The impact of pre-morbid headaches on headache features and long-term health outcomes following traumatic brain injury: Insights from the American Registry for Migraine Research.

OBJECTIVE: To investigate the impact of having headaches prior to traumatic brain injury (TBI) on headache features and long-term patient health outcomes. BACKGROUND AND METHODS: This was an exploratory analysis of patients with TBI who were enrolled in the American Registry for Migraine Research (ARMR), a multicenter, prospective, longitudinal patient registry composed of patients with International Classification of Headache Disorders, 3rd edition (ICHD-3)-defined headache diagnoses. The ARMR study enrolled 2,707 patients between February 1, 2016 and May 6, 2020, 565 of whom qualified for this analysis. Those with headaches prior to their TBI were compared to those without headaches prior to their TBI for ICHD-3 diagnoses, headache frequency and intensity, headache-related disability (Migraine Disability Assessment score), symptoms of anxiety (General Anxiety Disorder [GAD-7]), depression (two items from Patient Health Questionnaire-9), post-traumatic stress disorder (PTSD), cutaneous allodynia (12-item Allodynia Symptom Checklist [ASC-12]), cognitive dysfunction (Migraine Attacks Subjective Cognitive Impairments Scale [Mig-SCog]), pain interference (Patient-Reported Outcomes Measurement Information System-Pain Interference), and work productivity (Work Productivity and Activity Impairment). RESULTS: Among 565 participants with TBI, 350 had headaches prior to their TBI. Those with pre-TBI headaches were less likely to receive a diagnosis of post-traumatic headache (PTH; 14/350 [4.0%] vs. 21/215 [9.8%], p = 0.006), even though 25.7% reported new or worsening headaches within 7 days of their TBI. Those with pre-TBI headaches had higher ASC-12 scores (2.4 ± 3.5 vs. 1.8 ± 3.4, p = 0.030), Mig-SCog scores (9.3 ± 4.7 vs. 8 ± 4.9, p = 0.004), and GAD-7 scores (6.9 ± 5.1 vs. 6.2 ± 5.4, p = 0.039), and were more likely to have a migraine diagnosis (335/350 [95.7%] vs. 192/215 [89.3%], p = 0.003). CONCLUSIONS: Those with headaches prior to TBI are less likely to receive a diagnosis of PTH. They have more severe symptoms of cutaneous allodynia, cognitive impairment, and generalized anxiety. This analysis suggests that pre-TBI headaches might impact post-TBI headache diagnoses and associated features.

Chronic migraine is associated with reduced corneal nerve fiber density and symptoms of dry eye.

BACKGROUND: We used in vivo corneal confocal microscopy to investigate structural differences in the sub-basal corneal nerve plexus in chronic migraine patients and a normal population. We used a validated questionnaire and tests of lacrimal function to determine the prevalence of dry eye in the same group of chronic migraine patients. Activation of the trigeminal system is involved in migraine. Corneal nociceptive sensation is mediated by trigeminal axons that synapse in the gasserian ganglion and the brainstem, and serve nociceptive, protective, and trophic functions. Noninvasive imaging of the corneal sub-basal nerve plexus is possible with in vivo corneal confocal microscopy. METHODS: For this case-control study, we recruited chronic migraine patients and compared them with a sex- and age-similar group of control subjects. Patients with peripheral neuropathy, a disease known to be associated with a peripheral neuropathy, or prior corneal or intraocular surgery were excluded. Participants underwent in vivo corneal confocal microscopy using a Heidelberg Retinal Tomography III confocal microscope with a Rostock Cornea Module. Nerve fiber length, nerve branch density, nerve fiber density, and tortuosity coefficient were measured using established methodologies. Migraine participants underwent testing of basal tear production with proparacaine, corneal sensitivity assessment with a cotton-tip applicator, measurement of tear break-up time, and completion of a validated dry eye questionnaire. RESULTS: A total of 19 chronic migraine patients and 30 control participants completed the study. There were no significant differences in age or sex. Nerve fiber density was significantly lower in migraine patients compared with controls (48.4 ± 23.5 vs. 71.0 ± 15.0 fibers/mm2 , P < .001). Nerve fiber length was decreased in the chronic migraine group compared with the control group, but this difference was not statistically significant (21.5 ± 11.8 vs. 26.8 ± 5.9 mm/mm2, P < .084). Nerve branch density was similar in the two groups (114.0 ± 92.4 vs. 118.1 ± 55.9 branches/mm2 , P < .864). Tortuosity coefficient and log tortuosity coefficient also were similar in the chronic migraine and control groups. All migraine subjects had symptoms consistent with a diagnosis of dry eye syndrome. CONCLUSIONS: We found that in the sample used in this study, the presence of structural changes in nociceptive corneal axons lends further support to the hypothesis that the trigeminal system plays a critical role in the pathogenesis of migraine. In vivo corneal confocal microscopy holds promise as a biomarker for future migraine research as well as for studies examining alterations of corneal innervation. Dry eye symptoms appear to be extremely prevalent in this population. The interrelationships between migraine, corneal nerve architecture, and dry eye will be the subject of future investigations.

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.

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.

A mathematical model of the metabolic and perfusion effects on cortical spreading depression.

