The role of stroke-induced immunosuppression as a predictor of functional outcome in the neurorehabilitation setting.

Stroke affects the interconnection between the nervous and immune systems, leading to a down-regulation of immunity called stroke-induced immunosuppression (SII). The primary aim of this study is to investigate SII role as a predictor of functional, neurological, and motor outcomes in the neurorehabilitation setting (NRB). We conducted a prospective observational study enrolling post-acute stroke patients hospitalized for neurorehabilitation. At NRB admission (T0) and discharge (T1), we assessed presence of SII (defined by a neutrophil-to-lymphocyte ratio ≥ 5) and we evaluated functional independence (Functional Independence Measure-FIM, Barthel Index-BI), motor performances (Tinetti Score, Hauser Ambulation Index) and neurological impairment (NIHSS). We enrolled 96 patients (45.8% females, 70.6 ± 13.9 years, 88.5% ischemic stroke). At T0, 15.6% of patients (15/96) had SII. When compared to immunocompetent patients (IC), the SII group was characterized by worse baseline functional independence, motor performances and neurological disability. The same was confirmed at T1 (FIM p = 0.012, BI p = 0.007, Tinetti p = 0.034, NIHSS p = 0.001). Neurological disability demonstrated a less pronounced improvement in SII (ΔNIHSS: SII: - 2.1 ± 2.3 vs. IC: - 3.1 ± 2.5, p = 0.035). SII group presented a higher percentage of infectious complications during the neurorehabilitation period (SII 80% vs. IC 25.9%; p = 0.001). SII may represent a negative prognostic factor in the neurorehabilitation setting. SII patients were characterized by poorer functional, motor, neurological performances and higher risk of infectious complications. ClinicaTrial registration: NCT05889169.

Theory of mind in chronic migraine with medication overuse assessed with the MASC.

Theory of Mind (ToM) is the ability to infer one's own and others' mental states. Growing research indicates that ToM is impaired in Chronic Migraine with Medication Overuse (CM + MO). However, the research in this field has been conducted using static scenario-based tasks, often failing to test mentalization in everyday situations and measuring only performance accuracy. We filled this gap by administering the Movie for the Assessment of Social Cognition (MASC) to subjects with CM + MO compared to episodic migraine (EM). This test allows us to assess both affective and cognitive ToM and which, in addition to being accurate, also analyzes the type of error in attribution of mental states, distinguishing between hypo-mentalization and hyper-mentalization. Thirty patients suffering from CM + MO and 42 from EM were enrolled. Results showed that CM + MO patients were less accurate in mental state attribution than EM. In addition, compared to EM, CM + MO individuals were more impaired in the affective ToM dimensions and committed more errors of hypo-mentalization. In conclusion, the application of MASC in patients with CM + MO allowed for the detection of an alteration in their ability to correctly draw conclusions about other people's mental states. This latter contributes critically to appropriate social reactions and also, possibly, to satisfactory social interactions.

Searching for the Predictors of Response to BoNT-A in Migraine Using Machine Learning Approaches.

OnabotulinumtoxinA (BonT-A) reduces migraine frequency in a considerable portion of patients with migraine. So far, predictive characteristics of response are lacking. Here, we applied machine learning (ML) algorithms to identify clinical characteristics able to predict treatment response. We collected demographic and clinical data of patients with chronic migraine (CM) or high-frequency episodic migraine (HFEM) treated with BoNT-A at our clinic in the last 5 years. Patients received BoNT-A according to the PREEMPT (Phase III Research Evaluating Migraine Prophylaxis Therapy) paradigm and were classified according to the monthly migraine days reduction in the 12 weeks after the fourth BoNT-A cycle, as compared to baseline. Data were used as input features to run ML algorithms. Of the 212 patients enrolled, 35 qualified as excellent responders to BoNT-A administration and 38 as nonresponders. None of the anamnestic characteristics were able to discriminate responders from nonresponders in the CM group. Nevertheless, a pattern of four features (age at onset of migraine, opioid use, anxiety subscore at the hospital anxiety and depression scale (HADS-a) and Migraine Disability Assessment (MIDAS) score correctly predicted response in HFEM. Our findings suggest that routine anamnestic features acquired in real-life settings cannot accurately predict BoNT-A response in migraine and call for a more complex modality of patient profiling.

Social cognition in chronic migraine with medication overuse: a cross-sectional study on different aspects of mentalization and social relationships.

