Habituation of Brain Activity with Repetition in Color and Picture-Word Stroop Tests.

As a widely used mental task for functional near-infrared spectroscopy (fNIRS), the original color-word Stroop task has the advantage of being difficult to habituate, but also the disadvantage of being difficult to understand, especially for children. While the introduction of derived Stroop tasks offers highly promising countermeasures, changes in brain activity during these tests have not been well tested. We investigated the degree of habituation between the original and a derived Stroop task by measuring brain activity to obtain a better fNIRS task design. Fourteen healthy adults participated in the study, and a 10-channel fNIRS device was used. A picture-word Stroop task with lower linguistic conflict than the original was conducted. The original and derived Stroop tests were repeated four times in a 1-week interval. We found that the original Stroop test did not show any significant changes in brain activity with repeated measures; however, brain activity decreased during the derived test. The differences in habituation between the original and derived tests may be due to the differences in the strength of the linguistic conflict. Our findings also highlight the need to consider the effects of habituation when using derived Stroop tasks in repeated measures.

Transforming leisure time physical activity into a habit through social institutions.

Physical activity is a positive health behavior that has been shown to reduce the risk of physical and mental illnesses; There's strong evidence suggesting that Physical activity, as one of the components of a healthy lifestyle, if transformed into a consistent behavior or habit early in life, becomes easier to sustain throughout the lifecycle and leads to valuable outcomes for the society's health in various physical, mental, and social dimensions. Each social institution, considering its unique role and characteristics, can contribute to shaping individuals' behaviors in societies. Consequently, identifying the role of social institutions in the development of leisure-time physical activity (LTPA) as a regular activity and a behavioral habit can result in the selection and implementation of highly effective intervention strategies. Therefore, this research aimed to present a model of the role of social institutions in institutionalizing leisure-time physical activity among Iranian adolescent girls. To collect data, the questionnaires were employed, and for presenting the model, structural equation modeling was utilized. Data analysis showed that the role of three social institutions in the institutionalization of physical activities including habituation, objectification and sedimentation was confirmed, although sedimentation was confirmed in all three institutions at the 0.05 level, which indicates that factors in this area can be investigated. Examining the role of social institutions in institutionalizing behaviors may vary across different ages and genders, which is open to investigation in future studies.

Tracking the habituation of the event-related EEG potential in automatic change detection using an auditory two-tone oddball paradigm.

The mismatch negativity and the P3a of the event-related EEG potential reflect the electrocortical response to a deviant stimulus in a series of stimuli. Although both components have been investigated in various paradigms, these paradigms usually incorporate many repetitions of the same deviant, thus leaving open whether both components vary as a function of the deviant's position in a series of deviant stimuli-i.e. whether they are subject to qualitative/quantitative habituation from one instantiation of a deviant to the next. This is so because the detection of mismatch negativity/P3a in the event-related EEG potential requires an averaging over dozens or hundreds of stimuli, i.e. over many instantiations of the deviant per participant. The present study addresses this research gap. We used a two-tone oddball paradigm implementing only a small number of (deviant) stimuli per participant, but applying it to a large number of participants (n > 230). Our data show that the mismatch negativity amplitude exhibits no decrease as a function of the deviant's position in a series of (standard and) deviant stimuli. Importantly, only after the very first deviant stimulus, a distinct P3a could be detected, indicative of an orienting reaction and an attention shift, and thus documenting a dissociation of mismatch negativity and P3a.

Pronounced Olfactory Habituation with Age.

