Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: An American Headache Society position statement update.

OBJECTIVE: To provide a position statement update from The American Headache Society specifically regarding therapies targeting calcitonin gene-related peptide (CGRP) for the prevention of migraine. BACKGROUND: All migraine preventive therapies previously considered to be first-line treatments were developed for other indications and adopted later for migraine. Adherence to these therapies is often poor due to issues with efficacy and tolerability. Multiple new migraine-specific therapies have been developed based on a broad foundation of pre-clinical and clinical evidence showing that CGRP plays a key role in the pathogenesis of migraine. These CGRP-targeting therapies have had a transformational impact on the management of migraine but are still not widely considered to be first-line approaches. METHODS: Evidence regarding migraine preventive therapies including primary and secondary endpoints from randomized placebo-controlled clinical trials, post hoc analyses and open-label extensions of these trials, and prospective and retrospective observational studies were collected from a variety of sources including PubMed, Google Scholar, and ClinicalTrials.gov. The results and conclusions based upon these results were reviewed and discussed by the Board of Directors of The American Headache Society to confirm consistency with clinical experience and to achieve consensus. RESULTS: The evidence for the efficacy, tolerability, and safety of CGRP-targeting migraine preventive therapies (the monoclonal antibodies: erenumab, fremanezumab, galcanezumab, and eptinezumab, and the gepants: rimegepant and atogepant) is substantial, and vastly exceeds that for any other preventive treatment approach. The evidence remains consistent across different individual CGRP-targeting treatments and is corroborated by extensive "real-world" clinical experience. The data indicates that the efficacy and tolerability of CGRP-targeting therapies are equal to or greater than those of previous first-line therapies and that serious adverse events associated with CGRP-targeting therapies are rare. CONCLUSION: The CGRP-targeting therapies should be considered as a first-line approach for migraine prevention along with previous first-line treatments without a requirement for prior failure of other classes of migraine preventive treatment.

Pain Following Endoscopic Foreheadplasty Surgery in Women.

BACKGROUND: Endoscopic foreheadplasty surgery (EFS) is a common procedure; however, little has been reported about the nature or treatment of postoperative headache pain and associated symptoms. OBJECTIVES: The objective of this study was to describe the intensity, quality, location, and duration of headache pain in women following EFS. We also compared post-EFS symptoms with migraine, described medication use and efficacy, and measured emotional and functional outcomes. METHODS: This descriptive study used an observational repeated-measures design. Forty-two women (mean [standard deviation] age, 59.0 [7.9] years) undergoing EFS were prospectively recruited from 12 private cosmetic practices in 3 California counties. Telephone interviews with the Acute Short-Form 12v2 and the Headache Pain Questionnaire were conducted on postoperative days (POD) 1, 3, 7, and 30. RESULTS: On POD 1, 93% reported at least moderate pain and 64% severe pain. Severe pain was characterized as throbbing (71%), sharp (53%), dull (76%), exploding (41%), imploding (53%), continuous (53%), or intermittent (41%) on POD 1. Moderate pain was most frequent on POD 3 (21%) compared to POD 1 (19%), 7 (12%) and 30 (12%). Mild pain predominated on POD 3 (40%) and 7 (40%), with 20% remaining on POD 30. The majority (79%) of post-EFS symptoms included light sensitivity and nausea, and therefore met most International Classification of Headache Disorders criteria for migraine. Analgesic use provided inconsistent relief. Functional and emotional status did not return to baseline throughout the 30-day postoperative period. CONCLUSIONS: Immediately following EFS, most women experience moderate to severe headache pain, despite use of medications. Pain persists in many patients for up to 1 month. Headache is associated with migraine symptoms, including light sensitivity and nausea.

Cortical spreading depression as a site of origin for migraine: Role of CGRP.

