysiology, in our view, neuronal hyperexcitability depends on activation of peripheral nociceptors. Although the onset of a migraine attack might take place in deep-brain structures, some evidence indicates that the headache phase depends on nociceptive input from perivascular sensory nerve terminals. The input from arteries is probably more important than the input from veins. Several studies provide evidence for input from extracranial, dural, and pial arteries but, likewise, there is also evidence against all three of these locations. On balance, afferents are most probably excited in all three territories or the importance of individual territories varies from patient to patient. We suggest that migraine can be explained to patients as a disorder of the brain, and that the headache originates in the sensory fibres that convey pain signals from intracranial and extracranial blood vessels.

14 Clinical Trial Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. 2015

Bigal, Marcelo E / Dodick, David W / Rapoport, Alan M / Silberstein, Stephen D / Ma, Yuju / Yang, Ronghua / Loupe, Pippa S / Burstein, Rami / Newman, Lawrence C / Lipton, Richard B. ·Research and Development Department, Teva Pharmaceuticals, Frazer, PA, USA. Electronic address: marcelo.bigal@tevapharm.com. · Department of Neurology, Mayo Clinic, Phoenix, AZ, USA. · The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · Department of Neurology, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA, USA. · Statistics Department, Teva Pharmaceuticals, Frazer, PA, USA. · Research and Scientific Affairs Department, Teva Pharmaceuticals, Frazer, PA, USA. · Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. · Headache Institute and St Luke's-Roosevelt Hospital Center, New York, NY, USA. · Department of Neurology, Albert Einstein College of Medicine, New York, NY, USA. ·Lancet Neurol · Pubmed #26432182.

ABSTRACT: BACKGROUND: Calcitonin gene-related peptide (CGRP) is a validated target for the treatment of episodic migraine. Here we assess the safety, tolerability, and efficacy of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of high-frequency episodic migraine. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 2b study, we enrolled men and women (aged 18-65 years) from 62 sites in the USA who had migraine headaches 8-14 days per month. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1; stratified by sex and use of concomitant preventive drugs) after a 28 day run-in period to three 28 day treatment cycles of subcutaneous 225 mg TEV-48125, 675 mg TEV-48125, or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Patients reported headache information daily using an electronic diary. Primary endpoints were change from baseline in migraine days during the third treatment cycle (weeks 9-12) and safety and tolerability. The secondary endpoint was change relative to baseline in headache-days during weeks 9-12. Efficacy endpoints were analysed for the intention-to-treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered at ClinicalTrials.gov, number NCT02025556. FINDINGS: Between Jan 8, 2014, and Oct 15, 2014, we enrolled 297 participants: 104 were randomly assigned to receive placebo, 95 to receive 225 mg TEV-48125, and 96 to receive 675 mg TEV-48125. The least square mean (LSM) change in number of migraine-days from baseline to weeks 9-12 was -3.46 days (SD 5.40) in the placebo group, -6.27 days (5.38) in the 225 mg dose group, and -6.09 days (5.22) in the 675 mg dose group. The LSM difference in the reduction of migraine-days between the placebo and 225 mg dose groups was -2.81 days (95% CI -4.07 to -1.55; p<0.0001), whereas the difference between the placebo and 675 mg dose group was -2.64 days (-3.90 to -1.38; p<0.0001). LSM differences in the reduction of headache-days were -2.63 days (-3.91 to -1.34; p<0.0001) between the placebo group and 225 mg dose group and -2.58 days (-3.87 to 1.30; p <0.0001) between the placebo group and the 675 mg dose group. Adverse events occurred in 58 (56%) patients in the placebo group, 44 (46%) patients in the 225 mg dose group, and 57 (59%) patients in the 675 mg dose group; moderate or severe adverse events were reported for 29 (27%) patients, 24 (25%) patients, and 26 (27%) patients, respectively. INTERPRETATION: TEV-48125, at doses of 225 mg and 675 mg given once every 28 days for 12 weeks, was safe, well tolerated, and effective as a preventive treatment of high-frequency episodic migraine, thus supporting advancement of the clinical development programme to phase 3 clinical trials. FUNDING: Teva Pharmaceuticals.

