Acute sleep deprivation enhances susceptibility to the migraine substrate cortical spreading depolarization.

BACKGROUND: Migraine is a common headache disorder, with cortical spreading depolarization (CSD) considered as the underlying electrophysiological event. CSD is a slowly propagating wave of neuronal and glial depolarization. Sleep disorders are well known risk factors for migraine chronification, and changes in wake-sleep pattern such as sleep deprivation are common migraine triggers. The underlying mechanisms are unknown. As a step towards developing an animal model to study this, we test whether sleep deprivation, a modifiable migraine trigger, enhances CSD susceptibility in rodent models. METHODS: Acute sleep deprivation was achieved using the "gentle handling method", chosen to minimize stress and avoid confounding bias. Sleep deprivation was started with onset of light (diurnal lighting conditions), and assessment of CSD was performed at the end of a 6 h or 12 h sleep deprivation period. The effect of chronic sleep deprivation on CSD was assessed 6 weeks or 12 weeks after lesioning of the hypothalamic ventrolateral preoptic nucleus. All experiments were done in a blinded fashion with respect to sleep status. During 60 min of continuous topical KCl application, we assessed the total number of CSDs, the direct current shift amplitude and duration of the first CSD, the average and cumulative duration of all CSDs, propagation speed, and electrical CSD threshold. RESULTS: Acute sleep deprivation of 6 h (n = 17) or 12 h (n = 11) duration significantly increased CSD frequency compared to controls (17 ± 4 and 18 ± 2, respectively, vs. 14 ± 2 CSDs/hour in controls; p = 0.003 for both), whereas other electrophysiological properties of CSD were unchanged. Acute total sleep deprivation over 12 h but not over 6 h reduced the electrical threshold of CSD compared to controls (p = 0.037 and p = 0.095, respectively). Chronic partial sleep deprivation in contrast did not affect CSD susceptibility in rats. CONCLUSIONS: Acute but not chronic sleep deprivation enhances CSD susceptibility in rodents, possibly underlying its negative impact as a migraine trigger and exacerbating factor. Our findings underscore the importance of CSD as a therapeutic target in migraine and suggest that headache management should identify and treat associated sleep disorders.

Abnormal synaptic Ca(2+) homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice.

OBJECTIVE: Migraine is among the most common and debilitating neurological conditions. Familial hemiplegic migraine type 1 (FHM1), a monogenic migraine subtype, is caused by gain-of-function of voltage-gated CaV 2.1 calcium channels. FHM1 mice carry human pathogenic mutations in the α1A subunit of CaV 2.1 channels and are highly susceptible to cortical spreading depression (CSD), the electrophysiologic event underlying migraine aura. To date, however, the mechanism underlying increased CSD/migraine susceptibility remains unclear. METHODS: We employed in vivo multiphoton microscopy of the genetically encoded Ca(2+)-indicator yellow cameleon to investigate synaptic morphology and [Ca(2+)]i in FHM1 mice. To study CSD-induced cerebral oligemia, we used in vivo laser speckle flowmetry and multimodal imaging. With electrophysiologic recordings, we investigated the effect of the CaV 2.1 gating modifier tert-butyl dihydroquinone on CSD in vivo. RESULTS: FHM1 mutations elevate neuronal [Ca(2+)]i and alter synaptic morphology as a mechanism for enhanced CSD susceptibility that we were able to normalize with a CaV 2.1 gating modifier in hyperexcitable FHM1 mice. At the synaptic level, axonal boutons were larger, and dendritic spines were predominantly of the mushroom type, which both provide a structural correlate for enhanced neuronal excitability. Resting neuronal [Ca(2+)]i was elevated in FHM1, with loss of compartmentalization between synapses and neuronal shafts. The percentage of calcium-overloaded neurons was increased. Neuronal [Ca(2+)]i surge during CSD was faster and larger, and post-CSD oligemia and hemoglobin desaturation were more severe in FHM1 brains. INTERPRETATION: Our findings provide a mechanism for enhanced CSD susceptibility in hemiplegic migraine. Abnormal synaptic Ca(2+) homeostasis and morphology may contribute to chronic neurodegenerative changes as well as enhanced vulnerability to ischemia in migraineurs.

Migraine prophylaxis, ischemic depolarizations, and stroke outcomes in mice.