PREMISE: Migraine is a complex neurologic disorder that leads to significant disability, yet remains poorly understood. PROBLEM: One potential triggering mechanism in migraine with aura is cortical spreading depression, which can activate the trigeminal nociceptive system both peripherally and centrally in animal models. A primary neuropeptide of the trigeminal system is calcitonin gene-related peptide, which is a potent vasodilatory peptide and is currently a major therapeutic target for migraine treatment. Despite the importance of both cortical spreading depression and calcitonin gene-related peptide in migraine, the relationship between these two players has been relatively unexplored. However, recent data suggest several potential vascular and neural connections between calcitonin gene-related peptide and cortical spreading depression. CONCLUSION: This review will outline calcitonin gene-related peptide-cortical spreading depression connections and propose a model in which cortical spreading depression and calcitonin gene-related peptide act at the intersection of the vasculature and cortical neurons, and thus contribute to migraine pathophysiology.

A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE Study).

Objective To evaluate the efficacy and tolerability of single pulse transcranial magnetic stimulation (sTMS) for the preventive treatment of migraine. Background sTMS was originally developed for the acute treatment of migraine with aura. Open label experience has suggested a preventive benefit. The objective of this trial was to evaluate the efficacy and tolerability of sTMS for migraine prevention. Methods The eNeura SpringTMS Post-Market Observational U.S. Study of Migraine (ESPOUSE) Study was a multicenter, prospective, open label, observational study. From December 2014 to March 2016, patients with migraine (n = 263) were consented to complete a 1-month baseline headache diary followed by 3 months of treatment. The treatment protocol consisted of preventive (four pulses twice daily) and acute (three pulses repeated up to three times for each attack) treatment. Patients reported daily headache status, medication use, and device use with a monthly headache diary. The primary endpoint, mean reduction of headache days compared to baseline, was measured over the 28-day period during weeks 9 to 12. The primary endpoint was compared to a statistically-derived placebo estimate (performance goal). Secondary endpoints included: 50% responder rate, acute headache medication consumption, HIT-6, and mean reduction in total headache days from baseline of any intensity. Results Of a total of 263 consented subjects, 229 completed a baseline diary, and 220 were found to be eligible based on the number of headache days. The device was assigned to 217 subjects (Safety Data Set) and 132 were included in the intention to treat Full Analysis Set. For the primary endpoint, there was a -2.75 ± 0.40 mean reduction of headache days from baseline (9.06 days) compared to the performance goal (-0.63 days) ( p < 0.0001). The 50% responder rate of 46% (95% CI 37%, 56%) was also significantly higher ( p < 0.0001) than the performance goal (20%). There was a reduction of -2.93 (5.24) days of acute medication use, headache impact measured by HIT-6, -3.1 (6.4) ( p < 0.0001), and total headache days of any intensity -3.16 days (5.21) compared to the performance goal (-0.63 days) ( p < 0.0001). The most common adverse events were lightheadedness (3.7%), tingling (3.2%), and tinnitus (3.2%). There were no serious adverse events. Conclusions This open label study suggests that sTMS may be an effective, well-tolerated treatment option for migraine prevention. Trial registration number NCT02357381.

Variability of clinical features in attacks of migraine with aura.

BACKGROUND: There is significant variability in the clinical presentation of migraine, both among patients, and between attacks in an individual patient. We examined clinical features of migraine with aura in a large group of patients enrolled in a clinical trial, and compared retrospective migraine attack characteristics reported upon enrollment in the trial with those recorded prospectively in the trial. METHODS: Patients with migraine (n = 267) with typical visual aura in more than 30% of their attacks were enrolled from 16 centers for a clinical trial. Upon enrollment, patients provided a detailed retrospective description of the clinical features of their attacks of migraine. During the trial, clinical symptoms in migraine attacks starting with aura were recorded prospectively in 861 attacks. RESULTS: Retrospectively reported visual aura symptoms were variable and often overlapping; the most common symptoms were dots or flashing lights, wavy or jagged lines, blind spots, and tunnel vision. Multiple patients reported more than one visual phenomenon. Approximately half of the patients reported nonvisual aura symptoms, the most common were numbness and tingling, followed by difficulty in recalling or speaking words. A significant percentage of patients also reported a change in olfaction. There were several inconsistencies between the features of prospectively recorded and retrospectively reported attacks. Headache, nausea, photophobia, and phonophobia were all less common in prospectively recorded attacks as compared with retrospective reporting. Nausea was prospectively recorded in only 51% of attacks and mostly with mild intensity. The occurrence and severity of nausea was reduced with advancing patient age. Phonophobia was not consistently recorded in conjunction with photophobia. CONCLUSION: These findings are consistent with variable involvement of different brain regions during a migraine attack. The variable occurrence of nausea, and phonophobia in conjunction with photophobia, both defining features of migraine, may be an important consideration in designing clinical studies of migraine in which prospectively recorded attacks are diagnosed based on these clinical features.

