Frequency and Clinical Features of Space Headache Experienced by Astronauts During Long-Haul Space Flights.

BACKGROUND AND OBJECTIVES: Few anecdotal cases and 1 small retrospective study during short-duration space missions suggest that headache may occur early in flight, as part of the space motion syndrome. Whether headaches may also occur at later stages of space flights is unknown. We aimed to prospectively characterize the incidence, timing, clinical features, and management of space headaches during long-duration flights. METHODS: We prospectively evaluated the occurrence, characteristics, and evolution of space headaches and the effects of treatment and countermeasures during long-haul flights with onboard questionnaires and correlated them with prevailing temperature, pressure, and ambient O2 and CO2 levels, measured within the International Space Station. In addition, we analyzed retrospective headache data from a different astronaut cohort. Headache data were reported using descriptive statistics and correlation data with intraindividual logistic regression models. Astronauts were included through (inter)national aerospace organizations. RESULTS: In the prospective study, 22/24 (91.7%) astronauts (mean ± SD age: 46.6 ± 6.5 years, 95.8% male) experienced ≥1 episode of headache during a total of 3,596 space days. A total of 378 episodes were reported (median 9; range 1-128) with detailed information on 189. Phenotypically, 170/189 (89.9%) episodes were tension-type headache (TTH) and 19/189 (10.1%) were migraine. Episodes in the first week differed from those in later periods in terms of phenotype (migraine 12/51 [23.5%] vs 7/138 [5.1%]; TTH 39/51 [86.5%] vs 131/138 [94.9%]; overall p = 0.0002) and accompanying symptoms: nausea: 17.6% vs 6.9%, p = 0.05; vomiting: 9.8% vs 0.7%, p = 0.005; nasal congestion: 52.9% vs 29.7%, p = 0.004; facial edema: 41.2% vs 1.4%, p < 0.001; and duration (p = 0.001). Severity and treatments were similar: acute antiheadache medication: 55.6%; other medication: 22.4%; and alternative treatments: 41.1%. Headache occurrence was not associated with temperature or ambient pressure/levels of O2 and CO2 (all p > 0.05). In the retrospective study, 23/42 (54.8%) astronauts (43.5 ± 7.2 years, 90.5% male) reported experiencing ≥1 headache episode during mission. Nasal congestion was the most common (8/33; 24.2%) accompanying symptom. Seventeen of 42 astronauts have been previously described. DISCUSSION: Astronauts during space flights frequently experience headaches. These most often have characteristics of TTHs but sometimes have migrainous features, particularly during the first week of flight in astronauts without a history of recurrent headaches before or after the space flight.

Visual hypersensitivity in patients treated with anti-calcitonin gene-related peptide (receptor) monoclonal antibodies.

OBJECTIVE: To evaluate the effect of treatment with anti-calcitonin gene-related peptide (CGRP; receptor) antibodies on visual hypersensitivity in patients with migraine. BACKGROUND: Increased visual sensitivity can be present both during and outside migraine attacks. CGRP has been demonstrated to play a key role in light-aversive behavior. METHODS: In this prospective follow-up study, patients treated for migraine with erenumab (n = 105) or fremanezumab (n = 100) in the Leiden Headache Center were invited to complete a questionnaire on visual sensitivity (the Leiden Visual Sensitivity Scale [L-VISS]), pertaining to both their ictal and interictal state, before starting treatment (T0) and 3 months after treatment initiation (T1). Using a daily e-diary, treatment effectiveness was assessed in weeks 9-12 compared to a 4-week pre-treatment baseline period. L-VISS scores were compared between T0 and T1. Subsequently, the association between the reduction in L-VISS scores and the reduction in monthly migraine days (MMD) was investigated. RESULTS: At 3 months, the visual hypersensitivity decreased, with a decrease in mean ± standard deviation (SD) ictal L-VISS (from 20.1 ± 7.7 to 19.2 ± 8.1, p = 0.042) and a decrease in mean ± SD interictal L-VISS (from 11.8 ± 6.6 to 11.1 ± 7.0, p = 0.050). We found a positive association between the reduction in MMD and the decrease in interictal L-VISS (ß = 0.2, p = 0.010) and the reduction in ictal L-VISS (ß = 0.3, p = 0.001). CONCLUSION: A decrease in visual hypersensitivity in patients with migraine after treatment with anti-CGRP (receptor) antibodies is positively associated with clinical response on migraine.

TMS-evoked EEG potentials demonstrate altered cortical excitability in migraine with aura.