OBJECTIVES: Olfactory habituation is a transient decrease in olfactory sensitivity caused by prolonged odor exposure, aiding in the discernment of new olfactory stimuli against the background. We explored the impact of subclinical olfactory impairment on odor habituation using age as a proxy. METHODS: Before the actual experiment, the individual olfactory threshold for the rose-like odorant phenylethyl alcohol (PEA) was assessed separately for the left and right nostril using the "Sniffin' Sticks" test, and ratings for odor intensity and pleasantness were collected. After applying a nasal clip continuously delivering PEA odor to one nostril for 10 min and 2 h, respectively, threshold, intensity, and pleasantness were reassessed immediately after clip removal. RESULTS: In the group of 80 participants (younger adults-mean age 27.7 ± 4.5 years; older adults-mean age 61.5 ± 4.7 years), olfactory thresholds were already significantly elevated after just 10 min, and this habituation was even more pronounced after 2 h. This effect could be observed bilaterally even though significantly more distinct on the exposed side. Older participants generally exhibited a more pronounced habituation on the exposed side after 2 h compared to the younger participants. CONCLUSION: The results indicate that older people experience more notable habituation after extended exposure to odors. This is most likely due to the compromised olfactory function in age. Although older and younger subjects scored in the normosmic range when tested with standardized olfactory tests, the stress on the system after exposure to an odor clearly revealed the lower functionality of the aging sense of smell. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

A network analysis of mechanisms of change during exposures over the course of intensive OCD treatment.

Exposure and response prevention (ERP) is an evidence-based treatment for obsessive-compulsive disorder (OCD). Theories for how it works vary in their emphasis on active mechanisms of change. The current study aimed to clarify mechanisms of change in ERP for OCD using network analysis, comparing ERP networks at the start and end of intensive treatment (partial hospital and residential). In our sample of 182 patients, the most central node in both networks was engagement with exposure, which was consistently related to greater understanding of ERP rationale, higher willingness, and less ritualization, accounting for all other variables in the network. There were no significant differences in networks between the start and end of treatment. These results suggest that nonspecific parameters like facilitating engagement in exposures without ritualizing and providing a clear rationale to clients may be key to effective treatment. As such, it may be useful for clinicians to spend adequate time underscoring the need to eliminate rituals to fully engage in exposure tasks and explaining the rationale for ERP prior to doing exposures, regardless of theoretical orientation. Nonetheless, findings represent group-level statistics and more fine-grained idiographic analyses may reveal individual-level differences with respect to central mechanisms of change. Other limitations include demographic homogeneity of our sample.

Habituation disorders in auditory middle latency response of persistent postural-perceptual dizziness patients.

Objectives: To study habituation disorders in auditory middle latency response (AMLR) to repetitive stimuli of persistent postural-perceptual dizziness (PPPD) patients. Subjects: Twenty-eight PPPD (10 men and 18 women, mean 59.5 years of age, 26-81 years of age) were enrolled. For comparison, data of 13 definite vestibular migraine (VM) patients (3 men, 10 women, mean age 45.5), 13 definite unilateral Meniere's disease (MD) patients (2 men, 11 women, mean age 50.6), and 8 healthy control (HC) subjects (2 men, 6 women, mean age 37.1) in the previous study were utilized. Methods: The electrodes were placed on the vertex and the spinal process of the fifth cervical vertebra. Clicks (0.1 msec, 70 dB nHL) were binaurally presented and averaged (800 times). Averaged responses were divided into 4 sets (S1 to S4) according to the temporal order. As peaks, Na, and Pa were identified, and relative Na-Pa amplitudes in S2-S4 to S1 were analyzed. Results: The mean relative amplitude of PPPD patients showed lack of habituation (potentiation) as shown in VM patients, although the extent of potentiation was weaker than VM. Comparison of relative S4 amplitudes showed significant differences among the 4 groups (p = 0.0013 one-way ANOVA), Multiple comparison revealed significant differences between PPPD and MD (p = 0.0337 Dunnet's test). Conclusion: PPPD patients showed lack of habituation (potentiation) of Na-Pa amplitude in AMLR to repetitive stimuli. Lack of habituation (potentiation) might be associated with sensory processing disorders in PPPD.