15 Clinical Trial Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. 2015

Bigal, Marcelo E / Edvinsson, Lars / Rapoport, Alan M / Lipton, Richard B / Spierings, Egilius L H / Diener, Hans-Christoph / Burstein, Rami / Loupe, Pippa S / Ma, Yuju / Yang, Ronghua / Silberstein, Stephen D. ·Research and Development Department, Teva Pharmaceuticals, Frazer, PA, USA. Electronic address: marcelo.bigal@tevapharm.com. · Department of Internal Medicine, Lund University Hospital, Lund, Sweden. · The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · Department of Neurology, Albert Einstein College of Medicine, New York, NY, USA. · Clinical Research, MedVadis Research, Boston, MA, USA. · Department of Neurology, Essen Headache Center, Essen, Germany. · Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. · Research and Scientific Affairs Department, Teva Pharmaceuticals, Frazer, PA, USA. · Statistics Department, Teva Pharmaceuticals, Frazer, PA, USA. · Department of Neurology, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA, USA. ·Lancet Neurol · Pubmed #26432181.

ABSTRACT: BACKGROUND: Benefits of calcitonin-gene related peptide (CGRP) inhibition have not been established in chronic migraine. Here we assess the safety, tolerability, and efficacy of two doses of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of chronic migraine. METHODS: In this multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel-group phase 2b study, we enrolled men and women (aged 18-65 years) from 62 sites in the USA who had chronic migraine. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1, stratified by sex and use of concomitant preventive drugs) to three 28-day treatment cycles of subcutaneous TEV-48125 675/225 mg (675 mg in the first treatment cycle and 225 mg in the second and third treatment cycles), TEV-48125 900 mg (900 mg in all three treatment cycles), or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Daily headache information was captured using an electronic diary. Primary endpoints were change from baseline in the number of headache-hours during the third treatment cycle (weeks 9-12) and safety and tolerability during the study. Secondary endpoint was change in the number of moderate or severe headache-days in weeks 9-12 relative to baseline. Efficacy endpoints were analysed for the intention-to-treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered with ClinicalTrials.gov, number, NCT02021773. FINDINGS: Between Jan 8, 2014, and Aug 27, 2014, we enrolled 264 participants: 89 were randomly assigned to receive placebo, 88 to receive 675/225 mg TEV-48125, and 87 to receive 900 mg TEV-48125. The mean change from baseline in number of headache-hours during weeks 9-12 was -59.84 h (SD 80.38) in the 675/225 mg group and -67.51 h (79.37) in the 900 mg group, compared with -37.10 h (79.44) in the placebo group. The least square mean difference in the reduction of headache-hours between the placebo and 675/225 mg dose groups was -22.74 h (95% CI -44.28 to -1.21; p=0.0386), whereas the difference between placebo and 900 mg dose groups was -30.41 h (-51.88 to -8.95; p=0.0057). Adverse events were reported by 36 (40%) patients in the placebo group, 47 (53%) patients in the 675/225 mg dose group, and 41 (47%) patients in the 900 mg dose group, whereas treatment-related adverse events were recorded in 15 (17%) patients, 25 (29%) patients, and 28 (32%) patients, respectively. The most common adverse events were mild injection-site pain and pruritus. Four (1%) patients had serious non-treatment-related adverse events (one patient in the placebo group, one patient in the 675/225 mg group, and two patients in the 900 mg group); no treatment-related adverse events were serious and there were no relevant changes in blood pressure or other vital signs. INTERPRETATION: TEV-48125 given by subcutaneous injection every 28 days seems to be tolerable and effective, thus supporting the further development of TEV-48125 for the preventive treatment of chronic migraine in a phase 3 trial. FUNDING: Teva Pharmaceuticals.

16 Clinical Trial Predicting migraine responsiveness to botulinum toxin type A injections. 2010

Kim, Christine C / Bogart, Megan M / Wee, Sue Ann / Burstein, Rami / Arndt, Kenneth A / Dover, Jeffrey S. ·SkinCare Physicians, Chestnut Hill, Massachusetts, USA. cmchoi76@hotmail.com ·Arch Dermatol · Pubmed #20157026.

ABSTRACT: BACKGROUND: Botulinum toxin type A (BTX) is used prophylactically to reduce the frequency of migraine headaches, with inconsistent responses reported in the literature. The purpose of our study was to determine whether BTX injections at doses used for upper-face cosmetic purposes, which differ from doses typically used by headache specialists, could prevent imploding and ocular but not exploding migraines. OBSERVATIONS: Study participants were recruited among patients who had received or were planning to receive BTX injections for upper-face cosmetic purposes but also reported having migraines. Among the 18 patients who completed the study, most with imploding and ocular migraines experienced a significant reduction in their headache frequency, whereas those with exploding migraines generally did not. CONCLUSIONS: Our study supports the hypothesis that patients with imploding and ocular migraines are more responsive to BTX than those with exploding migraines. Injections of BTX at doses appropriate for cosmetic purposes may be sufficient to prevent migraine attacks.