Memantine enhances recovery from stroke.

BACKGROUND AND PURPOSE: Stroke treatment is constrained by limited treatment windows and the clinical inefficacy of agents that showed preclinical promise. Yet animal and clinical data suggest considerable poststroke plasticity, which could allow treatment with recovery-modulating agents. Memantine is a well-tolerated N-methyl-D-aspartate glutamate receptor antagonist in common use for Alzheimer disease. METHODS: Memantine, 30 mg/kg per day, or vehicle, was delivered chronically in drinking water beginning >2 hours after photothrombotic stroke. RESULTS: Although there was no difference in infarct size, behavior, or optical intrinsic signal maps in the first 7 days after stroke, mice treated chronically with memantine showed significant improvements in motor control, measured by cylinder test and grid-walking performance, compared with vehicle-treated animals. Optical intrinsic signal revealed an increased area of forepaw sensory maps at 28 days after stroke. There was decreased reactive astrogliosis and increased vascular density around the infarcted cortex. Peri-infarct Western blots revealed increased brain-derived neurotrophic factor and phosphorylated-tropomyosin-related kinase-B receptor expression. CONCLUSIONS: Our results suggest that memantine improves stroke outcomes in an apparently non-neuroprotective manner involving increased brain-derived neurotrophic factor signaling, reduced reactive astrogliosis, and improved vascularization, associated with improved recovery of sensory and motor cortical function. The clinical availability and tolerability of memantine make it an attractive candidate for clinical translation.

Pain referral patterns of the C1 to C3 nerves: implications for headache disorders.

The cervical nerves may play a significant role in primary headache disorders. We reviewed the patterns of pain evoked by stimulation of the first 3 cervical nerves (C1-C3) in 10 patients with chronic occipital pain, 6 of whom also had migraine. Stimulation at the C1 level evoked periorbital and frontal pain in 6 of 6 patients with migraine but evoked occipital or cervical pain in those without migraine. C2 and C3 stimulation resulted in occipital or cervical pain in all patients. The C1 nerve may have an important sensory function in headache disorders that have orbital and frontal pain as a prominent feature.

Spontaneous behavioral responses in the orofacial region: a model of trigeminal pain in mouse.

OBJECTIVES: To develop a translational mouse model for the study and measurement of non-evoked pain in the orofacial region by establishing markers of nociceptive-specific grooming behaviors in the mouse. BACKGROUND: Some of the most prevalent and debilitating conditions involve pain in the trigeminal distribution. Although there are current therapies for these pain conditions, for many patients, they are far from optimal. Understanding the pathophysiology of pain disorders arising from structures innervated by the trigeminal nerve is still limited, and most animal behavioral models focus on the measurement of evoked pain. In patients, spontaneous (non-evoked) pain responses provide a more accurate representation of the pain experience than do responses that are evoked by an artificial stimulus. Therefore, the development of animal models that measure spontaneous nociceptive behaviors may provide a significant translational tool for a better understanding of pain neurobiology. METHODS: C57BL/6 mice received either an injection of 0.9% saline solution or complete Freund's adjuvant into the right masseter muscle. Animals were video-recorded and then analyzed by an observer blind to the experiment group. The duration of different facial grooming patterns performed in the area of injection were measured. After 2 hours, mice were euthanized and perfused, and the brainstem was removed. Fos protein expression in the trigeminal nucleus caudalis was quantified using immunohistochemistry to investigate nociceptive-specific neuronal activation. A separate group of animals was treated with morphine sulfate to determine the nociceptive-specific nature of their behaviors. RESULTS: We characterized and quantified 3 distinct patterns of acute grooming behaviors: forepaw rubbing, lower lip skin/cheek rubbing against enclosure floor, and hindpaw scratching. These behaviors occurred with a reproducible frequency and time course, and were inhibited by the analgesic morphine. Complete Freund's adjuvant-injected animals also showed Fos labeling consistent with neuronal activation in nociceptive-specific pathways of the trigeminal nucleus after 2 hours. CONCLUSIONS: These behaviors and their correlated cellular responses represent a model of trigeminal pain that can be used to better understand basic mechanisms of orofacial pain and identify new therapeutic approaches to this common and challenging condition.