Sensibilidad de la respuesta simpática cutánea y de la gammagrafía en el diagnóstico del síndrome dolor regional complejo / Sensitivity of the sympathetic skin response and scintigraphy in the diagnosis of complex regional pain syndrome

Objetivo: Evaluar la sensibilidad de la respuesta simpática cutánea (RSC) y compararla con la gammagrafía en pacientes con síndrome de dolor regional complejo diagnosticados según criterios de Budapest. Material y métodos: Se evaluó prospectivamente a 22 pacientes con síndrome de dolor regional complejo que acudieron al Servicio de Rehabilitación y Medicina Física entre enero-2018 y mayo-2022. La gammagrafía se consideró positiva si en la 1.a-2.a fase se apreció leve captación asimétrica y difusa, o cuando en la 3.a fase se apreció marcada captación periarticular del radioisótopo. La RSC era anormal si se observaba: a) ausencia de respuesta tras 20 estímulos; b) falta de habituación con permanencia de los estímulos mayor al 67,2%. Resultados: Edad 55,4±8,57 años. Síndrome de dolor regional complejo más frecuente en mujeres (90,9%), más común en miembros superiores (68,2%) que en inferiores (31,8%). En la RSC hemos observado respuesta normal (<67,2%) en 2 pacientes (11,1%), falta de RSC en 2 pacientes (11,1%) y falta de habituación (>67,2%) en 14 pacientes (77,8%). En total, 16 pacientes presentaron respuestas anormales o ausentes (88,8%). La sensibilidad diagnóstica de la gammagrafía es similar a la de la RSC (89,5 vs. 88,8%), sin diferencia estadística (p=0,6721). Conclusión: La Gammagrafía ha demostrado una sensibilidad similar a la RSC, aunque la simpleza, el bajo coste y la no invasividad de esta última técnica sugieren que podría ser más coste/efectiva y segura (no ionizante). La falta de habituación y la ausencia de respuesta podrían identificar patrones de respuesta y localizar la afectación en las vías aferente, central, eferente o post ganglionar.(AU)

Objective: To evaluate the sensitivity of sympathetic skin response (SSR) and compare it with scintigraphy in patients with complex regional pain syndrome diagnosed according to the Budapest criteria. Material and methods: Twenty-two patients with complex regional pain syndrome who attended the Rehabilitation and Physical Medicine Department between January-2018 and May-2022 have been prospectively evaluated. The scintigraphy was considered positive if in the 1st-2nd phase slight asymmetric and diffuse uptake was observed, or when in the 3rd phase marked periarticular radioisotope uptake was observed. SSR was abnormal if: a) no response after 20 stimuli; b) lack of habituation with permanence of the stimuli greater than 67.2%. Results: Age 55.4±8.57 years. Complex regional pain syndrome was more frequent in women (90.9%), more common in upper limbs (68.2%) than lower limbs (31.8%). In SSR, we have observed normal response (<67.2%) in 2 patients (11.1%), lack of SSR in 2 patients (11.1%) and lack of habituation (>67.2%) in 14 patients (77.8%). In total, 16 patients presented abnormal or absent responses (88.8%). The diagnostic sensitivity of scintigraphy is similar to that of SSR (89.5% vs 88.8%), with no statistical difference (P=.6721). Conclusion: Scintigraphy has shown similar sensitivity to SSR, although the simplicity, security, low cost, non-ionizing and non-invasiveness of the latter technique suggest that it could be more cost-effective. The lack of habituation and the absence of response could identify response patterns and localize the involvement in the afferent, central, efferent or post-ganglionic pathways.(AU)

Letrozole delays acquisition of water maze task in female BALB/c mice: Possible involvement of anxiety.

Letrozole, an aromatase inhibitor preventing estrogen synthesis from testosterone, is used as an adjuvant therapy in estrogen receptor-positive breast cancer patients. However, like other aromatase inhibitors, it induces many side effects, including impaired cognition. Despite its negative effect in humans, results from animal models are inconsistent and suggest that letrozole can either impair or improve cognition. Here, we studied the effects of chronic letrozole treatment on cognitive behavior of adult female BALB/c mice, a relevant animal model for breast cancer studies, to develop an appropriate animal model aimed at testing therapies to mitigate side effects of letrozole. In Morris water maze, letrozole 0.1 mg/kg impaired reference learning and memory. Interestingly, most of the letrozole 0.1 mg/kg-treated mice were able to learn the new platform position in reversal training and performed similar to control mice in a reversal probe test. Results of the reversal test suggest that letrozole did not completely disrupt spatial navigation, but rather delayed acquisition of spatial information. The delay might be related to increased anxiety as suggested by increased thigmotactic behavior during the reference memory training. The learning impairment was water maze-specific since we did not observe impairment in other spatial tasks such as in Y-maze or object location test. In contrast, the dose of 0.3 mg/kg did not have effect on water maze learning and facilitated locomotor habituation and recognition in novel object recognition test. The current study shows that letrozole dose-dependently modulates behavioral response and that its effects are task-dependent.