17 Clinical Trial Revisiting the efficacy of sumatriptan therapy during the aura phase of migraine. 2009

Aurora, Sheena K / Barrodale, Patricia M / McDonald, Susan A / Jakubowski, Moshe / Burstein, Rami. ·The Swedish Medical Center, Seattle, WA, USA. ·Headache · Pubmed #19438735.

ABSTRACT: OBJECTIVE: To reexamine the efficacy of terminating migraine headache by administration of sumatriptan during the visual-aura phase of the attack. Background.- Although the antimigraine action of triptans is most effective soon after onset of the headache, treatment during the aura phase has been found to be ineffective. METHODS: Nineteen subjects having migraine with aura were studied using a 4-way crossover, open-label design. Each patient was asked to treat 8 consecutive attacks with 100 mg of sumatriptan RT: 3 attacks treated at a timing of the patient's discretion (baseline); 1 attack treated 4 hours after onset of pain (late); 2 attacks treated within 1 hour of onset of pain (early); 2 attacks treated during the aura phase - before the onset of pain (aura). Pain level and cutaneous allodynia were reported by the patients at the onset of pain, at the time of treatment, and 2 and 24 hours after treatment. RESULTS: Sumatriptan treatment during the aura preempted the development of headache in 34/38 (89%) attacks. The same patients were rendered pain-free in 30/38 (79%) of attacks treated within 1 hour of pain onset, and in 4/19 (21%) of attacks treated 4 hours after the onset of pain. The incidence of allodynia at the time of treatment was 2/38 (5%) in attacks treated during aura, 8/38 (21%) in attacks treated early, and 14/19 (74%) in attacks treated late. CONCLUSION: Considering the discrepancy between the present and previous clinical studies, it is worthwhile revisiting the efficacy of preemptive triptan therapy during the aura phase of migraine attacks, using larger-scale, 3-way, crossover, placebo-controlled studies.

18 Clinical Trial Migraine prophylaxis with botulinum toxin A is associated with perception of headache. 2009

Burstein, Rami / Dodick, David / Silberstein, Stephen. ·Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. rburstei@caregroup.harvard.edu ·Toxicon · Pubmed #19344670.

ABSTRACT: The purpose of this study was to test whether the efficacy of prophylactic treatment with botulinum toxin A (BTX-A) on migraine frequency is related to the individual perception of the pain and its directionality, namely, exploding, imploding, or ocular migraine headache. Episodic and chronic migraine patients (n=82) previously treated with BTX-A were interviewed to characterize their migraine headache and its directionality. The magnitude of their response to treatment was analyzed vis-à-vis their individual type of headache. Patients showing a >67% drop in number of migraine days/month were classified as responders; those showing a drop smaller than 33% were labeled non-responders; patients showing a drop between 34% and 66% were considered questionable responders. After BTX-A treatment, the number of migraine days/month dropped 85.2+/-1.6% (from 20.1+/-1.5 to 2.8+/-0.4; p<0.0001) in 37 responders, 52.4+/-2.4% (from 16.3+/-3.5 to 7.2+/-1.5; p=0.003) in 11 questionable responders, and remained unchanged (21.2+/-1.8 vs. 21.1+/-1.7; p>0.78) in 34 non-responders. The frequency of headache types differed significantly (p<0.0001) across the 3 response sub-groups. Among non-responders, 83% described a buildup of pressure inside their head (exploding headache). Among responders and questionable responders, 84 and 64%, respectively, perceived their head to be crushed, clamped or stubbed by external forces (imploding headache) or an eye-popping pain (ocular headache). The prevalence of exploding, imploding, and ocular headache was similar between episodic and chronic migraine patients. Imploding/ocular migraine headache is more likely than exploding headache to be prevented by prophylactic BTX-A treatment. Further validation of this principle should await large-scale prospective, placebo-controlled studies.

