Comparative sensitivity of laboratory animals used for preclinical convulsion risk assessment to drug-induced convulsion.

Drug-induced convulsion is a serious concern in drug development, such that the convulsion liability of drug candidates must be evaluated in preclinical safety studies. However, information on the differences among species regarding their sensitivity to convulsions induced by convulsant drugs in humans remains limited. Here, we selected 11 test articles from several pharmacological classes and compared the sensitivities of three types of laboratory animal to convulsion. All 11 test articles were examined in mice via intraperitoneal injection and in rats via intravenous bolus; and 6 of the 11 test articles, selected mainly based on availabilities of data on drug plasma concentrations in humans at convulsion, were examined in non-human primates (NHPs) via intravenous infusion. Plasma concentrations of the test articles shortly after convulsion onset or 5 min after administration were measured. All 11 articles tested in mice, 10 of 11 articles tested in rats, and all 6 articles tested in NHPs induced convulsion with premonitory signs. Although there was a general tendency that rats and NHPs exhibited convulsions at lower plasma drug concentrations than did mice, the plasma concentrations at convulsion onset were generally comparable, within 3-fold differences, across the animal species. We conclude that the mice, rats, and NHPs examined in the present study generally showed similar sensitivities to convulsion induced by the test articles. Thus, each of these laboratory animals can be used for the assessment of convulsion risk in the early stages of drug development, depending on throughput, cost, and test article-specific requirements.

Sensory Phenomenon Assessment Scale: a new tool for assessment of tic-associated sensations.

Background: Sensory symptoms linked to tic disorder (TD) are challenging to quantify via self- or parent-reported measures. The current study aimed to develop a novel observer-rated semi-structured interview, namely, the Sensory Phenomenon Assessment Scale (SPAS), to aid clinical evaluation on symptoms of TD among children. Methods: To test its psychometric properties, tic, premonitory urge (PU), and obsessive-compulsive symptoms (OCS) were also assessed in 223 children via the Yale Global Tic Severity Scale (YGTSS), the Premonitory Urge for Tic Scale (PUTS), and the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). Factor analysis and internal consistency test were carried out using data from TD-diagnosed individuals. Results: Good internal consistency and test-retest reliability were observed. Criterion validity was established by significant correlations between the PUTS, the YGTSS, the CY-BOCS, and scores of the SPAS. Factor analyses supported a single-factor model of the SPAS, in which the five items each showed a factor loading above 0.6. Conclusion: This study demonstrated that the SPAS is reliable and valid and, thus, can serve as a good and concise measure of clinical symptoms among children and adolescents with TD.

Functional brain networks associated with the urge for action: Implications for pathological urge.

Tics in Tourette syndrome (TS) are often preceded by sensory urges that drive the motor and vocal symptoms. Many everyday physiological behaviors are associated with sensory phenomena experienced as an urge for action, which may provide insight into the neural correlates of this pathological urge to tic that remains elusive. This study aimed to identify a brain network common to distinct physiological behaviors in healthy individuals, and in turn, examine whether this network converges with a network we previously localized in TS, using novel 'coordinate network mapping' methods. Systematic searches were conducted to identify functional neuroimaging studies reporting correlates of the urge to micturate, swallow, blink, or cough. Using activation likelihood estimation meta-analysis, we identified an 'urge network' common to these physiological behaviors, involving the bilateral insula/claustrum/inferior frontal gyrus/supplementary motor area, mid-/anterior- cingulate cortex (ACC), right postcentral gyrus, and left thalamus/precentral gyrus. Similarity between the urge and TS networks was identified in the bilateral insula, ACC, and left thalamus/claustrum. The potential role of the insula/ACC as nodes in the network for bodily representations of the urge to tic are discussed.

Extended Phenotyping of Migraine in Children: A Cross-Sectional Study in a Specialist Children's Headache Clinic.

