OBJECTIVE: Calcitonin gene-related peptide ligand/receptor (CGRP) antibodies effectively reduce headache frequency in migraine. It is understood that they act peripherally, which raises the question whether treatment merely interferes with the last stage of headache generation or, alternatively, causes secondary adaptations in the central nervous system and might thus possess disease modifying potential. This study addresses this question by investigating the nociceptive blink reflex (nBR), which is closely tied to central disease activity, before and after treatment with CGRP antibodies.
METHODS: We enrolled 22 patients suffering episodic migraine (21 female, 46.2 ± 13.8 years of age) and 22 age-/gender-matched controls. Patients received assessments of the nBR (R2 component, 10 trials, 6 stimuli/trial) before (V0) and three months (V3) after treatment with CGRP antibodies started, controls were assessed once. The R2 area (R2a) and habituation (R2h; gradient of R2a against stimulus order) of the stimulated/non-stimulated side (_s/_ns) following repeated supraorbital stimulation provide a direct readout of brainstem excitability and habituation as key mechanisms in migraine.
RESULTS: All patients showed a substantial reduction of headache days/month (V0: 12.4±3.3, V3: 6.6 ± 4.9). R2a_s (Fglobal=5.86, p<0.001; block 1: R2a_s: -28%, p<0.001) and R2a_ns (Fglobal=8.22, p<0.001, block 1: R2a_ns: -22%, p=0.003) were significantly decreased, and R2h_ns was significantly enhanced (Fglobal=3.07, p<0.001; block 6: R2h_ns: r=-1.36, p=0.007) from V0 to V3. The global test for changes of R2h_s was non-significant (Fglobal=1.46, p=0.095). Changes of R2h significantly correlated with improvement of headache frequency (R2h_s, r=0.56, p=0.010; R2h_ns: r=0.45, p=0.045). None of the nBR parameters assessed at baseline predicted treatment response.
CONCLUSIONS: We provide evidence that three months of treatment with CGRP antibodies restores brain stem responses to painful stimuli and thus might be considered disease modifying. The nociceptive blink reflex may provide a biomarker to monitor central disease activity. Future studies should evaluate the blink reflex as a clinical biomarker to predict treatment response at baseline and to establish the risk of relapse after treatment discontinuation.
BACKGROUND: This trial was prospectively registered at clinicaltrials.gov (ID: NCT04019496, date of registration: July 15, 2019).

Migraine is characterized by sensory hypersensitivity and habituation deficits. Slow brushing over the skin activates C-tactile nerve fibers, which mediate pleasant touch and analgesic effects in healthy subjects. As this function is altered in painful conditions, we aimed to examine whether the C-tactile processing is disrupted in migraines.
To psychophysically assess C-tactile function, we applied optimal and suboptimal C-tactile stroking stimuli on the dorsal forearm (body reference area) and the trigeminally innervated skin of 52 interictal migraineurs and 52 matched healthy controls. For habituation testing, 60 repeated C-tactile optimal stimuli were presented in both test areas. The participants rated each stimulus on a visual analogue scale by intensity, pleasantness, and painfulness.
Regarding C-tactile function, migraineurs showed unphysiological rating patterns but no significantly different pleasantness ratings than controls. During repeated stimulation, controls showed stable pleasantness ratings while migraineurs\' ratings decreased, especially in those experiencing tactile allodynia during headaches. Migraineurs taking triptans responded like controls.
The C-tactile function of migraineurs is subclinically altered. Repeated C-tactile stimulation leads to altered habituation but differs from previous work by the direction of the changes. Although the pathophysiology remains unknown, causative mechanisms could include central and peripheral neuronal sensitization, tactile allodynia and hedonic stimulus attributions.

OBJECTIVE: The association of habitual behaviors with the prevalence of synchronous colorectal cancer (sCRC) is unknown. Here, we investigated whether these behaviors, which are known risk factors for colorectal polyps, may be related to sCRC risk.
METHODS: We enrolled 17,093 patients who underwent cancer treatment between January 1995 and December 2016 and examined the association of age, sex, familial history of hereditary colorectal cancer (CRC), and status of three common habitual behaviors (smoking and alcohol and coffee consumption) with the prevalence of sCRC.
RESULTS: Of the enrolled patients, 960 (5.6%) patients had sCRC. The independent risk factors for sCRC prevalence included advanced age, male sex, hereditary CRC, smoking, and daily alcohol consumption of more than one bottle (> 600 mL). Contrary to these factors, daily coffee consumption of more than one cup seemed to provide a protection from sCRC. In the Kaplan-Meier test, the significantly worse 5-year overall survival (OS) was noted in smokers with stage 0-III CRC. The effect of alcohol consumption on 5-year OS was significant in stages II and III. Compared with those without daily coffee consumption, patients with daily coffee consumption had significantly higher 5-year OS in stages I (93.0% vs. 86.4%), II (87.1% vs. 77.2%), III (71.5% vs. 61.9%), and IV (18.0% vs. 13.0%).
CONCLUSIONS: sCRC prevalence was significantly associated with habitual behaviors. Patients with smoking or with daily alcohol consumption of one bottle had higher sCRC prevalence than did those without these habits. Coffee consumption could be a protective factor for lowering sCRC risk.