19 Article Color-selective photophobia in ictal vs interictal migraineurs and in healthy controls. 2018

Nir, Rony-Reuven / Lee, Alice J / Huntington, Shaelah / Noseda, Rodrigo / Bernstein, Carolyn A / Fulton, Anne B / Bertisch, Suzanne M / Hovaguimian, Alexandra / Buettner, Catherine / Borsook, David / Burstein, Rami. ·Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States. · Harvard Medical School, Boston, MA, United States. · Harvard Catalyst Clinical Research Center, Beth Israel Deaconess Medical Center, Boston, MA, United States. · Department of Neurology, Brigham and Women's Faulkner Hospital, Boston, MA, United States. · Department of Ophthalmology, Children's Hospital Boston, Boston, MA, United States. · Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States. · Department of Medicine, Mount Auburn Hospital, Cambridge, MA, United States. · Department of Anesthesia, Center for Pain and the Brain, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, United States. ·Pain · Pubmed #29905657.

ABSTRACT: Aversion to light is common among migraineurs undergoing acute attacks. Using psychophysical assessments in patients with episodic migraine, we reported that white, blue, amber, and red lights exacerbate migraine headache in a significantly larger percentage of patients and to a greater extent compared with green light. This study aimed at determining whether these findings are phase-dependent-namely, manifested exclusively during migraine (ictally) but not in its absence (interictally), or condition-dependent-ie, expressed uniquely in migraineurs but not in healthy controls. To determine whether the color preference of migraine-type photophobia is phase- or condition-dependent, we compared the effects of each color of light in each intensity between migraineurs during and in-between attacks and healthy controls. During the ictal and interictal phases, the proportion of migraineurs reporting changes in headache severity when exposed to the different colors of light increased in accordance with elevated light intensities. During the ictal phase, white, blue, amber, and red lights exacerbated headaches in ∼80% of the patients; however, during the interictal phase, light initiated headache in only 16% to 19%. Notably, green light exacerbated headaches in 40% and triggered headaches in 3% of the patients studied during the ictal and interictal phases, respectively. With one exception (highest red light intensity), no control subject reported headache in response to the light stimuli. These findings suggest that color preference is unique to migraineurs-as it was not found in control subjects-and that it is independent of whether or not the patients are in their ictal or interictal phase.

20 Article Neural mechanism for hypothalamic-mediated autonomic responses to light during migraine. 2017

Noseda, Rodrigo / Lee, Alice J / Nir, Rony-Reuven / Bernstein, Carolyn A / Kainz, Vanessa M / Bertisch, Suzanne M / Buettner, Catherine / Borsook, David / Burstein, Rami. ·Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215. · Harvard Medical School, Boston, MA 02115. · Harvard Catalyst Clinical Research Center, Beth Israel Deaconess Medical Center, Boston, MA 02215. · Department of Neurology, Rambam Health Care Campus, Haifa, Israel 31096. · Laboratory of Clinical Neurophysiology, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel 31096. · Department of Neurology, Brigham and Women Hospital, Boston, MA 02115. · Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215. · Center for Pain and the Brain, Department of Anesthesia Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA 02115. · Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215; rburstei@bidmc.harvard.edu. ·Proc Natl Acad Sci U S A · Pubmed #28652355.

ABSTRACT: Migraineurs avoid light because it intensifies their headache. However, this is not the only reason for their aversion to light. Studying migraineurs and control subjects, we found that lights triggered more changes in autonomic functions and negative emotions during, rather than in the absence of, migraine or in control subjects, and that the association between light and positive emotions was stronger in control subjects than migraineurs. Seeking to define a neuroanatomical substrate for these findings, we showed that, in rats, axons of retinal ganglion cells converge on hypothalamic neurons that project directly to nuclei in the brainstem and spinal cord that regulate parasympathetic and sympathetic functions and contain dopamine, histamine, orexin, melanin-concentrating hormone, oxytocin, and vasopressin. Although the rat studies define frameworks for conceptualizing how light triggers the symptoms described by patients, the human studies suggest that the aversive nature of light is more complex than its association with headache intensification.

21 Article Allodynia Is Associated With Initial and Sustained Response to Acute Migraine Treatment: Results from the American Migraine Prevalence and Prevention Study. 2017

Lipton, Richard B / Munjal, Sagar / Buse, Dawn C / Bennett, Alix / Fanning, Kristina M / Burstein, Rami / Reed, Michael L. ·Montefiore Medical Center, Bronx, NY, USA. · Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA. · Dr. Reddy's Laboratories and its affiliate Promius Pharma, Princeton, NJ, USA. · Vedanta Research, Chapel Hill, NC, USA. · Beth Israel Deaconess Medical Center, Boston, MA, USA. ·Headache · Pubmed #28603893.