BACKGROUND: The pediatric migraine phenotype may exhibit differences to adults, leading to diagnostic challenges. We aimed to perform a cross-sectional systematic study to characterize the extended phenotype of pediatric migraine. METHODS: New migraine patients presenting to the Children's Headache Clinic were included (n = 105). Data were collected via a detailed symptom questionnaire at the first clinical encounter and were analyzed using descriptive statistics, Cohen kappa (k), Spearman correlation (ρ), and Poisson and binomial logistic regression models within SPSS. RESULTS: Patients were 65% female and aged five to 17 years (median 14, interquartile range [IQR] 11 to 15), with a mean disease duration of 4.7 years (S.D. 2.8). Monthly headache frequency was 1 to 30 days (median 30, IQR 12 to 30). Attack duration varied between 2 and 168 hours (median 12, IQR 5 to 72). The majority (81%) experienced bilateral headache. Premonitory symptoms (PS) were reported by 93% (range 0 to 7; mood change and tiredness most commonly), cranial autonomic symptoms (CAS) by 58% (range 0 to 6; pallor and lacrimation most commonly), and premonitory CAS by 23%. Vertigo (53%) and allodynia (16%) were present. The laterality of headache and CAS showed agreement (k = 0.5, P < 0.001). For every year of disease duration, 1.07 times more PS were reported (95% confidence interval [CI] 1.03 to 1.12, P < 0.001). The number of CAS (odds ratio 2.13, 95% CI 1.2 to 3.8, P = 0.01) significantly predicted allodynia. CONCLUSIONS: Children display a more enriched PS phenotype with disease chronicity. CAS and allodynia may be markers of central sensitization with shared neurobiological mechanisms in the absence of peripheral nociceptor activation.

Multifunctional fluorescence/photoacoustic bimodal imaging of γ-glutamyltranspeptidase in liver disorders under different triggering conditions.

Hepatocellular carcinoma (HCC) seriously threatens the human health. Previous investigations revealed that γ-glutamyltranspeptidase (GGT) was tightly associated with the chronic injury, hepatic fibrosis, and the development of HCC, therefore might act as a potential indicator for monitoring the HCC-related processes. Herein, with the contribution of a structurally optimized probe ETYZE-GGT, the bimodal imaging in both far red fluorescence (FL) and photoacoustic (PA) modes has been achieved in multiple HCC-related models. To our knowledge, this work covered the most comprehensive models including the fibrosis and developed HCC processes as well as the premonitory induction stages (autoimmune hepatitis, drug-induced liver injury, non-alcoholic fatty liver disease). ETYZE-GGT exhibited steady and practical monitoring performances on reporting the HCC stages via visualizing the GGT dynamics. The two modes exhibited working consistency and complementarity with high spatial resolution, precise apparatus and desirable biocompatibility. In cooperation with the existing techniques including testing serum indexes and conducting pathological staining, ETYZE-GGT basically realized the universal application for the accurate pre-clinical diagnosis of as many HCC stages as possible. By deeply exploring the mechanically correlation between GGT and the HCC process, especially during the premonitory induction stages, we may further raise the efficacy for the early diagnosis and treatment of HCC.

Exploring the psychometric properties of the premonitory urge for tics scale (PUTS) and its association with psychiatric symptoms in Chinese children with tic disorders.

BACKGROUND: The Premonitory Urge for Tics Scale (PUTS) is a common self-report measure of premonitory urges for patients with tic disorders. This study aims to evaluate the Chinese version of the PUTS (PUTS-C) and to explore its association with psychiatric symptoms in Chinese children diagnosed with tic disorders. METHODS: The psychometric evaluation involved 204 outpatients with tic disorders, aged 7-16 years, who were divided into two age groups: (7-10 years, n = 103; 11-16 years, n = 95). RESULTS: The PUTS-C demonstrated good internal consistency (McDonald'sω = 0.84) and two-week test-retest reliability (0.76). We observed a statistically significant correlation between the total PUTS-C score and various Yale Global Tic Severity Scale (YGTSS) subscales and total tic severity scores. The PUTS-C score also showed significant correlations with the Children Yale-Brown Obsessive Compulsive Scale (CY-BOCS), Screening Child Anxiety-Related Emotional Disorders (SCARED), and Children's Depression Inventory (CDI). Notably, premonitory urges independently predicted tic severity, beyond the influence of comorbid symptoms. A two-factor structure of the PUTS-C was identified in the total sample through factor analysis. CONCLUSIONS: The PUTS-C possesses acceptable validity and good reliability. It appears that premonitory urges in Chinese patients with tic disorders are associated with obsessive-compulsive symptoms, anxiety, and depression, but can independently predict tic severity. Specific PUTS-C factors possibly related to motor and vocal tics. Future research should continue to investigate age-related differences and the association with tics and other sensory symptoms.