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Background Many studies have shown that migraine patients have an interictal habituation deficit of visual evoked potentials (VEPs). Some discordant results were attributed to non-blinded analyses and a lack of repeatability. Aims In this study, we compared blinded and non-blinded analyses of the same recordings and assessed test-retest repeatability. Methods VEP recordings of 25 healthy volunteers (HVs) and 78 episodic migraine patients (EMs; 52 interictal, 26 ictal) were analysed by two investigators, one of whom was blinded to diagnosis and headache phase. Twelve HVs and nine EMs had two recordings for test repeatability. Results In both blinded and non-blinded analyses, VEP habituation was normal in HVs and EMs during an attack, but deficient in EMs interictally. Intra-individual habituation percentages were highly correlated in two recordings separated by ≥7 days. Conclusions The studies showing a VEP habituation deficit in migraineurs between attacks are unlikely to be biased by non-blinding analysis or poor repeatability.

BACKGROUND: In migraine most studies report an interictal deficit of habituation of visual-evoked potentials (VEP-hab) and reduced thresholds for phosphene induction (PT) by transcranial magnetic stimulation (TMS). We searched for a possible correlation between VEP-hab and PT in migraine patients and healthy controls to test whether they reflect the same pathophysiological abnormality.
METHODS: We assessed PT and VEP-hab measured as the percentage change of N1/P1 amplitude over six blocks of 100 responses in 15 healthy volunteers (HV) and in 13 episodic migraineurs without aura (MO) between attacks. Results were compared using Mann-Whitney U test. Interrelationships were examined using Spearman\'s correlation.
RESULTS: In MO patients VEP-hab was reduced compared to HV (p = 0.001), while PT were not significantly different between HV and MO. There was no correlation between PT and VEP-hab in either group of participants.
CONCLUSIONS: We confirm that in interictal migraine VEP habituation is deficient, but magnetophosphene threshold normal. VEP-hab and PT were not correlated with each other in healthy controls or in migraineurs. This finding suggests that they index different facets of cortical excitability in migraine, i.e. a punctual normal measure of the cortical activation threshold for PT and a dynamic response pattern to repeated stimuli for VEP habituation.

Sustained effects of emotion are well known in everyday experience. Surprisingly, such effects are seldom recorded in laboratory studies of the emotional Stroop task, in which participants name the color of emotion and neutral words. Color performance is more sluggish with emotion words than with neutral words, the emotional Stroop effect (ESE). The ESE is not sensitive to the order in which the two groups of words are presented, so the effect of exposure to emotion words does not extend to disrupting performance in a subsequent block with neutral words. We attribute this absence of a sustained effect to habituation engendered by excessive repetition of the experimental stimuli. In a series of four experiments, we showed that sustained effects do occur when habituation is removed, and we also showed that the massive exposure to negative stimuli within the ESE paradigm induces a commensurately negative mood. A novel perspective is offered, in which the ESE is considered a special case of mood induction.

BACKGROUND: Chronic cluster headache (CCH) is characterized by recurrent bouts of facial pain lasting up to 180 minutes in the absence of a long remission period.
METHODS: We report the case of a 43-year-old male patient with treatment-resistant CCH, who improved with administration of transdermal rotigotine. We also evaluated the nociceptive blink reflex habituation that was reduced before the treatment (as is usual in CH patients) and normalized by transdermal rotigotine.
CONCLUSIONS: We suggest that rotigotine could represent a further therapeutic option in the treatment of drug-resistant CCH.

Recent evidence suggests adults and infants selectively attend to features of action, such as how a hand contacts an object. The current research investigated whether this bias stems from infants\' processing of the functional consequences of grasps: understanding that different grasps afford different future actions. A habituation paradigm assessed 10-month-old infants\' (N = 62) understanding of the functional consequences of precision and whole-hand grasps in others\' actions, and infants\' own precision grasping abilities were also assessed. The results indicate infants understood the functional consequences of another\'s grasp only if they could perform precision grasps themselves. These results highlight a previously unknown aspect of early action understanding, and deepen our understanding of the relation between motor experience and cognition.

Traditional techniques used to capture New World monkeys, such as net capture, can induce high levels of acute stress detrimental to welfare. Alternatively, training nonhuman animals via operant conditioning to voluntarily participate in husbandry and/or veterinary practices is accepted as a humane process that can reduce stress and improve welfare. This study details the use of operant conditioning using positive reinforcement training (PRT) and target training to train a family of 5 captive red-bellied tamarins (Saguinus labiatus) in a wildlife park to voluntarily enter a transportation box and remain calm for 1 min after 54 training sessions. Observations of 2 unrelated net-capture processes provided measures of locomotion and vocalizations as indicators of stress behavior that were compared with those of the trained tamarins. Net-captured monkeys exhibited rapid erratic locomotion and emitted long, high-frequency vocalizations during capture whereas the trained tamarins exhibited minimal locomotion and emitted only 4 brief vocalizations (root mean square 35 dB) during capture. This indicates that the use of PRT considerably reduced potential for stress and improved welfare during the capture and containment of the tamarins.