Cyclic changes of sensory parameters in migraine patients.

BACKGROUND: Migraine shows a cyclic pattern with an inter-ictal-, a pre-ictal, an ictal- and a post-ictal phase. We aimed to examine changes in psychophysical parameters during the migraine cycle. METHODS: The perception of nociceptive and non-nociceptive stimuli and an electrically induced axon-reflex-erythema were assessed in 20 healthy controls and 14 migraine patients on five consecutive days according to different phases of the migraine cycle. Pain was rated three times during a 10-second electrical stimulus. The size of the axon-reflex-erythema was determined using laser-Doppler-imaging. Intensity and hedonic estimates of odours presented by Sniffin' Sticks were rated. RESULTS: In healthy controls, no significant changes over the test days were observed. In migraine patients pain thresholds at the head decreased with an ictal minimum. Less habituation after five seconds of stimulation at the head was found pre-ictally, whereas reduced habituation to 10-second electrical stimulation was present in all phases. The axon-reflex-erythema size showed an inter-ictal-specific minimum at the head. odours were perceived ictally as more unpleasant and intense. CONCLUSIONS: Somatosensory functions, pain thresholds and habituation as predominantly central parameters, axon-reflex-erythema as a peripheral function of trigeminal neurons and odour perception as a predominantly extra-thalamic sensation change specifically over the migraine cycle indicating complex variations of neuronal signal processing.

Impact of cyclic changes in pharmacokinetics and absorbed dose in pediatric neuroblastoma patients receiving [177Lu]Lu-DOTATATE.

PURPOSE: Recent reports personalizing the administered activity (AA) of each cycle of peptide receptor radionuclide therapy based on the predicted absorbed dose (AD) to the kidneys (dose-limiting organ) have been promising. Assuming identical renal pharmacokinetics for each cycle is pragmatic, however it may lead to over- or under-estimation of the optimal AA. Here, we investigate the influence that earlier cycles of [177Lu]Lu-DOTATATE had on the biokinetics and AD of subsequent cycles in a recent clinical trial that evaluated the safety and activity of [177Lu]Lu-DOTATATE in pediatric neuroblastoma (NBL). We investigated whether predictions based on an assumption of unchanging AD per unit AA (Gy/GBq) prove robust to cyclical changes in biokinetics. METHODS: A simulation study, based on dosimetry data from six children with NBL who received four-cycles of [177Lu]Lu-DOTATATE in the LuDO trial (ISRCTN98918118), was performed to explore the effect of variable biokinetics on AD. In the LuDO trial, AA was adapted to the patient's weight and SPECT/CT-based dosimetry was performed for the kidneys and tumour after each cycle. The largest tumour mass was selected for dosimetric analysis in each case. RESULTS: The median tumour AD per cycle was found to decrease from 15.6 Gy (range 8.12-26.4) in cycle 1 to 11.4 Gy (range 9.67-28.8), 11.3 Gy (range 2.73-32.9) and 4.3 Gy (range 0.72-20.1) in cycles 2, 3 and 4, respectively. By the fourth cycle, the median of the ratios of the delivered AD (ADD) and the predicted (or "expected") AD (ADE) (which was based on an assumption of stable biokinetics from the first cycle onwards) were 0.16 (range 0.02-0.92, p = 0.013) for the tumour and 1.08 (range 0.84-1.76, p > 0.05) for kidney. None of the patients had an objective response at 1 month follow up. CONCLUSION: This study demonstrates variability in Gy/GBq and tumour AD per cycle in children receiving four administrations of [177Lu]Lu-DOTATATE treatment for NBL. NBL is deemed a radiation sensitive tumour; therefore, dose-adaptive treatment planning schemes may be appropriate for some patients to compensate for decreasing tumour uptake as treatment progresses. Trial registration ISRCTN ISRCTN98918118. Registered 20 December 2013 (retrospectively registered).

Diffusivity mapping of the ovaries: Variability of apparent diffusion and kurtosis variables over the menstrual cycle and influence of oral contraceptives.

PURPOSE: We aimed to investigate whether quantitative diffusivity variables of healthy ovaries vary during the menstrual cycle and to evaluate alterations in women using oral contraceptives (OC). METHODS: This prospective study (S-339/2016) included 30 healthy female volunteers, with (n = 15) and without (n = 15) intake of OC between 07/2017 and 09/2019. Participants underwent 3T diffusion-weighted MRI (b-values 0-2000 s/mm2) three times during a menstrual cycle (T1 = day 1-5; T2 = day 7-12; T3 = day 19-24). Both ovaries were manually three-dimensionally segmented on b = 1500 s/mm2; apparent diffusion coefficient (ADC) calculation and kurtosis fitting (Dapp, Kapp) were performed. Differences in ADC, Dapp and Kapp between time points and groups were compared using repeated measures ANOVA and t-test after Shapiro-Wilk and Brown-Forsythe test for normality and equal variance. RESULTS: In women with a natural menstrual cycle, ADC and kurtosis variables showed significant changes in ovaries with the dominant follicle between T1 vs T2 and T1 vs T3, whilst no differences were observed between T2 vs T3: ADC ± SD for T1 1.524 ± 0.160, T2 1.737 ± 0.160, and T3 1.747 ± 0.241 µm2/ms (p = 0.01 T2 vs T1; p = 1.0 T2 vs T3, p = 0.003 T3 vs T1); Dapp ± SD for T1 2.018 ± 0.140, T2 2.272 ± 0.189, and T3 2.230 ± 0.256 µm2/ms (p = 0.003 T2 vs T1, p = 1.0 T2 vs T3, p = 0.02 T3 vs T1); Kapp ± SD for T1 0.614 ± 0.0339, T2 0.546 ± 0.0637, and T3 0.529 ± 0.0567 (p < 0.001 T2 vs T1, p = 0.86 T2 vs T3, p < 0.001 T3 vs T1). No significant differences were found in the contralateral ovaries or in females taking OC. CONCLUSION: Physiological cycle-dependent changes in quantitative diffusivity variables of ovaries should be considered especially when interpreting radiomics analyses in reproductive women.