High intraspecific variability and previous experience affect polyphenol metabolism in polyphagous Lymantria mathura caterpillars.

Polyphagous insect herbivores feed on multiple host-plant species and face a highly variable chemical landscape. Comparative studies of polyphagous herbivore metabolism across a range of plants is an ideal approach for exploring how intra- and interspecific chemical variation shapes species interactions. We used polyphagous caterpillars of Lymantria mathura (Erebidae, Lepidoptera) to explore mechanisms that may contribute to its ability to feed on various hosts. We focused on intraspecific variation in polyphenol metabolism, the fates of individual polyphenols, and the role of previous feeding experience on polyphenol metabolism and leaf consumption. We collected the caterpillars from Acer amoenum (Sapindaceae), Carpinus cordata (Betulaceae), and Quercus crispula (Fagaceae). We first fed the larvae with the leaves of their original host and characterized the polyphenol profiles in leaves and frass. We then transferred a subset of larvae to a different host species and quantified how host shifting affected their leaf consumption and polyphenol metabolism. There was high intraspecific variation in frass composition, even among caterpillars fed with one host. While polyphenols had various fates when ingested by the caterpillars, most of them were passively excreted. When we transferred the caterpillars to a new host, their previous experience influenced how they metabolized polyphenols. The one-host larvae metabolized a larger quantity of ingested polyphenols than two-host caterpillars. Some of these metabolites could have been sequestered, others were probably activated in the gut. One-host caterpillars retained more of the ingested leaf biomass than transferred caterpillars. The pronounced intraspecific variation in polyphenol metabolism, an ability to excrete ingested metabolites and potential dietary habituation are factors that may contribute to the ability of L. mathura to feed across multiple hosts. Further comparative studies can help identify if these mechanisms are related to differential host-choice and response to host-plant traits in specialist and generalist insect herbivores.

Preexposure to running attenuates rats' running-based flavour avoidance: Testing associative blocking with a cover cues or context change.

Voluntary running in activity wheels by rats leads to a Pavlovian conditioned aversion to the flavour consumed immediately before the running, causing the rats to avoid that flavour. This learning process, known as running-based flavour avoidance learning (FAL), is weakened when the rats have had repeated exposure to the wheels before. According to the associative account, the association between the background context and running established during the preexposure phase blocks the conditioning of the target flavour because the running is highly predictable by the background context from the outset of the FAL phase. Experiments 1 and 2 examined this account by introducing another flavour as a cue signalling wheel access during the preexposure phase. In the framework of the associative account, the introduction of this cue should impede the formation of the context-running association during the preexposure phase, thereby hindering the contextual blocking of aversive conditioning for the target flavour in the FAL phase. This would result in unweakened FAL. Although the results of Experiment 1 align with this prediction, in Experiment 2, when highly distinct flavours were used as the target and second cues, the preexposure effect was not eliminated. This contradicts the predictions of the associative account, indicating that Experiment 1 may have been influenced by stimulus generalisation. In Experiment 3, changing background contexts between the preexposure and FAL phases had no impact on the preexposure effect, contrary to the predictions of the associative account. In general, the associative account was not supported.

A partial habituation method to test for anterograde and retrograde amnestic treatment effects: Evidence that antagonism of the NMDA receptor can induce anterograde but not retrograde amnestic effects.