A meta-analysis of transcranial magnetic stimulation in Tourette syndrome.

There is growing enthusiasm for the treatment of neuropsychiatric disorders using neuromodulation. While some reports claim that transcranial magnetic stimulation (TMS) can be used to treat Tourette Syndrome (TS), little research exists to support this assertion. This meta-analysis examined the efficacy of TMS to reduce tic severity in patients with TS. Additionally, it explored the effect of TMS to reduce premonitory urge severity-the primary mechanism implicated in the frontline evidence-based treatment of TS. Five treatment comparisons were selected using PRISMA guidelines. All studies included were required to be (1) a randomized controlled trial, (2) compare TMS to a sham condition, and (3) have all participants meet diagnostic criteria for a persistent tic disorder and/or TS. A random effects model meta-analysis examined the efficacy of using TMS to reduce tic severity and explored the effect of TMS to reduce premonitory urge severity. TMS did not significantly reduce tic severity (g = 0.44; 95% CI = -0.17, 1.05; z = 1.40; p = 0.16), but a moderate reduction in premonitory urge severity was found (g = 0.63; 95% CI = 0.9, 1.17; z = 2.27; p < 0.02). Trials with larger sample sizes and a preponderance of women were found to have greater therapeutic effects of TMS for tic severity. There is limited support for the use of TMS to reduce tic severity, though reductions in premonitory urge severity were observed. Major limitations of the existing literature are examined, with a call for research investigating newer TMS protocols and their use as a treatment augmentation strategy.

Premonitory Urge in Patients with Tics and Functional Tic-like Behaviors.

BACKGROUND: Premonitory urges (PU) are well described in primary tics, but their frequency and intensity in functional tic-like behaviors (FTLB) are unclear. OBJECTIVE: To study the experience of PU in patients with FTLB. METHODS: We compared the results of the premonitory urge for tics scale (PUTS) in adults with tics and FTLB in the University of Calgary Adult Tic Registry. RESULTS: We included 83 patients with tics and 40 with FTLB. When comparing patients with tics, FTLB with tics and FTLB only, we did not detect significant differences either in the total PUTS score (P = 0.39), or in any of the individual PUTS item sub-scores (P values ranging between 0.11 and 0.99). CONCLUSIONS: Patients with FTLB report PU at similar frequency and intensity to patients with tics. This finding confirms that PU are not a useful feature to discriminate FTLB from tics.

Postdromal symptoms in migraine: a REFORM study.

BACKGROUND: Migraine is a multiphasic neurovascular disorder, where headache can be succeeded by postdromal symptoms. However, there are limited research on postdromal symptoms. This study aimed to investigate the proportion of individuals with migraine from a tertiary care unit reporting postdromal symptoms in adherence with the ICHD-3 definition. We also aimed to examine how the means of enquiry might influence the estimated proportions. Additionally, we explored whether any clinical features might affect the likelihood of reporting postdromal symptoms. Finally, we assessed to what extend the postdromal symptoms might impact the disease burden. METHODS: In a cross-sectional study, we enrolled adult participants diagnosed with migraine who were asked to report their postdromal symptoms (i.e., unprompted reporting). Subsequently, a 16-item list was used to further ascertain the occurrence of postdromal symptoms (i.e., prompted reporting). Clinical characteristics were obtained through a semi-structured interview. Moreover, electronic questionnaires were used to assess the disease burden, i.e., the Six-Item Headache Impact Test (HIT-6), Migraine Disability Assessment (MIDAS), and the World Health Organization Disability Assessment 2.0 (WHODAS 2.0). RESULTS: Among 631 participants with migraine, a higher proportion experienced at least one postdromal symptom when prompted (n = 509 [80.7%]) compared with unprompted reporting (n = 421 [66.7%], P < 0.001). Furthermore, the total number of postdromal symptoms experienced was greater with prompted than unprompted reporting (medians 3 [IQR 1 - 6] versus 1 [IQR 0 - 2]; P < 0.001). Furthermore, the likelihood of reporting postdromal symptoms increased with the presence of premonitory symptoms and decreased with higher number of monthly migraine days. Weak correlations were identified between the number of postdromal symptoms reported and both HIT-6 (ρ = 0.14; P < 0.001) and WHODAS scores (ρ = 0.15; P < 0.001), whilst no correlation was observed with MIDAS score (ρ = 0.08; P = 0.054). CONCLUSIONS: Postdromal symptoms are prevalent in individuals with migraine from a tertiary care unit. However, reported estimates warrant cautious interpretation as they depend on the means of enquiry, presence of premonitory symptoms, and frequency of monthly migraine days. Moreover, a weak correlation was identified between the number of postdromal symptoms and both HIT-6 and WHODAS scores, indicating only a marginal influence on the disease burden.