Cortical spreading depression (CSD) is a slow-moving ionic and metabolic disturbance that propagates in cortical brain tissue. In addition to massive cellular depolarizations, CSD also involves significant changes in perfusion and metabolism-aspects of CSD that had not been modeled and are important to traumatic brain injury, subarachnoid hemorrhage, stroke, and migraine. In this study, we develop a mathematical model for CSD where we focus on modeling the features essential to understanding the implications of neurovascular coupling during CSD. In our model, the sodium-potassium-ATPase, mainly responsible for ionic homeostasis and active during CSD, operates at a rate that is dependent on the supply of oxygen. The supply of oxygen is determined by modeling blood flow through a lumped vascular tree with an effective local vessel radius that is controlled by the extracellular potassium concentration. We show that during CSD, the metabolic demands of the cortex exceed the physiological limits placed on oxygen delivery, regardless of vascular constriction or dilation. However, vasoconstriction and vasodilation play important roles in the propagation of CSD and its recovery. Our model replicates the qualitative and quantitative behavior of CSD--vasoconstriction, oxygen depletion, extracellular potassium elevation, prolonged depolarization--found in experimental studies. We predict faster, longer duration CSD in vivo than in vitro due to the contribution of the vasculature. Our results also help explain some of the variability of CSD between species and even within the same animal. These results have clinical and translational implications, as they allow for more precise in vitro, in vivo, and in silico exploration of a phenomenon broadly relevant to neurological disease.

Memantine for prevention of migraine: a retrospective study of 60 cases.

The objective was to retrospectively characterise the efficacy of memantine as preventive therapy in a series of patients with frequent migraine. Patients in a university headache clinic completed a survey regarding their experience with memantine, and medical records were reviewed. All patients who received memantine as preventive therapy for migraine over a 15-month period were mailed surveys and consent forms for record review. Patients were treated with memantine beginning at a dose of 5 mg/day, increasing if needed by 5 mg/week up to 10 mg twice a day. The majority of patients (36 out of 54) treated with memantine for at least 2 months reported a significant reduction in estimated headache frequency, and improved function. Side effects were uncommon and generally mild. This limited retrospective case review suggests that memantine may be an effective preventive therapy for patients with frequent migraine. A prospective trial is warranted.

Reduced threshold for cortical spreading depression in female mice.

The prevalence of migraine is much greater in female than male individuals. Cortical spreading depression (CSD) is thought to be a fundamental mechanism of migraine, and CSD in rodents is used as a model for migraine. We used optical intrinsic signal imaging and electrophysiological techniques to investigate CSD in C57Bl/6 mice. Using two different methods for induction of CSD, we found that female mice had a significantly reduced threshold for induction of CSD compared with male mice. These results suggest an increased cortical excitability in female mice that may be independent of the estrous cycle.

Distinct vascular conduction with cortical spreading depression.

Cortical spreading depression (CSD) is associated with significant vasodilatation and vasoconstriction, but the relationship between the cortical parenchymal and vascular phenomena remains poorly understood. We used optical intrinsic signal (OIS) imaging and electrophysiology to simultaneously examine the vascular and parenchymal changes that occur with CSD in anesthetized mice and rats. CSD was associated with a propagated multiphasic change in optical reflectance, with correlated negative DC shift in field potential. Dilatation of cortical surface arterioles propagated with a significantly greater intrinsic velocity than the parenchymal CSD wavefront measured by OIS and electrophysiology. Dilatation traveled in a circuitous pattern along individual arterioles, indicating specific vascular conduction as opposed to concentric propagation of a parenchymal signal. Arteriolar dilatation propagated into areas beyond the spread of parenchymal OIS and electrophysiological changes of CSD. Conversely, vasomotor activity could be experimentally dissociated from the parenchymal CSD wave. Frequent repetitive CSD evoked by continuous stimulation was associated with a reduced or absent arteriolar response despite preserved parenchymal OIS and electrophysiological changes. Similarly, dimethylsulfoxide at high concentrations (10%) inhibited arteriolar reactivity despite preserved parenchymal OIS and electrophysiological changes. These results suggest a mechanism, intrinsic to the vasculature, for propagation of vasodilatation associated with CSD. Distinct vascular conduction could be important for the pathogenesis of conditions that involve CSD, including migraine, stroke, and traumatic brain injury.

Is essential tremor predominantly a kinetic or a postural tremor? A clinical and electrophysiological study.

Both postural and kinetic tremors may occur in essential tremor (ET), however the relative contribution of each is not clear. ET has been variably defined with respect to kinetic and postural tremors. To examine the relative severity of postural and kinetic tremors in ET, 50 ET cases from a clinic and 55 from a community underwent a videotaped tremor examination. Kinetic and postural tremors were rated using a validated clinical rating scale (score range, 0-3). Thirty-one cases also underwent accelerometry to precisely quantify tremor amplitude. In clinic cases, the mean postural tremor rating was 1.25 (S.D., 0.89). The mean kinetic tremor rating was 52% higher (1.90; S.D., 0.57; P < 0.001). The community cases had similar characteristics. Sixty percent of the 105 cases had postural tremor ratings scoring 0 or 1 (no tremor or low amplitude, intermittent tremor). In clinic cases, the mean amplitude of postural tremor during tremor analysis was 0.51 mm (S.D., 0.66 mm), and the mean amplitude of kinetic tremor was 2.91 mm (S.D., 2.11 mm; P < 0.01). Similar values were obtained for community cases. These quantitative data suggest that kinetic tremor is more severe than postural tremor in ET. The majority of cases had mild or absent postural tremor. Despite this, ET is defined only as a postural tremor in many studies. Our data argue for a more consistent inclusion of kinetic tremor in diagnostic criteria for ET.