BACKGROUND: A progressive decrease in spontaneous locomotion with repeated exposure to a novel environment has been assessed using both within and between-session measures. While both are well-established and reliable measurements, neither are useful alone as methods to concurrently assess treatment effects on acquisition and retention of habituation. NEW METHOD: We report a behavioral method that measures habituation by combining the within and between measurements of locomotion. We used a 30 min session divided into 6 five min blocks. In the first novel environment session activity was maximal in the first 5 min block but was reduced to a low level by the sixth block, indicative of within-session habituation. Using 8 daily sessions, we showed that this terminal block low level of activity progressed incrementally to the first block to achieve complete habituation. RESULTS/COMPARISON WITH EXISTING METHODS: Within-session activity across sessions was used to identify different stages of between session habituation. It was then possible to assess drug treatment effects from partial to complete habituation, so that treatment effects on retention of the previously acquired partial habituation, expressed as a reversion to an earlier within session habituation pattern (retrograde amnesia assessment), as well as the effects on new learning by the failure in subsequent sessions to acquire complete between-session habituation (anterograde amnesia assessment). CONCLUSIONS: The use of spontaneous motor activity to assess learning and memory effects provides the opportunity to assess direct treatment effects on behavior and motor activity in contrast to many learning and memory models.

Face masks in action: Birds show reduced fear responses to people wearing face masks during the COVID-19 pandemic in three Asian countries.

The 2019 zoonotic pandemic (COVID-19), has led to a massive global lockdown that provides a good opportunity to study how wildlife responds to changes in human activity. Wearing a mask after the COVID-19 outbreak was widely used to prevent the spread of the causative pathogen. It has been shown that tree sparrows (Passer montanus) at two sites in south China exhibit reduced fear responses to people with face masks after a period of heavy exposure to them, whereas European studies showed the opposite, with no changes in the behaviour of the birds towards mask wearers in either rural or urban areas. To further study this, from October 2021 to January 2022, we conducted a flight initiation distance (FID) survey in Pakistan, Bangladesh, and Xi'an, China for a variety of field bird species by comparing the FID for researchers wearing masks to that for researchers not wearing masks to assess whether wearing masks in public places caused birds to adjust their flight response. Results from the three Asian countries showed that after a period of sustained contact with people wearing masks, in both rural and urban areas, birds were significantly more adapted to them and had a shorter FID to people wearing masks. We suggest that the rapid habituation of birds to people wearing masks with a reduced fear response could have some fitness advantage, allowing them to adapt rapidly to the new environmental conditions induced by COVID-19.

Cellular forgetting, desensitisation, stress and ageing in signalling networks. When do cells refuse to learn more?

Recent findings show that single, non-neuronal cells are also able to learn signalling responses developing cellular memory. In cellular learning nodes of signalling networks strengthen their interactions e.g. by the conformational memory of intrinsically disordered proteins, protein translocation, miRNAs, lncRNAs, chromatin memory and signalling cascades. This can be described by a generalized, unicellular Hebbian learning process, where those signalling connections, which participate in learning, become stronger. Here we review those scenarios, where cellular signalling is not only repeated in a few times (when learning occurs), but becomes too frequent, too large, or too complex and overloads the cell. This leads to desensitisation of signalling networks by decoupling signalling components, receptor internalization, and consequent downregulation. These molecular processes are examples of anti-Hebbian learning and 'forgetting' of signalling networks. Stress can be perceived as signalling overload inducing the desensitisation of signalling pathways. Ageing occurs by the summative effects of cumulative stress downregulating signalling. We propose that cellular learning desensitisation, stress and ageing may be placed along the same axis of more and more intensive (prolonged or repeated) signalling. We discuss how cells might discriminate between repeated and unexpected signals, and highlight the Hebbian and anti-Hebbian mechanisms behind the fold-change detection in the NF-κB signalling pathway. We list drug design methods using Hebbian learning (such as chemically-induced proximity) and clinical treatment modalities inducing (cancer, drug allergies) desensitisation or avoiding drug-induced desensitisation. A better discrimination between cellular learning, desensitisation and stress may open novel directions in drug design, e.g. helping to overcome drug resistance.

Effectiveness of exposure-based treatment for childhood anxiety disorders: An open clinical trial to test its relation with indices of emotional processing and inhibitory learning.