Migraine prodromes and migraine triggers.

Migraine is characterized by a well-defined premonitory phase occurring hours or even days before the headache. Also, many migraineurs report typical triggers for their headaches. Triggers, however, are not consistent in their ability to precipitate migraine headaches. When looking at the clinical characteristics of both premonitory symptoms and triggers, a shared pathophysiological basis seems evident. Both seem to have their origin in basic homeostatic networks such as the feeding/fasting, the sleeping/waking, and the stress response network, all of which strongly rely on the hypothalamus as a hub of integration and are densely interconnected. They also influence the trigeminal pain processing system. Additionally, thalamic and hormonal mechanisms are involved. Activity within all those networks is influenced by various endogenous and external factors and might even cyclically change dependent on physiological internal rhythms. This might affect the threshold for the generation of migraine headaches. Premonitory symptoms thus appear as the result of an already ongoing alteration within those networks, whereas triggers might in this special situation only be able to further stress the system over the threshold for attack generation as catalysts of a process already in motion.

Integrated cognitive behavioral intervention for functional tics (I-CBiT): case reports and treatment formulation.

Introduction: The onset of the COVID-19 pandemic saw a global surge in functional tic-like behaviors (FTLBs). FTLBs are unique from primary tic disorders. They are thought to manifest through a complex interplay between environmental and personal factors, including the stress-arousal system, and are characterized by their sudden and explosive onset. Accordingly, common interventions for tic disorders show limited efficacy in this population. We present an Integrated Cognitive Behavioral Intervention for Functional Tics (I-CBiT) that uses an urge acceptance model to manage tics and related stress and anxiety. Methods: We describe the treatment outcomes of eight young people presenting with new and sudden onset FTLBs who underwent I-CBiT, which integrates traditional behavioral tic interventions with third-wave cognitive behavioral therapies. All cases completed the three-phase intervention involving core components of psychoeducation, exposure and response prevention with urge acceptance, sensory grounding strategies, and cognitive behavioral intervention targeting the stress-arousal system. Tic severity and impairment were assessed prior to treatment and at completion. Results: All cases showed a significant reduction in tic severity post I-CBiT and an improvement in overall daily living function. These cases highlight the role of urge acceptance in managing both tic urges and the underlying stress-arousal system to bring about long-term change. Conclusion: We demonstrated the efficacy of I-CBiT for managing FTLBs. Our findings illustrate the importance of treating underlying stress and anxiety in this population and, therefore, a need for greater interaction between multidisciplinary services in managing FTLBs to comprehensively cover the varied symptom presentations linked to thoughts, emotions, bodily sensations, and stress responses.

Clinical evaluation of premonitory urges in children and adolescents using the Chinese version of Individualized Premonitory Urge for Tics Scale.