Migraine is associated with altered sensory processing, that may be evident as changes in cortical responsivity due to altered excitability, especially in migraine with aura. Cortical excitability can be directly assessed by combining transcranial magnetic stimulation with electroencephalography (TMS-EEG). We measured TMS evoked potential (TEP) amplitude and response consistency as these measures have been linked to cortical excitability but were not yet reported in migraine.We recorded 64-channel EEG during single-pulse TMS on the vertex interictally in 10 people with migraine with aura and 10 healthy controls matched for age, sex and resting motor threshold. On average 160 pulses around resting motor threshold were delivered through a circular coil in clockwise and counterclockwise direction. Trial-averaged TEP responses, frequency spectra and phase clustering (over the entire scalp as well as in frontal, central and occipital midline electrode clusters) were compared between groups, including comparison to sham-stimulation evoked responses.Migraine and control groups had a similar distribution of TEP waveforms over the scalp. In migraine with aura, TEP responses showed reduced amplitude around the frontal and occipital N100 peaks. For the migraine and control groups, responses over the scalp were affected by current direction for the primary motor cortex, somatosensory cortex and sensory association areas, but not for frontal, central or occipital midline clusters.This study provides evidence of altered TEP responses in-between attacks in migraine with aura. Decreased TEP responses around the N100 peak may be indicative of reduced cortical GABA-mediated inhibition and expand observations on enhanced cortical excitability from earlier migraine studies using more indirect measurements.

Bi-sinusoidal light stimulation reveals an enhanced response power and reduced phase coherence at the visual cortex in migraine.

Introduction: Migraine is associated with enhanced visual sensitivity during and outside attacks. Processing of visual information is a highly non-linear process involving complex interactions across (sub)cortical networks. In this exploratory study, we combined electroencephalography with bi-sinusoidal light stimulation to assess non-linear features of visual processing in participants with migraine. Methods: Twenty participants with migraine (10 with aura, 10 without aura) and ten non-headache controls were measured (outside attacks). Participants received bi-sinusoidal 13 + 23 Hz red light visual stimulation. Electroencephalography spectral power and multi-spectral phase coherence were compared between groups at the driving stimulation frequencies together with multiples and combinations of these frequencies (harmonic and intermodulation frequencies) caused by non-linearities. Results: Only at the driving frequency of 13 Hz higher spectral power was found in migraine with aura participants compared with those with migraine without aura and controls. Differences in phase coherence were present for 2nd, 4th, and 5th-order non-linearities in those with migraine (migraine with and without aura) compared with controls. Bi-sinusoidal light stimulation revealed evident non-linearities in the brain's electroencephalography response up to the 5th order with reduced phase coherence for higher order interactions in interictal participants with migraine. Discussion: Insight into interictal non-linear visual processing may help understand brain dynamics underlying migraine attack susceptibility. Future research is needed to determine the clinical value of the results.

Unilateral increased visual sensitivity in cluster headache: a cross-sectional study.

BACKGROUND AND OBJECTIVES: Increased sensitivity to light and patterns is typically associated with migraine, but has also been anecdotally reported in cluster headache, leading to diagnostic confusion. We wanted to assess whether visual sensitivity is increased ictally and interictally in cluster headache. METHODS: We used the validated Leiden Visual Sensitivity Scale (L-VISS) questionnaire (range 0-36 points) to measure visual sensitivity in people with episodic or chronic cluster headache: (i) during attacks; (ii) in-between attacks; and in episodic cluster headache (iii) in-between bouts. The L-VISS scores were compared with the L-VISS scores obtained in a previous study in healthy controls and participants with migraine. RESULTS: Mean L-VISS scores were higher for: (i) ictal vs interictal cluster headache (episodic cluster headache: 11.9 ± 8.0 vs. 5.2 ± 5.5, chronic cluster headache: 13.7 ± 8.4 vs 5.6 ± 4.8; p < 0.001); (ii) interictal cluster headache vs controls (5.3 ± 5.2 vs 3.6 ± 2.8, p < 0.001); (iii) interictal chronic cluster headache vs interictal ECH in bout (5.9 ± 0.5 vs 3.8 ± 0.5, p = 0.009), and (iv) interictal episodic cluster headache in bout vs episodic cluster headache out-of-bout (5.2 ± 5.5 vs. 3.7 ± 4.3, p < 0.001). Subjective visual hypersensitivity was reported by 110/121 (91%; 9 missing) participants with cluster headache and was mostly unilateral in 70/110 (64%) and ipsilateral to the ictal pain in 69/70 (99%) participants. CONCLUSION: Cluster headache is associated with increased ictal and interictal visual sensitivity. In contrast to migraine, this is mostly unilateral and ipsilateral on the side of the ictal pain.

Responsivity to light in familial hemiplegic migraine type 1 mutant mice reveals frequency-dependent enhancement of visual network excitability.

Migraine patients often report (inter)ictal hypersensitivity to light, but the underlying mechanisms remain an enigma. Both hypo- and hyperresponsivity of the visual network have been reported, which may reflect either intra-individual dynamics of the network or large inter-individual variation in the measurement of human visual evoked potential data. Therefore, we studied visual system responsivity in freely behaving mice using combined epidural electroencephalography and intracortical multi-unit activity to reduce variation in recordings and gain insight into visual cortex dynamics. For better clinical translation, we investigated transgenic mice that carry the human pathogenic R192Q missense mutation in the α1A subunit of voltage-gated CaV 2.1 Ca2+ channels leading to enhanced neurotransmission and familial hemiplegic migraine type 1 in patients. Visual evoked potentials were studied in response to visual stimulation paradigms with flashes of light. Following intensity-dependent visual stimulation, FHM1 mutant mice displayed faster visual evoked potential responses, with lower initial amplitude, followed by less pronounced neuronal suppression compared to wild-type mice. Similar to what was reported for migraine patients, frequency-dependent stimulation in mutant mice revealed enhanced photic drive in the EEG beta-gamma band. The frequency-dependent increases in visual network responses in mutant mice may reflect the context-dependent enhancement of visual cortex excitability, which could contribute to our understanding of sensory hypersensitivity in migraine.