Brain state monitoring for the future prediction of migraine attacks.

BACKGROUND: Migraine attacks are unpredictable, precluding preemptive interventions and leading to lack of control over individuals' lives. Although there are neurophysiological changes 24-48 hours before migraine attacks, so far, they have not been used in patients' management. This study evaluates the applicability and the ability to identify pre-attack changes of daily "at home" electroencephalography obtained with a portable system for migraine patients. METHODS: Patients with episodic migraine fulfilling ICHD-3 beta criteria used a mobile system composed of a wireless EEG device (BrainStation®, Neuroverse®, Inc., USA) and mobile application (BrainVitalsM®, Neuroverse®, Inc., USA) to self-record their neural activity daily at home while resting and while performing an attention task, over the course of 2 weeks. Standard EEG spectral analysis and event-related brain potentials (ERP) methods were used and recordings were grouped by time from migraine attacks (i.e. "Interictal day", "24 h Before Migraine", "Migraine day" and "Post Migraine"). RESULTS: Twenty-four patients (22 women) recorded an average of 13.3 ± 1.9 days and had 2 ± 0.9 attacks. Twenty-four hours before attack onset, there was a statistically significant modulation of relative power in the delta (decrease) and beta (increase) frequency bands, at rest, and a significant reduction of the amplitude and inter-trial coherence measures of an attention event-related brain potential (P300). CONCLUSIONS: This proof-of-concept study shows that brain state monitoring, utilising an easy-to-use wearable EEG system to track neural modulations at home, can identify physiological changes preceding a migraine attack enabling valuable pre-symptom prediction and subsequent early intervention.

Cyclic changes in sensations to painful stimuli in migraine patients.

INTRODUCTION: Migraine is characterized by cycling phases (interictal, preictal, ictal and postictal) with differing symptoms, while in chronic tension type headache pain phases are fluctuating. The question we asked is whether these phases are associated with changes in parameters of somatosensation and axon-reflex erythema. METHODS: Patients with episodic migraine and chronic tension type headache were examined psychophysically in the interictal, preictal and ictal phase and healthy subjects on five different test days. Thresholds and suprathreshold ratings of pressure and electrical pain were assessed on three different regions of the head. In migraine patients and in healthy controls, electrically induced axon-reflex erythema was measured in the area of the first trigeminal branch. All migraine patients filled out questionnaires about prodromal symptoms at every visit. RESULTS: The axon-reflex erythema was always larger in patients with migraine in contrast to healthy subjects. The pressure pain threshold was lower in migraine patients and chronic tension type headache in comparison to healthy subjects. Electrical pain thresholds did not differ between headache patients and healthy subjects and showed no changes between the phases. However, suprathreshold pain ratings showed less habituation solely in the preictal phase of migraine. The number of prodromal symptoms in migraine patients was increased in the preictal and ictal phase. DISCUSSION: Reduced habituation was the unique sign of the preictal phase in migraine patients, independently of prodromal symptoms, whereas a larger axon-reflex erythema and higher pressure pain sensitivity are constitutional and non-phase dependent properties of migraine. Reduced inhibitory mechanisms in the preictal phase may contribute to trigger headache attacks in migraine.

EVIDENCE FOR AN ENDOGENOUS CYCLE OF DORMANCY IN DRY STORED SEEDS OF POA TRIVIALIS L.

Seeds of Poa trivialis L. (rough meadow-grass) were collected from two contrasting habitats during the summer of 1982. Collections from an arable population were obtained on three occasions and seeds from a grassland population were collected once. Although both populations responded similarly to various combinations of light, temperature and nitrate, the arable collections were markedly more dormant. Loss of dormancy of the grassland and early arable populations one month after collection was rapid in seeds stored at ambient temperatures and at 4 °C but more delayed in those stored at 23 °C. Despite a gradual loss of dormancy during storage, cyclic changes in dormancy were also evident, especially at 23 °C. The percentage germination of the various collections 7 d after incubation following storage at 23 °C increased over the first three months, but declined following six and 12 months storage and increased again after 15 months storage. At 4 °C the late arable collection lost dormancy more slowly than the other two collections and germination was greatest after six months storage; a reduction in percentage germination occurred after twelve months. Seeds buried at 5 and 15 cm showed cyclic changes of dormancy, being least dormant in autumn and spring, but most dormant in summer, corresponding to the natural periodicity of germination. It is proposed that cyclic changes in dormancy are regulated by endogenous rhythms and seasonal changes of temperature. The ecological implications of the germination behaviour of this species in various habitats are discussed.