Background: Premonitory urges (PUs) have been the focus of recent efforts to assess the severity and develop interventions for tic disorders (TD). We aimed to investigate the PUs in TD and its comorbidities from multiple dimensions, using the Chinese version of the Premonitory Urge for Tics Scale (C-PUTS) and the Chinese version of the Individualized Premonitory Urge for Tics Scale (C-IPUTS), in order to provide perspectives for the diagnosis and management of TD in children and adolescents. Methods: A total of 123 cases were included in the study. The IPUTS was translated, back-translated, culturally adjusted, and pre-investigated to determine the items of the C-IPUTS. The reliability and validity of the C-IPUTS scale were evaluated by a questionnaire survey on children and adolescents with TD at the Developmental Pediatrics Department of the Second Hospital of Jilin University. Meanwhile, the C-PUTS, which had been evaluated and used in China, Yale Global Tic Severity Scale (YGTSS), Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Depression Self-Rating Scale (DSRS), Screen for Childhood Anxiety-Related Disorders (SCARED), Achenbach Child Behavior Checklist (CBCL), and Swanson, Nolan and Pelham, Version IV (SNAP-IV), were used to assess the association of PUs with tics and comorbidities of TD. Results: All dimensions of the C-IPUTS demonstrated good reliability and validity. Our findings suggested that PUs in children and adolescents in China occurred primarily at the head/face and neck/throat. The different dimensions of the C-IPUTS (number, frequency, and intensity) and C-PUTS were positively correlated with the YGTSS total score, while the C-PUTS was positively correlated with the Y-BOCS, SCARED, DSRS, and SNAP-IV scale total scores. The three dimensions of the C-IPUTS demonstrated correlations with anxiety severity and obsessive-compulsive symptoms. Conclusion: The C-IPUTS can be used to assess PUs reliably and effectively and provide further information for the C-PUTS from various dimensions in a Chinese setting. PUs relate to obsessive-compulsive symptoms, anxiety, attention deficit hyperactivity, and behavioral problems in children and adolescents with TDs. Accordingly, PUs evaluation using the C-IPUTS combined with the PUTS might provide useful information for future therapies for TDs to achieve greater tic reduction.

Working Mechanisms of Exposure and Response Prevention in the Treatment of Tourette Syndrome and Tic Disorders Revisited: No Evidence for within-Session Habituation to Premonitory Urges.

BACKGROUND: Exposure and response prevention (ERP) has been shown to be an effective treatment for Tourette syndrome (TS) and chronic tic disorders (CTD). ERP is based on voluntary tic suppression in combination with prolonged exposure to premonitory urges preceding tics. A prevailing hypothesis of the working mechanism underlying ERP in tics is habituation to the premonitory urges as a result of prolonged exposure. However, results so far are equivocal. This study aims to further explore the relation between urges and ERP in tics, by investigating the course of premonitory urges during ERP sessions. METHODS: Using a data-driven approach, within-session habituation to premonitory urge intensity was investigated. In total, 29 TS patients rated urge intensity at seven timepoints during ten 1 h ERP sessions. RESULTS/CONCLUSIONS: Latent growth modeling showed an increase in urge intensity during the first 15 min of each session followed by a plateau in the remaining 45 min of the session. This does not support the idea of within-session habituation to premonitory urges as a working mechanism of ERP. Other potential underlying working mechanisms are discussed and should be tested in future research.

Co-Occurring Anxiety in Youth with Tic Disorders: A Review.

Objective: To review the current state of the literature regarding anxiety symptoms and anxiety disorders in chronic tic disorder (CTD). Results: We conducted a literature search on anxiety and tic disorders. Anxiety symptoms and anxiety disorders are common in youth with CTD, with ∼30%-50% of youth with CTD having at least one co-occurring anxiety disorder. Tics often improve by young adulthood but anxiety symptoms tend to persist, or worsen, over time. Anxiety and tics are closely related, but the exact nature of their relationship is poorly understood. We discuss some potential ways in which anxiety and tics are linked with an emphasis on the underlying brain circuitry involved. The relationship between anxiety and tics may be related to the premonitory urge. In addition, stress hormones may link anxiety and tics. Individuals with CTD have greater activation of their hypothalamic-pituitary-adrenal system in response to acute stress. We also review the impact of anxiety on youth with CTD and approaches to management of anxiety in youth. Conclusions: Anxiety is common in youth with CTD, is associated with more severe CTD, and can adversely affect a child's function. Thus, it is important to identify anxiety disorders in CTD and manage them appropriately.