Ultrasound stimulation of the motor cortex during tonic muscle contraction.

Transcranial ultrasound stimulation (tUS) shows potential as a noninvasive brain stimulation (NIBS) technique, offering increased spatial precision compared to other NIBS techniques. However, its reported effects on primary motor cortex (M1) are limited. We aimed to better understand tUS effects in human M1 by performing tUS of the hand area of M1 (M1hand) during tonic muscle contraction of the index finger. Stimulation during muscle contraction was chosen because of the transcranial magnetic stimulation-induced phenomenon known as cortical silent period (cSP), in which transcranial magnetic stimulation (TMS) of M1hand involuntarily suppresses voluntary motor activity. Since cSP is widely considered an inhibitory phenomenon, it presents an ideal parallel for tUS, which has often been proposed to preferentially influence inhibitory interneurons. Recording electromyography (EMG) of the first dorsal interosseous (FDI) muscle, we investigated effects on muscle activity both during and after tUS. We found no change in FDI EMG activity concurrent with tUS stimulation. Using single-pulse TMS, we found no difference in M1 excitability before versus after sparsely repetitive tUS exposure. Using acoustic simulations in models made from structural MRI of the participants that matched the experimental setups, we estimated in-brain pressures and generated an estimate of cumulative tUS exposure experienced by M1hand for each subject. We were unable to find any correlation between cumulative M1hand exposure and M1 excitability change. We also present data that suggest a TMS-induced MEP always preceded a near-threshold cSP.

Biphasic direct current shift, haemoglobin desaturation and neurovascular uncoupling in cortical spreading depression.

Cortical spreading depression is a propagating wave of depolarization that plays important roles in migraine, stroke, subarachnoid haemorrhage and brain injury. Cortical spreading depression is associated with profound vascular changes that may be a significant factor in the clinical response to cortical spreading depression events. We used a combination of optical intrinsic signal imaging, electro-physiology, potassium sensitive electrodes and spectroscopy to investigate neurovascular changes associated with cortical spreading depression in the mouse. We identified two distinct phases of altered neurovascular function, one during the propagating cortical spreading depression wave and a second much longer phase after passage of the wave. The direct current shift associated with the cortical spreading depression wave was accompanied by marked arterial constriction and desaturation of cortical haemoglobin. After recovery from the initial cortical spreading depression wave, we observed a second phase of prolonged, negative direct current shift, arterial constriction and haemoglobin desaturation, lasting at least an hour. Persistent disruption of neurovascular coupling was demonstrated by a loss of coherence between electro-physiological activity and perfusion. Extracellular potassium concentration increased during the cortical spreading depression wave, but recovered and remained at baseline after passage of the wave, consistent with different mechanisms underlying the first and second phases of neurovascular dysfunction. These findings indicate that cortical spreading depression is associated with a multiphasic alteration in neurovascular function, including a novel second direct current shift accompanied by arterial constriction and decrease in tissue oxygen supply, that is temporally and mechanistically distinct from the initial propagated cortical spreading depression wave. Vascular/metabolic uncoupling with cortical spreading depression may have important clinical consequences, and the different phases of dysfunction may represent separate therapeutic targets in the disorders where cortical spreading depression occurs.

Pooled Analysis of PFO Occluder Device Trials in Patients With PFO and Migraine.