BACKGROUND: Social cognition refers to all mental operations to decipher information needed in social interactions. Here we aimed to outline the socio-cognitive profile of Chronic Migraine with Medication Overuse (CM + MO), given they are recognized to be at risk of socio-cognitive difficulties. Given the multidimensionality of this construct, we considered: (1) socio-cognitive abilities, (2) socio-cognitive beliefs, (3) alexithymia and autism traits, and (4) social relationships. METHODS: Seventy-one patients suffering from CM + MO, 61 from episodic migraine (EM), and 80 healthy controls (HC) were assessed with a comprehensive battery: (1) the Faux Pas test (FP), the Strange Stories task (SS), the Reading Mind in the Eyes test (RMET), (2) the Tromsø Social Intelligence Scale, (3) the Toronto Alexithymia Scale, the Autism Spectrum Quotient, (4) the Lubben Social Network Scale, the Friendship Scale. RESULTS: CM + MO: (1) performed similar to EM but worse than HC in the FP and SS, while they were worse than EM and HC in the RMET; (2) were similar to EM and HC in social intelligence; (3) had more alexithymic/autistic traits than EM and HC; (4) reported higher levels of contact with their family members but felt little support from the people around them than HC. CONCLUSIONS: CM + MO results characterized by a profile of compromised socio-cognitive abilities that affects different dimensions. These findings may have a relevant role in multiple fields related to chronic headache: from the assessment to the management.

Validation of the Italian version of the Cluster Headache Impact Questionnaire (CHIQ).

BACKGROUND: The Cluster Headache Impact Questionnaire (CHIQ) is a specific and easy-to-use questionnaire to assess the current impact of cluster headache (CH). The aim of this study was to validate the Italian version of the CHIQ. METHODS: We included patients diagnosed with episodic CH (eCH) or chronic CH (cCH) according to the ICHD-3 criteria and included in the "Italian Headache Registry" (RICe). The questionnaire was administered to patients through an electronic form in two sessions: at first visit for validation, and after 7 days for test-retest reliability. For internal consistency, Cronbach's alpha was calculated. Convergent validity of the CHIQ with CH features and the results of questionnaires assessing anxiety, depression, stress, and quality of life was evaluated using Spearman's correlation coefficient. RESULTS: We included 181 patients subdivided in 96 patients with active eCH, 14 with cCH, and 71 with eCH in remission. The 110 patients with either active eCH or cCH were included in the validation cohort; only 24 patients with CH were characterized by a stable attack frequency after 7 days, and were included in the test-retest cohort. Internal consistency of the CHIQ was good with a Cronbach alpha value of 0.891. The CHIQ score showed a significant positive correlation with anxiety, depression, and stress scores, while showing a significant negative correlation with quality-of-life scale scores. CONCLUSION: Our data show the validity of the Italian version of the CHIQ, which represents a suitable tool for evaluating the social and psychological impact of CH in clinical practice and research.

Biomarkers of Migraine: An Integrated Evaluation of Preclinical and Clinical Findings.

In recent years, numerous efforts have been made to identify reliable biomarkers useful in migraine diagnosis and progression or associated with the response to a specific treatment. The purpose of this review is to summarize the alleged diagnostic and therapeutic migraine biomarkers found in biofluids and to discuss their role in the pathogenesis of the disease. We included the most informative data from clinical or preclinical studies, with a particular emphasis on calcitonin gene-related peptide (CGRP), cytokines, endocannabinoids, and other biomolecules, the majority of which are related to the inflammatory aspects and mechanisms of migraine, as well as other actors that play a role in the disease. The potential issues affecting biomarker analysis are also discussed, such as how to deal with bias and confounding data. CGRP and other biological factors associated with the trigeminovascular system may offer intriguing and novel precision medicine opportunities, although the biological stability of the samples used, as well as the effects of the confounding role of age, gender, diet, and metabolic factors should be considered.

The Virtual "Enfacement Illusion" on Pain Perception in Patients Suffering from Chronic Migraine: A Study Protocol for a Randomized Controlled Trial.

BACKGROUND: given the limited efficacy, tolerability, and accessibility of pharmacological treatments for chronic migraine (CM), new complementary strategies have gained increasing attention. Body ownership illusions have been proposed as a non-pharmacological strategy for pain relief. Here, we illustrate the protocol for evaluating the efficacy in decreasing pain perception of the enfacement illusion of a happy face observed through an immersive virtual reality (VR) system in CM. METHOD: the study is a double-blind randomized controlled trial with two arms, involving 100 female CM patients assigned to the experimental group or the control group. The experimental group will be exposed to the enfacement illusion, whereas the control group will be exposed to a pleasant immersive virtual environment. Both arms of the trial will consist in three VR sessions (20 min each). At the baseline and at the end of the intervention, the patients will fill in questionnaires based on behavioral measures related to their emotional and psychological state and their body satisfaction. Before and after each VR session, the level of pain, the body image perception, and the affective state will be assessed. DISCUSSION: this study will provide knowledge regarding the relationship between internal body representation and pain perception, supporting the effectiveness of the enfacement illusion as a cognitive behavioral intervention in CM.