BACKGROUND AND OBJECTIVES: The current study examined how effectiveness of exposure-based CBT was related to indices of emotional processing and inhibitory learning during exposure exercises. METHODS: Adolescents with anxiety disorder(s) (N = 72; age 11-19; 85% girls) received a group-based, intensive two-week treatment of which effectiveness was indexed by the SCARED and by ratings of anxiety and approach towards individualized goal situations. To index emotional processing, subjective units of distress (SUDs) were used to indicate both initial and final fear level, and absolute, relative, and total dose of fear reduction. To index inhibitory learning, subjective threat expectancies (STEs) were used to indicate initial and final threat expectancy, and absolute, relative, and total dose of expectancy change. RESULTS: From pre-treatment to follow-up, there was a large-sized reduction of anxiety symptoms, small-sized decrease of subjective anxiety and a large-sized increase in subjective approach towards individual treatment goals. Higher fear levels prior to exposure were related to a larger decrease of symptoms. Higher threat expectancies after exposure exercises were independently associated with less decrease of anxiety and increase of approach towards treatment goals. Total dose of experienced fear reduction and total dose of experienced expectancy change were (partly) independently related to more increase in approach towards individualized goal situations. LIMITATIONS: As patients also received other treatment elements, the results cannot be interpreted unequivocally. CONCLUSIONS: The pattern of findings seems to indicate that emotional processing (as indexed by fear reduction) and inhibitory learning (as indexed by expectancy change) are both relevant in exposure-based CBT.

Health protective behaviours during the COVID-19 pandemic: Risk adaptation or habituation?

Many epidemiological works show that human behaviours play a fundamental role in the spread of infectious diseases. However, we still do not know much about how people modify their Health Protective Behaviours (HPB), such as hygiene or social distancing measures, over time in response to the health threat during an epidemic. In this study, we examined the role of the epidemiological context in engagement in HPB through two possible mechanisms highlighted by research into decision-making under risk: risk adaptation and risk habituation. These two different mechanisms were assumed to explain to a large extent the temporal variations in the public's responsiveness to the health threat during the COVID-19 pandemic. To test them, we used self-reported data collected through a series of 25 cross-sectional surveys conducted in France among representative samples of the adult population, from March 2020 to September 2021 (N = 50,019). Interestingly, we found that both mechanisms accounted relatively well for the temporal variation in the adoption of social distancing during the pandemic, which is remarkable given their different assumptions about the underlying social cognitive processes involved in response to a health threat. These results suggest that strengthening the incentives to encourage people to maintain health protective behaviours and to counter risk habituation effects is crucial to disease control and prevention over time.

Fast habituation to semantic interference generated by taboo connotation in reading aloud.

The recognition of taboo words - i.e. socially inappropriate words - has been repeatedly associated to semantic interference phenomena, with detrimental effects on the performance in the ongoing task. In the present study, we investigated taboo interference in the context of reading aloud, a task configuration which prompts the overt violation of conventional sociolinguistic norms by requiring the explicit utterance of taboo items. We assessed whether this form of semantic interference is handled by habituative or cognitive control processes. In addition to the reading aloud task, participants performed a vocal Stroop task featuring different conditions to dissociate semantic, task, and response conflict. Taboo words were read slower than non-taboo words, but this effect was subject to a quick habituation, with a decreasing interference over the course of trials, which allowed participants to selectively attend to goal-relevant information. In the Stroop task, only semantic conflict was significantly reduced by habituation. These findings suggest that semantic properties can be quickly and flexibly weighed on the basis of contextual appropriateness, thus characterising semantic processing as a flexible and goal-directed component of reading aloud.

Effects of 700 and 3500 MHz 5G radiofrequency exposure on developing zebrafish embryos.