ABSTRACT: OBJECTIVE: In a population sample of persons with migraine treating with a single category of acute migraine medication, to identify rates and factors associated with acute treatment outcomes, including 2-hour pain freedom (2hPF), 24-hour pain response (24hPR), and 24-hour sustained pain response (24hSPR). Key predictors include acute treatment type (triptans and other medication categories), the influence of allodynia on response to medication, and the interaction between medication category and presence of allodynia in response to treatment among people with migraine. BACKGROUND: Cutaneous allodynia was previously associated with inadequate 2hPF, 24hPR, and 24hSPR (sustained response at 24 hours among those with adequate 2hPF) among people with migraine in the American Migraine Prevalence and Prevention (AMPP) Study. METHODS: The AMPP Study obtained data from a representative US sample of persons with migraine by mailed questionnaire. The 2006 survey included 8233 people with migraine aged 18 or over who completed the Migraine Treatment Optimization Questionnaire (mTOQ). mTOQ was used to assess acute treatment outcomes including 2hPF, 24hPR, and 24hSPR. Eligible individuals used only a single category of acute prescription migraine treatments (n  =  5236, 63.6%). This sample was stratified into 5 categories of type of acute prescription headache medication used (triptans, nonsteroidal anti-inflammatory drugs, barbiturate-combinations, opioids, and opioid combinations and ergot alkaloids). Separate binary logistic regression models evaluated: (1) triptans vs other medication types; (2) presence of allodynia vs no allodynia; and (3) the interaction of medication category with allodynia. Sociodemographic variables, health insurance status, over-the-counter and preventive medication use were included as covariates. Odds ratios (OR) and 95% confidence intervals (CI) were generated for each acute treatment outcome. RESULTS: Among eligible participants, the mean age was 46 years, and 82.5% were women. The triptan use group had better outcomes than other medication groups for 2hPF (OR range: 2.00-2.63, all significant except ergot alkaloids) and 24hPR (OR range: 2.10-6.22, all significant). No significant medication effects were found for the 24hSPR outcome. The presence of allodynia was associated with significantly worse outcomes for both 2hPF (OR range: 1.42-1.55, all significant) and 24hPR (OR range: 1.30-1.32, all significant, except for ergot alkaloids, P  =  .051). Allodynia effects were not significant for the 24hSPR. The interaction between medication and allodynia was also not significant (OR range for 2hPF: .68-2.02; OR range for 2hPR: .35-1.34; OR range for 24hSPR: 1.21-2.72) in any of the models, suggesting allodynia is an important predictor of treatment response regardless of the medication group prescribed. CONCLUSIONS: The use of triptan medication was associated with significantly better 2hPF (except vs ergot alkaloids) and significantly better 24hPR outcomes compared with other acute medication categories. The presence of allodynia significantly increased the likelihood of an inadequate treatment response for both of these outcomes. Triptan use was generally associated with the best outcomes. Because allodynia was associated with inadequate outcomes for all medication groups, we suggest that allodynia is an area of unmet treatment need.

22 Article In child and adult migraineurs the somatosensory cortex stands out … again: An arterial spin labeling investigation. 2017

Youssef, Andrew M / Ludwick, Allison / Wilcox, Sophie L / Lebel, Alyssa / Peng, Ke / Colon, Elisabeth / Danehy, Amy / Burstein, Rami / Becerra, Lino / Borsook, David. ·Center for Pain and the Brain, Department of Anesthesiology, Perioperative & Pain Medicine, Boston Children's Hospital, Boston, Massachusetts. · Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts. · Department of Radiology, Boston Children's Hospital, Boston, Massachusetts. · Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. ·Hum Brain Mapp · Pubmed #28560777.