Neuroimaging in the pre-ictal or premonitory phase of migraine: a narrative review.

BACKGROUND: The premonitory phase, or prodrome, of migraine, provides valuable opportunities to study attack initiation and for treating the attack before headache starts. Much that has been learned about this phase in recent times has come from the outcomes of functional imaging studies. This review will summarise these studies to date and use their results to provide some feasible insights into migraine neurobiology. MAIN BODY: The ability to scan repeatedly a patient without radiation and with non-invasive imaging modalities, as well as the recognition that human experimental migraine provocation compounds, such as nitroglycerin (NTG) and pituitary adenylate cyclase activating polypeptide (PACAP), can trigger typical premonitory symptoms (PS) and migraine-like headache in patients with migraine, have allowed feasible and reproducible imaging of the premonitory phase using NTG. Some studies have used serial scanning of patients with migraine to image the migraine cycle, including the 'pre-ictal' phase, defined by timing to headache onset rather than symptom phenotype. Direct observation and functional neuroimaging of triggered PS have also revealed compatible neural substrates for PS in the absence of headache. Various imaging methods including resting state functional MRI (rsfMRI), arterial spin labelling (ASL), positron emission tomography (PET) and diffusion tensor imaging (DTI) have been used. The results of imaging the spontaneous and triggered premonitory phase have been largely consistent and support a theory of central migraine attack initiation involving brain areas such as the hypothalamus, midbrain and limbic system. Early dysfunctional pain, sensory, limbic and homeostatic processing via monoaminergic and peptidergic neurotransmission likely manifests in the heterogeneous PS phenotype. CONCLUSION: Advances in human migraine research, including the use of functional imaging techniques lacking radiation or radio-isotope exposure, have led to an exciting opportunity to study the premonitory phase using repeated measures imaging designs. These studies have provided novel insights into attack initiation, migraine neurochemistry and therapeutic targets. Emerging migraine-specific therapies, such as those targeting calcitonin gene-related peptide (CGRP), are showing promise acutely when taken during premonitory phase to reduce symptoms and prevent subsequent headache. Therapeutic research in this area using PS for headache onset prediction and early treatment is likely to grow in the future.

Trastornos de tics e impulso premonitorio: validación de la versión espñola de la «Escala para el Impulso Premonitorio al Tic» en niños y adolescentes / Tic disorders and premonitory urges: validation of the Spanish-language version of the Premonitory Urge for Tics Scale in children and adolescents

Introducción: La mayoría de personas con tics persistentes refiere notar una sensación des-agradable (impulso premonitorio) antes de sufrir un tic. En los últimos a ̃nos, el interés haciaestos fenómenos sensoriales ha aumentado debido al importante papel que tienen en la terapiade conducta. Sin embargo, los instrumentos para evaluarlos aún son escasos. Entre ellos, laEscala para el Impulso Premonitorio al Tic (Premonitory Urge for Tics Scale, PUTS) es el másutilizado. Métodos: Examinamos las propiedades psicométricas y la estructura factorial de la versiónespa ̃nola de la PUTS en una muestra de 72 ni ̃nos y adolescentes con síndrome de Tourette otrastorno de tics persistentes. Analizamos los datos para el total de la muestra y por grupos deedad (ni ̃nos hasta los 10 a ̃nos y mayores de 10 a ̃nos). Resultados: La PUTS obtuvo una buena consistencia interna y correlaciones moderadas entreítems de la escala (excepto en el ítem uno). Se encontró una buena validez divergente, unaadecuada fiabilidad test-retest y una estructura bifactorial (con una dimensión de fenómenosmentales relacionados con el trastorno obsesivo-compulsivo y otra sobre las cualidades y fre-cuencia de los impulsos premonitorios). Estos resultados se replicaron para ambos grupos deedad, excepto la validez divergente y la fiabilidad test-retest que fueron inferiores en el grupode menor edad.(AU)