Telecommunications industries are rapidly deploying the fifth generation (5G) spectrum and there is public concern about the safety and health impacts of this type of Radio Frequency Radiation (RFR), in part because of the lack of comparable scientific evidence. In this study we have used a validated commercially available setting producing a uniform field to expose zebrafish embryos (ZFe) to unmodulated 700 and 3500 MHz frequencies. We have combined a battery of toxicity, developmental and behavioral assays to further explore potential RFR effects. Our neurobehavioral profiles include a tail coiling assay, a light/dark activity assay, two thigmotaxis anxiety assays (auditory and visual stimuli), and a startle response - habituation assay in response to auditory stimuli. ZFe were exposed for 1 and 4 h during the blastula period of development and endpoints evaluated up to 120 hours post fertilization (hpf). Our results show no effects on mortality, hatching or body length. However, we have demonstrated specific organ morphological effects, and behavioral effects in activity, anxiety-like behavior, and habituation that lasted in larvae exposed during the early embryonic period. A decrease in acetylcholinesterase activity was also observed and could explain some of the observed behavioral alterations. Interestingly, effects were more pronounced in ZFe exposed to the 700 MHz frequency, and especially for the 4 h exposure period. In addition, we have demonstrated that our exposure setup is robust, flexible with regard to frequency and power testing, and highly comparable. Future work will include exposure of ZFe to 5G modulated signals for different time periods to better understand the potential health effects of novel 5G RFR.

Increased presynaptic excitability in a migraine with aura mutation.

Migraine is a common and disabling neurological disorder. The headache and sensory amplifications of migraine are attributed to hyperexcitable sensory circuits, but a detailed understanding remains elusive. A mutation in casein kinase 1 delta (CK1δ) was identified in non-hemiplegic familial migraine with aura and advanced sleep phase syndrome. Mice carrying the CK1δT44A mutation were more susceptible to spreading depolarization (the phenomenon that underlies migraine aura), but mechanisms underlying this migraine-relevant phenotype were not known. We used a combination of whole-cell electrophysiology and multiphoton imaging, in vivo and in brain slices, to compare CK1δT44A mice (adult males) to their wild-type littermates. We found that despite comparable synaptic activity at rest, CK1δT44A neurons were more excitable upon repetitive stimulation than wild-type, with a reduction in presynaptic adaptation at excitatory but not inhibitory synapses. The mechanism of this adaptation deficit was a calcium-dependent enhancement of the size of the readily releasable pool of synaptic vesicles, and a resultant increase in glutamate release, in CK1δT44A compared to wild-type synapses. Consistent with this mechanism, CK1δT44A neurons showed an increase in the cumulative amplitude of excitatory post-synaptic currents, and a higher excitation-to-inhibition ratio during sustained activity compared to wild-type. At a local circuit level, action potential bursts elicited in CK1δT44A neurons triggered an increase in recurrent excitation compared to wild-type, and at a network level, CK1δT44A mice showed a longer duration of 'up state' activity, which is dependent on recurrent excitation. Finally, we demonstrated that the spreading depolarization susceptibility of CK1δT44A mice could be returned to wild-type levels with the same intervention (reduced extracellular calcium) that normalized presynaptic adaptation. Taken together, these findings show a stimulus-dependent presynaptic gain of function at glutamatergic synapses in a genetic model of migraine, that accounts for the increased spreading depolarization susceptibility and may also explain the sensory amplifications that are associated with the disease.

High intensity interval training as a novel treatment for impaired awareness of hypoglycaemia in people with type 1 diabetes (HIT4HYPOS): a randomised parallel-group study.