BACKGROUND: Although observational studies have shown percutaneous patent foramen ovale (PFO) closure to be a safe means of reducing the frequency and duration of migraine, randomized clinical trials have not met their primary efficacy endpoints. OBJECTIVES: The authors report the results of a pooled analysis of individual participant data from the 2 randomized trials using the Amplatzer PFO Occluder to assess the efficacy and safety of percutaneous device closure as a therapy for episodic migraine with or without aura. METHODS: The authors analyzed individual patient-level data from 2 randomized migraine trials (the PRIMA [Percutaneous Closure of Patent Foramen Ovale in Migraine With Aura] and PREMIUM [Prospective Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects with Migraine and PFO Using the Amplatzer PFO Occluder Compared to Medical Management] studies). Efficacy endpoints were mean reduction in monthly migraine days, responder rate (defined as ≥50% reduction in monthly migraine attacks), mean reduction in monthly migraine attacks, and percentage of patients who experienced complete cessation of migraine. The safety endpoint was major procedure- and device-related adverse events. RESULTS: Among 337 subjects, 176 were randomized by blocks to device closure and 161 to medical treatment only. At 12-month follow-up, the analysis met 3 of the 4 efficacy endpoints: mean reduction of monthly migraine days (-3.1 days vs. -1.9 days; p = 0.02), mean reduction of monthly migraine attacks (-2.0 vs. -1.4; p = 0.01), and number of subjects who experienced complete cessation of migraine (14 [9%] vs. 1 [0.7%]; p < 0.001). For the safety analysis, 9 procedure-related and 4 device-related adverse events occurred in 245 subjects who eventually received devices. All events were transient and resolved. CONCLUSIONS: This pooled analysis of patient-level data demonstrates that PFO closure was safe and significantly reduced the mean number of monthly migraine days and monthly migraine attacks, and resulted in a greater number of subjects who experienced complete migraine cessation.

Evaluation of Posttraumatic Headache Phenotype and Recovery Time After Youth Concussion.

Importance: The Four Corners Youth Consortium was created to fill the gap in our understanding of youth concussion. This study is the first analysis of posttraumatic headache (PTH) phenotype and prognosis in this cohort of concussed youth. Objective: To describe the characteristics of youth with PTH and determine whether the PTH phenotype is associated with outcome. Design, Setting, and Participants: This cohort study examined outcomes from patients in a multi-institutional registry of traumatic brain injury (TBI) clinics from December 2017 to June 2019. Inclusion criteria included being between ages 5 and 18 years at enrollment and presentation within 8 weeks of a mild TBI. Data were analyzed between February 2019 and January 2021. Exposure: Mild TBI with standard care. Main Outcomes and Measures: Time to recovery and headache 3 months after injury; measurement device is the Postconcussion Symptom Inventory (PCSI). PTH with migraine phenotype was defined as moderate-severe headache that is new or significantly worse compared with baseline and associated with nausea and/or photophobia and phonophobia. Results: A total of 612 patients with 625 concussions were enrolled, of whom 387 patients with 395 concussions consented to participate in this study. One hundred nine concussions were excluded (concussions, rather than patients, were the unit of analysis), leaving 281 participants with 286 concussions (168 [58.7%] girls; 195 [75.6%] White; 238 [83.2%] aged 13-18 years). At the initial visit, 133 concussions (46.5%) were from patients experiencing PTH with a migraine phenotype, 57 (20%) were from patients experiencing PTH with a nonmigraine phenotype, and 96 (34%) were from patients with no PTH. Patients with any PTH after concussion were more likely to have prolonged recovery than those without PTH (median [interquartile range], 89 [48-165] days vs 44 [26-96] days; log-rank P < .001). Patients with PTH and a migraine phenotype took significantly longer to recover than those with nonmigraine phenotype (median [interquartile range], 95 [54-195] days vs 70 [46-119] days; log-rank P = .01). Within each phenotype, there was no significant difference between sexes in recovery or PTH at 3 months. Conclusions and Relevance: PTH with a migraine phenotype is associated with persistent symptoms following concussion compared with nonmigraine PTH or no PTH. Given that female sex is associated with higher rates of migraine and migraine PTH, our finding may be one explanation for findings in prior studies that girls are at higher risk for persistent postconcussion symptoms than boys.

Bradykinin increases resensitization of purinergic receptor signaling in glioma cells.