Introduction: Most people with persistent tics report an unpleasant sensation (premonitoryurge) before the tic. In recent years, interest in these sensory phenomena has increased due totheir important role in behavioural therapy. However, instruments for assessing these sensationsremain scarce. Among the available instruments, the Premonitory Urge for Tics Scale (PUTS) isthe most widely used. Methods: We examined the psychometric properties and factor structure of the Spanish-language version of the PUTS in a sample of 72 children and adolescents with Tourette syndromeor persistent tic disorders. We analysed data from the total sample and by age group (childrenup to 10 years old and children/adolescents over 10). Results: The PUTS presented good internal consistency and moderate correlations betweenitems on the scale (except for item one). Divergent validity was good, test-retest reliabilitywas adequate, and a bifactorial structure was identified (one dimension related to mentalphenomena reported in obsessive-compulsive disorder, and another related to the quality andfrequency of premonitory urges). These results were replicated in both age groups, with lowerdivergent validity and test-retest reliability in the younger group.Conclusions: The Spanish-language version of the PUTS is a valid, reliable tool for assessingpremonitory urges in both children and adolescents, especially after the age of 10.(AU)

Perceived seizure risk in epilepsy: Chronic electronic surveys with and without concurrent electroencephalography.

OBJECTIVE: Previous studies suggested that patients with epilepsy might be able to forecast their own seizures. This study aimed to assess the relationships between premonitory symptoms, perceived seizure risk, and future and recent self-reported and electroencephalographically (EEG)-confirmed seizures in ambulatory patients with epilepsy in their natural home environments. METHODS: Long-term e-surveys were collected from patients with and without concurrent EEG recordings. Information obtained from the e-surveys included medication adherence, sleep quality, mood, stress, perceived seizure risk, and seizure occurrences preceding the survey. EEG seizures were identified. Univariate and multivariate generalized linear mixed-effect regression models were used to estimate odds ratios (ORs) for the assessment of the relationships. Results were compared with the seizure forecasting classifiers and device forecasting literature using a mathematical formula converting OR to equivalent area under the curve (AUC). RESULTS: Fifty-four subjects returned 10 269 e-survey entries, with four subjects acquiring concurrent EEG recordings. Univariate analysis revealed that increased stress (OR = 2.01, 95% confidence interval [CI] = 1.12-3.61, AUC = .61, p = .02) was associated with increased relative odds of future self-reported seizures. Multivariate analysis showed that previous self-reported seizures (OR = 5.37, 95% CI = 3.53-8.16, AUC = .76, p < .001) were most strongly associated with future self-reported seizures, and high perceived seizure risk (OR = 3.34, 95% CI = 1.87-5.95, AUC = .69, p < .001) remained significant when prior self-reported seizures were added to the model. No correlation with medication adherence was found. No significant association was found between e-survey responses and subsequent EEG seizures. SIGNIFICANCE: Our results suggest that patients may tend to self-forecast seizures that occur in sequential groupings and that low mood and increased stress may be the result of previous seizures rather than independent premonitory symptoms. Patients in the small cohort with concurrent EEG showed no ability to self-predict EEG seizures. The conversion from OR to AUC values facilitates direct comparison of performance between survey and device studies involving survey premonition and forecasting.

Premonitory Urge and Tic Severity, Comorbidities, and Quality of Life in Chronic Tic Disorders.

Background: Tics are intimately associated with premonitory urges (PU) but knowledge about urges is still limited, with small sample sizes often limiting the generalizability of findings. Objectives: This study addressed the following open questions: (1) is tic severity associated with urge severity, (2) how common is relief, (3) which comorbidities are associated with urges, (4) are urges, tics, and comorbidities associated with lower quality of life, and (5) can complex and simple, motor and vocal tics be differentiated based on PU? Methods: N = 291 patients who reported a confirmed diagnosis of chronic primary tic disorder (age = 18-65, 24% female) filled out an online survey assessing demographic data, comorbid conditions, location, quality and intensity of PU, as well as quality of life. Every tic was recorded, and whether the patient experienced a PU, the frequency, intensity, and quality of that urge. Results: PU and tic severity were significantly associated, and 85% of urge-related tics were followed by relief. A diagnosis of attention deficit/hyperactivity disorder (ADHD) or depression, female gender, and older age increased the likelihood of experiencing PU, while more obsessive compulsive (OCD) symptoms and younger age were associated with higher urge intensities. PU, complex vocal tics, ADHD, OCD, anxiety, and depression were related to lower quality of life. Motor and vocal, complex and simple tics did not differ regarding PU intensity, frequency, and quality, or relief. Conclusions: The results shed light on the relationship between PU, tics, comorbidities, age, gender, and quality of life in tic disorders.