AIMS/HYPOTHESIS: Impaired awareness of hypoglycaemia (IAH) in type 1 diabetes may develop through a process referred to as habituation. Consistent with this, a single bout of high intensity interval exercise as a novel stress stimulus improves counterregulatory responses (CRR) to next-day hypoglycaemia, referred to as dishabituation. This longitudinal pilot study investigated whether 4 weeks of high intensity interval training (HIIT) has sustained effects on counterregulatory and symptom responses to hypoglycaemia in adults with type 1 diabetes and IAH. METHODS: HIT4HYPOS was a single-centre, randomised, parallel-group study. Participants were identified using the Scottish Diabetes Research Network (SDRN) and from diabetes outpatient clinics in NHS Tayside, UK. The study took place at the Clinical Research Centre, Ninewells Hospital and Medical School, Dundee, UK. Participants were aged 18-55 years with type 1 diabetes of at least 5 years' duration and HbA1c levels <75 mmol/mol (<9%). They had IAH confirmed by a Gold score ≥4, modified Clarke score ≥4 or Dose Adjustment For Normal Eating [DAFNE] hypoglycaemia awareness rating of 2 or 3, and/or evidence of recurrent hypoglycaemia on flash glucose monitoring. Participants were randomly allocated using a web-based system to either 4 weeks of real-time continuous glucose monitoring (RT-CGM) or RT-CGM+HIIT. Participants and investigators were not masked to group assignment. The HIIT programme was performed for 20 min on a stationary exercise bike three times a week. Hyperinsulinaemic-hypoglycaemic (2.5 mmol/l) clamp studies with assessment of symptoms, hormones and cognitive function were performed at baseline and after 4 weeks of the study intervention. The predefined primary outcome was the difference in hypoglycaemia-induced adrenaline (epinephrine) responses from baseline following RT-CGM or RT-CGM+HIIT. RESULTS: Eighteen participants (nine men and nine women) with type 1 diabetes (median [IQR] duration 27 [18.75-32] years) and IAH were included, with nine participants randomised to each group. Data from all study participants were included in the analysis. During the 4 week intervention there were no significant mean (SEM) differences between RT-CGM and RT-CGM+HIIT in exposure to level 1 (28 [7] vs 22 [4] episodes, p=0.45) or level 2 (9 [3] vs 4 [1] episodes, p=0.29) hypoglycaemia. The CGM-derived mean glucose level, SD of glucose and glucose management indicator (GMI) did not differ between groups. During the hyperinsulinaemic-hypoglycaemic clamp studies, mean (SEM) change from baseline was greater for the noradrenergic responses (RT-CGM vs RT-CGM+HIIT: -988 [447] vs 514 [732] pmol/l, p=0.02) but not the adrenergic responses (-298 [687] vs 1130 [747] pmol/l, p=0.11) in those participants who had undergone RT-CGM+HIIT. There was a benefit of RT-CGM+HIIT for mean (SEM) change from baseline in the glucagon CRR to hypoglycaemia (RT-CGM vs RT-CGM+HIIT: 1 [4] vs 16 [6] ng/l, p=0.01). Consistent with the hormone response, the mean (SEM) symptomatic response to hypoglycaemia (adjusted for baseline) was greater following RT-CGM+HIIT (RT-CGM vs RT-CGM+HIIT: -4 [2] vs 0 [2], p<0.05). CONCLUSIONS/INTERPRETATION: In this pilot clinical trial in people with type 1 diabetes and IAH, we found continuing benefits of HIIT for overall hormonal and symptomatic CRR to subsequent hypoglycaemia. Our findings also suggest that HIIT may improve the glucagon response to insulin-induced hypoglycaemia. TRIAL REGISTRATION: ISRCTN15373978. FUNDING: Sir George Alberti Fellowship from Diabetes UK (CMF) and the Juvenile Diabetes Research Foundation.

Seasickness susceptibility and the vestibular time constant: a prospective study.

Human passive motion during boat, car or airplane travel may trigger motion sickness. Seasickness is the most provoking manifestation of motion sickness. It imposes major constraints on quality of life and human performance. Based on seasickness susceptibility the population is usually categorized into susceptible (S) and non-susceptible (NS). During repeated exposure some susceptible individuals undergo habituation and obtain symptoms relief, reflecting a third group of habituating (H) individuals. Recently, accumulative evidence suggests that the vestibular time constant (Tc) is associated with motion sickness susceptibility and attenuation of symptoms. These studies demonstrated that repeated passive motion stimuli lead to temporary short-term (days) changes in Tc, whereas sea sickness habituation process lasts 3 to 6 months. Therefore, the goal of the present study was to examine the behavior of Tc during the entire span of the seasickness habituation process between the H, S and NS groups to find an objective test for seasickness severity prediction. Tc of 30 subjects was prospectively evaluated pre, 3 and 6 months post exposure to sea environment using a computerized rotatory chair system protocol. Seasickness severity was evaluated by Wiker questionnaire. Significantly shorter Tc was found in the S group compared with the NS and H groups. Further analysis revealed lower maximal Slow Phase Velocity (mSPV) and nystagmus frequency (total number of beats/second) in the S group. Our results suggest that Tc, mSPV and nystagmus frequency might serve as a prediction for seasickness severity. This study was retrospectively registered on December 7th 2022 and assigned the identifier number NCT05640258.