BACKGROUND: Purinergic receptor-mediated signaling plays an important role in the function of glial cells, including glial tumor cells. Bradykinin is also an important paracrine mediator which is highly expressed in brain tumors and may correlate with their pathological grade. Interaction between bradykinin and purinergic signaling may therefore be involved in the regulation of glial tumor cells. RESULTS: We examined the effect of bradykinin on glial purinergic signaling in an immortalized glioma cell line. Confocal calcium imaging revealed that ATP evokes an increase in [Ca2+]i in the U87 human astrocytoma cell line. This response was reduced with repetitive application of ATP, likely due to receptor desensitization. However exposure to bradykinin increased the Ca2+ response to a second application of ATP, consistent with increased resensitization. The bradykinin effect on resensitization was similar in the absence of extracellular Ca2+ or in the presence of the PKC activator PMA, but was inhibited by the protein phosphatase inhibitor okadaic acid and the PI3K inhibitor LY294002. CONCLUSIONS: Modulation of protein phosphatases and the PI3K pathway may represent a mechanism by which bradykinin potentiates purinergic signaling in glial cells.

Advanced Imaging in the Evaluation of Migraine Headaches.

The use of advanced imaging in routine diagnostic practice appears to provide only limited value in patients with migraine who have not experienced recent changes in headache characteristics or symptoms. However, advanced imaging may have potential for studying the biological manifestations and pathophysiology of migraine headaches. Migraine with aura appears to have characteristic spatiotemporal changes in structural anatomy, function, hemodynamics, metabolism, and biochemistry, whereas migraine without aura produces more subtle and complex changes. Large, controlled, multicenter imaging-based observational trials are needed to confirm the anecdotal evidence in the literature and test the scientific hypotheses thought to underscore migraine pathophysiology.

Lowering cyclic adenosine-3',5'-monophosphate (cAMP) levels by expression of a cAMP-specific phosphodiesterase decreases intrinsic pulsatile gonadotropin-releasing hormone secretion from GT1 cells.

Pulsatile GnRH secretion is an intrinsic property of GnRH neurons. Since increases in cAMP levels increase excitability and GnRH secretion in the GT1-1 GnRH cell line, we asked whether cAMP levels play a role in timing excitability and intrinsic pulsatile GnRH secretion. The expression of the cAMP-specific phosphodiesterase (PDE4D1) was used in a genetic approach to lower cAMP levels. Cells were infected with an adenovirus vector (Ad) expressing PDE4D1 (PDE-Ad), or for controls with an empty Ad (Null-Ad) or an Ad expressing green fluorescent protein (GFP-Ad). Infection with the PDE-Ad significantly inhibited forskolin-induced increases in cAMP production, GnRH secretion, and Ca2+ oscillations. Infection of GT1-1 cells with the PDE-Ad vs. GFP-Ad or Null-Ad controls significantly decreased spontaneous Ca2+ oscillations and inhibited the frequency of GnRH pulses. These data support the hypothesis that the level of cAMP in GT1 neurons is a component of the biological clock timing neuron excitability and pulsatile GnRH secretion. Genetically targeted expression of PDE4D1 represents a powerful approach to study the role of cAMP levels in specific populations of neurons in transgenic animals.

EGF activates intracellular and intercellular calcium signaling by distinct pathways in tumor cells.

Epidermal growth factor (EGF)-mediated Ca2+ signaling in multiple cell lines derived from human gliomas and in the A431 epidermoid carcinoma cell line was observed using fluorescence videomicroscopy. Bath application of EGF evoked an oscillatory increase in [Ca2+]i in 4 different human glioma cell lines as well as the A431 cell line. This effect was blocked by the EGF receptor tyrosine kinase inhibitors gefitinib and erlotinib, as well as by the EGFR antibody cetuximab. In addition to this acute Ca2+ signaling response, transient exposure to EGF also potentiated subsequent Ca2+ signaling responses to other stimuli. Tumor cells transiently exposed to EGF (5 minutes), showed a sustained increase in propagation of intercellular Ca2+ waves, which have been previously shown to involve release of ATP and activation of purinergic receptors. Cells transiently exposed to EGF also showed a sustained potentiation of the Ca2+ signaling response to ATP. In contrast to the acute Ca2+ signaling response to EGF, this sustained potentiation of purinergic intercellular signaling was not blocked by gefitinib or erlotinib, while it was blocked by cetuximab. These results indicate that while the acute Ca2+ signaling response requires tyrosine kinase activation, the sustained potentiation of intercellular signaling occurs via a distinct pathway. Distinct intra- and intercellular Ca2+ signaling pathways may be mechanisms by which EGF modulates the growth and migration of tumor cells.