Regional cerebral perfusion during the premonitory phase of triggered migraine: A double-blind randomized placebo-controlled functional imaging study using pseudo-continuous arterial spin labeling.

OBJECTIVE: To identify changes in regional cerebral blood flow (CBF) associated with premonitory symptoms (PS) of nitroglycerin (NTG)-triggered migraine attacks. BACKGROUND: PS could provide insights into attack initiation and alterations in neuronal function prior to headache onset. METHODS: We undertook a functional imaging study using a double-blind placebo-controlled randomized approach in patients with migraine who spontaneously experienced PS, and in whom PS and migraine-like headache could be induced by administration of NTG. All study visits took place in a dedicated clinical research facility housing a monitoring area with clinical beds next to a 3Tesla magnetic resonance imaging scanner. Fifty-three patients with migraine were enrolled; imaging on at least one triggered visit was obtained from 25 patients, with 21 patients completing the entire imaging protocol including a placebo visit. Whole brain CBF maps were acquired using 3D pseudo-continuous arterial spin labeling (3D pCASL). RESULTS: The primary outcome was that patients with migraine not taking preventive treatment (n = 12) displayed significant increases in CBF in anterior cingulate cortex, caudate, midbrain, lentiform, amygdala and hippocampus (p < 0.05 family-wise error-corrected) during NTG-induced PS. A separate region of interest analysis revealed significant CBF increases in the region of the hypothalamus (p = 0.006, effect size 0.77). Post hoc analyses revealed significant reductions in CBF over the occipital cortices in participants with a history of migraine with underlying aura (n = 14). CONCLUSIONS: We identified significant regional CBF changes associated with NTG-induced PS, consistent with other investigations and with novel findings, withstanding statistical comparison against placebo. These findings were not present in patients who continually took preventive medication. Additional findings were identified only in participants who experience migraine with aura. Understanding this biological and treatment-related heterogeneity is vital to evaluating functional imaging outcomes in migraine research.

Migraine attacks are of peripheral origin: the debate goes on.

BACKGROUND: Despite the pervasiveness of migraine, the underlying pathophysiological mechanisms initiating migraine attacks are far from well understood and are matter of scientific debate. OBJECTIVE: In this narrative review, we discuss key evidence for that suggest a peripheral origin or central origin and provide directions for future studies that may provide further clarification. DISCUSSION: Migraine pathogenesis is considered to involve the trigeminovascular system, a term that encompasses the trigeminal nerve and its axonal projections to the intracranial blood vessels. Beyond any doubt both peripheral and central mechanisms are involved in migraine pathogenesis, but an unresolved question is the how the initial activation occurs in a migraine attack. Evidence favoring a peripheral origin of migraine attacks, i.e., initial events occur outside of the blood-brain barrier, include the importance of sensitization of perivascular sensory afferents early on in a migraine attack. Evidence favoring a central origin include the occurrence of prodromal symptoms, migraine aura, and activation of structures within the central nervous system early in and during a migraine attack. CONCLUSIONS: Both peripheral and central mechanisms are likely involved in a migraine attack, e.g., peripheral nociceptive input is necessary for pain transmission and cortical activity is necessary for pain perception. Yet, the debate of whether migraine attacks are initiated a peripheral or central site remains unresolved. The increased focus on prodromal symptoms and on the development of a human model of migraine aura will possibly provide key arguments needed to answer this question in the near future. Until then, we cannot draw firm conclusions and the debate goes on. VIDEO LINK: Video recording of the debate held at the 1st International Conference on Advances in Migraine Sciences (ICAMS 2022, Copenhagen, Denmark) is available at: https://www.youtube.com/watch?v=NC0nlcKohz0 .