BACKGROUND AND PURPOSE: Migraine with aura is an established stroke risk factor, and excitatory mechanisms such as spreading depression (SD) are implicated in the pathogenesis of both migraine and stroke. Spontaneous SD waves originate within the peri-infarct tissue and exacerbate the metabolic mismatch during focal cerebral ischemia. Genetically enhanced SD susceptibility facilitates anoxic depolarizations and peri-infarct SDs and accelerates infarct growth, suggesting that susceptibility to SD is a critical determinant of vulnerability to ischemic injury. Because chronic treatment with migraine prophylactic drugs suppresses SD susceptibility, we tested whether migraine prophylaxis can also suppress ischemic depolarizations and improve stroke outcome. METHODS: We measured the cortical susceptibility to SD and ischemic depolarizations, and determined tissue and neurological outcomes after middle cerebral artery occlusion in wild-type and familial hemiplegic migraine type 1 knock-in mice treated with vehicle, topiramate or lamotrigine daily for 7 weeks or as a single dose shortly before testing. RESULTS: Chronic treatment with topiramate or lamotrigine reduced the susceptibility to KCl-induced or electric stimulation-induced SDs as well as ischemic depolarizations in both wild-type and familial hemiplegic migraine type 1 mutant mice. Consequently, both tissue and neurological outcomes were improved. Notably, treatment with a single dose of either drug was ineffective. CONCLUSIONS: These data underscore the importance of hyperexcitability as a mechanism for increased stroke risk in migraineurs, and suggest that migraine prophylaxis may not only prevent migraine attacks but also protect migraineurs against ischemic injury.

The negative effect of triple-negative breast cancer on outcome after breast-conserving therapy.

PURPOSE: To evaluate disease failure patterns and overall survival (OS) of women with triple-negative (TN) breast cancer who underwent breast-conserving therapy (BCT) and to understand the relationship of TN tumors with other prognostic factors. PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) registry identified 562 women diagnosed and/or treated with unilateral invasive breast cancer during 2003-2004 at three Emory hospitals. After medical record review, 193 eligible women, with all tumor types, received BCT. Primary endpoints (local, regional, and distant recurrences) and secondary endpoint (OS) were evaluated using chi-square tests and Cox proportional hazards models. RESULTS: Of the 193 women, 33 (17.1%) had TN tumors and 160 (82.9%) had non-TN tumors. Patient characteristics were similar between the two tumor types; however, tumor grade and use of chemotherapy and hormones differed between the two groups. Median follow-up was 3.4 years; 22 patients had recurrence (12.2%), and 12 died (6.2%). Patients with TN tumors had higher local (12% versus 4% for non-TN) and distant recurrences (15% versus 4% for non-TN) rates (p = 0.01). On multivariate survival analyses, TN status [hazard ratio (HR) 1.8, 95% confidence interval (CI) 1.13-2.93] and African American (AA) race (HR 1.9, 95%CI 1.2-3.07) were independent predictors of inferior OS. CONCLUSIONS: Patients with TN breast cancer showed significant increases in local and distant metastatic recurrence rates after BCT, and TN status and AA race were independent negative predictors of survival. For the future, identification of these high risk features may bring personalized medicine closer to reality.

Caffeine does not affect susceptibility to cortical spreading depolarization in mice.

Several factors that modulate migraine, a common primary headache disorder, also affect susceptibility to cortical spreading depolarization (CSD). CSD is a wave of neuronal and glial depolarization and thought to underlie the migraine aura and possibly headache. Here, we tested whether caffeine, known to alleviate or trigger headache after acute exposure or chronic use/withdrawal, respectively, modulates CSD. We injected C57BL/6J mice with caffeine (30, 60, or 120 mg/kg; i.p.) once ( acute) or twice per day for one or two weeks ( chronic). Susceptibility to CSD was evaluated by measuring the electrical CSD threshold and by assessing KCl-induced CSD. Simultaneous laser Doppler flowmetry was used to assess CSD-induced cortical blood flow changes. Recordings were performed 15 min after caffeine/vehicle administration, or 24 h after the last dose of chronic caffeine in the withdrawal group. The latter paradigm was also tested in mice carrying the familial hemiplegic migraine type 1 R192Q missense mutation, considered a valid migraine model. Neither acute/chronic administration nor withdrawal of caffeine affected CSD susceptibility or related cortical blood flow changes, either in WT or R192Q mice. Hence, adverse or beneficial effects of caffeine on headache seem unrelated to CSD pathophysiology, consistent with the non-migrainous clinical presentation of caffeine-related headache.

Locoregional and Distant Recurrence Patterns in Young versus Elderly Women Treated for Breast Cancer.

Objective. This study examined recurrence patterns in breast cancer patients younger than age of 40 and older than age of 75, two groups that are underrepresented in clinical trials and not routinely screened by mammography. Methods. The records of 230 breast cancer patients (n = 125 less than 40 and n = 105 greater than 75) who presented to the Emory University Department of Radiation Oncology for curative treatment between 1997 and 2010 were reviewed. Data recorded included disease presentation, treatment, and areas of locoregional recurrence. Results. Women less than 40 years of age had higher rates of locoregional recurrence (20% versus 7%, P = 0.004) and distant recurrence (18% versus 5%, P = 0.003) than patients above 75 years of age. On multivariate analysis, patient age less than 40 was the only significant predictor of locoregional recurrence (P = 0.018). In a univariate analysis of each age group, receptor status and postlumpectomy radiation were significant predictors of locoregional recurrence-free survival in younger women while mammography screening predicted for distant recurrence-free survival in older patients. Conclusion. The factors identified in our age-stratified analysis highlight patients who are at high risk of locoregional and distant recurrence. Future studies aimed at enhancing therapies in young patients are warranted.