Phase clustering in transcranial magnetic stimulation-evoked EEG responses in genetic generalized epilepsy and migraine.

BACKGROUND: Epilepsy and migraine are paroxysmal neurological conditions associated with disturbances of cortical excitability. No useful biomarkers to monitor disease activity in these conditions are available. Phase clustering was previously described in electroencephalographic (EEG) responses to photic stimulation and may be a potential epilepsy biomarker. OBJECTIVE: The objective of this study was to investigate EEG phase clustering in response to transcranial magnetic stimulation (TMS), compare it with photic stimulation in controls, and explore its potential as a biomarker of genetic generalized epilepsy or migraine with aura. METHODS: People with (possible) juvenile myoclonic epilepsy (JME), migraine with aura, and healthy controls underwent single-pulse TMS with concomitant EEG recording during the interictal period. We compared phase clustering after TMS with photic stimulation across the groups using permutation-based testing. RESULTS: We included eight people with (possible) JME (five off medication, three on), 10 with migraine with aura, and 37 controls. The TMS and photic phase clustering spectra showed significant differences between those with epilepsy without medication and controls. Two phase clustering-based indices successfully captured these differences between groups. One participant was tested multiple times. In this case, the phase clustering-based indices were inversely correlated with the dose of antiepileptic medication. Phase clustering did not differ between people with migraine and controls. CONCLUSION: We present methods to quantify phase clustering using TMS-EEG and show its potential value as a measure of brain network activity in genetic generalized epilepsy. Our results suggest that the higher propensity to phase clustering is not shared between genetic generalized epilepsy and migraine.

Quantifying visual allodynia across migraine subtypes: the Leiden Visual Sensitivity Scale.

Enhanced sensitivity to light (photophobia) and patterns is common in migraine and can be regarded as visual allodynia. We aimed to develop and validate a questionnaire to easily quantify sensitivity to light and patterns in large populations, and to assess and compare visual allodynia across different migraine subtypes and states. We developed the Leiden Visual Sensitivity Scale (L-VISS), a 9-item scale (score range 0-36 points), based on literature and patient interviews, and examined its construct validity. Furthermore, we assessed ictal and interictal visual sensitivity in episodic migraine with (n = 67) and without (n = 66) aura and chronic migraine with (n = 20) and without (n = 19) aura, and in healthy controls (n = 86). Differences between migraine subtypes and states were tested using a linear mixed model with 3 fixed factors (episodic/chronic, with/without aura, and ictal/interictal). Test-retest reliability and construct validity of L-VISS were good. Leiden Visual Sensitivity Scale scores correlated in the expected direction with light discomfort (Kendall's τ = -0.25) and pattern glare tests (τ = 0.35). Known-group comparisons confirmed its construct validity. Within migraine subtypes, L-VISS scores were higher in migraine with aura versus without aura and in chronic versus episodic migraine. The linear mixed model showed all factors affected the outcome (P < 0.001). The L-VISS is an easy-to-use scale to quantify and monitor the burden of bothersome visual sensitivity to light and patterns in large populations. There are remarkable ictal and interictal differences in visual allodynia across migraine subtypes, possibly reflecting dynamic differences in cortical excitability.

TMS brain mapping in less than two minutes.

BACKGROUND: Transcranial magnetic stimulation (TMS) corticospinal excitability maps are a valuable tool to study plasticity in the corticospinal tract. Traditionally, data acquisition for a single map is time consuming, limiting the method's applicability when excitability changes quickly, such as during motor learning, and in clinical investigations where assessment time is a limiting factor. OBJECTIVE: To reduce the time needed to create a reliable map by 1) investigating the minimum interstimulus interval (ISI) at which stimuli may be delivered, and 2) investigating the minimum number of stimuli required to create a map. METHOD: Frameless stereotaxy was used to monitor coil position as the coil was moved pseudorandomly within a 6 × 6 cm square. Maps were acquired using 1-4 s ISIs in 12 participants. The minimum number of stimuli was determined by randomly extracting data and comparing the resulting map to the original data set. To confirm validity, the pseudorandom walk method was compared against a traditional mapping method. RESULTS: Reliable maps could be created with 63 stimuli recorded with a 1 s ISI. Maps created acquiring data using the pseudorandom walk method were not significantly different from maps acquired following the traditional method. CONCLUSIONS: To account for inter-participant variability, outliers, coil positioning errors and, most importantly, participant comfort during data acquisition, we recommend creating a map with 80 stimuli and a 1.5 s ISI. This makes it possible to acquire TMS maps in 2 min, making mapping a more feasible tool to study short- and long-term changes in cortical organization.