From inhibition to excitation: functional effects of interaction between opioid receptors.

Opioids have excitatory effects in multiple regions of the nervous system. Excitation by opioids is generally attributed to inhibition of inhibitory pathways (disinhibition). However, recent studies indicate that opioids can directly excite individual cells. These effects may occur when opioid receptors interact with other G protein coupled receptors, when different subtypes of opioid receptors interact, or when opioids transactivate other receptors such as receptor tyrosine kinases. Changes in the relative level of expression of different receptors in an individual cell may therefore determine its functional response to a given ligand. This phenomenon could represent an adaptive mechanism involved in tolerance, dependence and subsequent withdrawal.

Cortical spreading depression and migraine.

Cortical spreading depression (CSD), a slowly propagated wave of depolarization followed by suppression of brain activity, is a remarkably complex event that involves dramatic changes in neural and vascular function. Since its original description in the 1940s, CSD has been hypothesized to be the underlying mechanism of the migraine aura. Substantial evidence from animal models provides indirect support for this hypothesis, and studies showing that CSD is common in humans with brain injury clearly demonstrate that the phenomenon can occur in the human brain. Considerable uncertainty about the role of CSD in migraine remains, however, and key questions about how this event is initiated, how it spreads, and how it might cause migraine symptoms remain unanswered. This Review summarizes current concepts of CSD and its potential roles in migraine, and addresses ongoing studies aimed at a clearer understanding of this fundamental brain phenomenon.

Multimodal examination of structural and functional remapping in the mouse photothrombotic stroke model.

Recent studies show a limited capacity for neural repair after stroke, which includes remapping of sensorimotor functions and sprouting of new connections. However, physiologic and connectional plasticity of sensory maps during long-term functional recovery in the mouse have not been determined. Using a photothrombotic stroke model, we targeted the motor cortex, which we show results in lasting behavioral deficits on the grid-walking and in the cylinder tasks out to 8 weeks after stroke. Mice recovered performance in a skilled reaching task, showing no deficit from week 2 after stroke. Long-term optical intrinsic signal imaging revealed functional reorganization of sensory cortical maps for both forelimb and hindlimb, with more diffuse sensory physiologic maps. There was a small but significant increase in motor neuron projections within the areas of functional cortical reorganization as assessed using the neuroanatomic tracer biotinylated dextran amine. These findings show that the sensorimotor cortex undergoes remapping of cortical functions and axonal sprouting within the same regions during recovery after stroke. This suggests a linked structural and physiologic plasticity underlying recovery. Combined long-term structural and functional mapping after stroke in the mouse is practical and provides a rich data set for mechanistic analysis of stroke recovery.

Casein kinase iδ mutations in familial migraine and advanced sleep phase.

Migraine is a common disabling disorder with a significant genetic component, characterized by severe headache and often accompanied by nausea, vomiting, and light sensitivity. We identified two families, each with a distinct missense mutation in the gene encoding casein kinase Iδ (CKIδ), in which the mutation cosegregated with both the presence of migraine and advanced sleep phase. The resulting alterations (T44A and H46R) occurred in the conserved catalytic domain of CKIδ, where they caused reduced enzyme activity. Mice engineered to carry the CKIδ-T44A allele were more sensitive to pain after treatment with the migraine trigger nitroglycerin. CKIδ-T44A mice also exhibited a reduced threshold for cortical spreading depression (believed to be the physiological analog of migraine aura) and greater arterial dilation during cortical spreading depression. Astrocytes from CKIδ-T44A mice showed increased spontaneous and evoked calcium signaling. These genetic, cellular, physiological, and behavioral analyses suggest that decreases in CKIδ activity can contribute to the pathogenesis of migraine.