ABSTRACT: Over the past decade, human brain imaging investigations have reported altered regional cerebral blood flow (rCBF) in the interictal phase of migraine. However, there have been conflicting findings across different investigations, making the use of perfusion imaging in migraine pathophysiology more difficult to define. These inconsistencies may reflect technical constraints with traditional perfusion imaging methods such as single-photon emission computed tomography and positron emission tomography. Comparatively, pseudocontinuous arterial spin labeling (pCASL) is a recently developed magnetic resonance imaging technique that is noninvasive and offers superior spatial resolution and increased sensitivity. Using pCASL, we have previously shown increased rCBF within the primary somatosensory cortex (S1) in adult migraineurs, where blood flow was positively associated with migraine frequency. Whether these observations are present in pediatric and young adult populations remains unknown. This is an important question given the age-related variants of migraine prevalence, symptomology, and treatments. In this investigation, we used pCASL to quantitatively compare and contrast blood flow within S1 in pediatric and young adult migraineurs as compared with healthy controls. In migraine patients, we found significant resting rCBF increases within bilateral S1 as compared with healthy controls. Furthermore, within the right S1, we report a positive correlation between blood flow value with migraine attack frequency and cutaneous allodynia symptom profile. Our results reveal that pediatric and young adult migraineurs exhibit analogous rCBF changes with adult migraineurs, further supporting the possibility that these alterations within S1 are a consequence of repeated migraine attacks. Hum Brain Mapp 38:4078-4087, 2017. © 2017 Wiley Periodicals, Inc.

23 Article Terminating Migraine-Associated Allodynia Using Oral Suspension Diclofenac: A Prospective Non-Randomized Drug Trial. 2017

Buettner, Catherine / Melo-Carrillo, Agustin / Burstein, Rami. ·Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. · Harvard Medical School, Boston, MA, USA. · Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Boston, MA, USA. ·Headache · Pubmed #28225188.

ABSTRACT: -- No abstract --

24 Article Cortical Spreading Depression Closes Paravascular Space and Impairs Glymphatic Flow: Implications for Migraine Headache. 2017

Schain, Aaron J / Melo-Carrillo, Agustin / Strassman, Andrew M / Burstein, Rami. ·Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and. · Harvard Medical School, Boston, Massachusetts 02215. · Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and rburstei@bidmc.harvard.edu. ·J Neurosci · Pubmed #28193695.

ABSTRACT: Functioning of the glymphatic system, a network of paravascular tunnels through which cortical interstitial solutes are cleared from the brain, has recently been linked to sleep and traumatic brain injury, both of which can affect the progression of migraine. This led us to investigate the connection between migraine and the glymphatic system. Taking advantage of a novel

25 Article Brain network alterations in the inflammatory soup animal model of migraine. 2017

Becerra, Lino / Bishop, James / Barmettler, Gabi / Kainz, Vanessa / Burstein, Rami / Borsook, David. ·Pain/Analgesia Imaging Neuroscience (P.A.I.N.) Group, Department of Anesthesia, Boston Children's Hospital, Center for Pain and the Brain, Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA; Departments of Psychiatry and Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: lino.becerra@childrens.harvard.edu. · Pain/Analgesia Imaging Neuroscience (P.A.I.N.) Group, Department of Anesthesia, Boston Children's Hospital, Center for Pain and the Brain, Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA. · Department of Anaesthesia and Critical Care, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. · Pain/Analgesia Imaging Neuroscience (P.A.I.N.) Group, Department of Anesthesia, Boston Children's Hospital, Center for Pain and the Brain, Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA; Departments of Psychiatry and Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ·Brain Res · Pubmed #28167076.

ABSTRACT: Advances in our understanding of the human pain experience have shifted much of the focus of pain research from the periphery to the brain. Current hypotheses suggest that the progression of migraine depends on abnormal functioning of neurons in multiple brain regions. Accordingly, we sought to capture functional brain changes induced by the application of an inflammatory cocktail known as inflammatory soup (IS), to the dura mater across multiple brain networks. Specifically, we aimed to determine whether IS alters additional neural networks indirectly related to the primary nociceptive pathways via the spinal cord to the thalamus and cortex. IS comprises an acidic combination of bradykinin, serotonin, histamine and prostaglandin PGE2 and was introduced to basic pain research as a tool to activate and sensitize peripheral nociceptors when studying pathological pain conditions associated with allodynia and hyperalgesia. Using this model of intracranial pain, we found that dural application of IS in awake, fully conscious, rats enhanced thalamic, hypothalamic, hippocampal and somatosensory cortex responses to mechanical stimulation of the face (compared to sham synthetic interstitial fluid administration). Furthermore, resting state MRI data revealed altered functional connectivity in a number of networks previously identified in clinical chronic pain populations. These included the default mode, sensorimotor, interoceptive (Salience) and autonomic networks. The findings suggest that activation and sensitization of meningeal nociceptors by IS can enhance the extent to which the brain processes nociceptive signaling, define new level of modulation of affective and cognitive responses to pain; set new tone for hypothalamic regulation of autonomic outflow to the cranium; and change cerebellar functions.

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