Does MIDAS reduction at 3 months predict the outcome of erenumab treatment? A real-world, open-label trial.

BACKGROUND: In Italy, monoclonal antibodies targeting the CGRP pathway are subsidized for the preventive treatment of high frequency and chronic migraine (CM) in patients with a MIgraine Disability ASsessment (MIDAS) score ≥ 11. Eligibility to treatment continuation requires a ≥ 50% MIDAS score reduction at three months (T3). In this study, we evaluate whether a ≥ 50% MIDAS score reduction at T3 is a reliable predictor of response to one-year erenumab treatment. METHODS: In this prospective, open-label, real-world study, 77 CM patients were treated with erenumab 70-140 mg s.c. every 28 days for one year (T13). We collected the following variables: monthly migraine days (MMDs), monthly headache days (MHDs), days of acute medication intake, MIDAS, HIT-6, anxiety, depression, quality of life and allodynia. Response to erenumab was evaluated as: i) average reduction in MMDs during the 1-year treatment period; and ii) percentage of patients with ≥ 50% reduction in MMDs during the last 4 weeks after the 13th injection (RespondersT13). RESULTS: Erenumab induced a sustained reduction in MMDs, MHDs and intake of acute medications across the 12-month treatment period, with 64.9% of patients qualifying as RespondersT13. At T3, 55.8% of patients reported a ≥ 50% reduction in MIDAS score (MIDASRes) and 55.4% of patients reported a ≥ 50% reduction in MMDs (MMDRes). MIDASRes and MMDRes patients showed a more pronounced reduction in MMDs during the 1-year treatment as compared to NON-MIDASRes (MIDASRes: T0: 23.5 ± 4.9 vs. T13: 7.7 ± 6.2; NON- MIDASRes: T0: 21.6 ± 5.4 vs. T13: 11.3 ± 8.8, p = 0.045) and NON-MMDRes (MMDRes: T0: 23.0 ± 4.5 vs. T13: 6.6 ± 4.8; NON-MMDRes: T0: 22.3 ± 6.0 vs. T13: 12.7 ± 9.2, p < 0.001) groups. The percentage of RespondersT13 did not differ between MIDASRes (74.4%) and NON-MIDASRes (52.9%) patients (p = 0.058), while the percentage of RespondersT13 was higher in the MMDRes group (83.3%) when compared to NON-MMDRes (42.9%) (p = 0.001). MMDRes predicted the long-term outcome according to a multivariate analysis (Exp(B) = 7.128; p = 0.001), while MIDASRes did not. Treatment discontinuation based on MIDASRes would have early excluded 36.0% of RespondersT13. Discontinuation based on "either MIDASRes or MMDRes" would have excluded a lower percentage (16%) of RespondersT13. CONCLUSION: MIDASRes only partly reflects the 12-month outcome of erenumab treatment in CM, as it excludes more than one third of responders. A criterion based on the alternative consideration of ≥ 50% reduction in MIDAS score or MMDs in the first three months of treatment represents a more precise and inclusive option. TRIAL REGISTRATION: The trial was retrospectively registered at www. CLINICALTRIALS: gov (NCT05442008). CGRP: Calcitonin Gene Related Peptide. MIDAS: MIgraine Disability Assessment. MMDs: monthly migraine days. MIDASRes: Patients with a MIDAS score reduction of at least 50% at T3. MMDRes: Patients with a MMDs reduction of at least 50% at T3. ResponderT13: Patients with a MMDs reduction from baseline of at least 50% in the last 4 weeks of observation period (after 13 erenumab administrations). T0: First erenumab administration. T3, T6, T9, T12: Follow-up visits at three, six, nine, and twelve months after first erenumab administration. T13: Last visit of the protocol.

Oculo-vestibular signs in experimentally induced migraine attacks: an exploratory analysis.

Vestibular symptoms accompanying headache are quite common in migraine patients. Based on the association of vertigo with migraine, vestibular migraine was included in the appendix of the 3rd edition of the International Classification of Headache Disorders as a possible migraine subtype worthy of further investigation. In this post hoc, exploratory analysis, we investigated the occurrence of oculo-vestibular signs (OVSs) during experimentally induced migraine attacks in 24 episodic migraine patients and 19 healthy controls exposed to sublingual nitroglycerin (NTG - 0.9 mg). A comprehensive clinical examination was performed at baseline, at the onset of the migraine-like attack, and immediately before hospital discharge (180 minutes after NTG administration). Three of the 13 migraine patients who developed a spontaneous-like migraine attack during the hospital observation period (23.1%) also developed OVSs during the induction test. Noteworthy, none of the patients with a negative induction test developed OVSs and no OVSs were reported in healthy subjects at any time point. The exploratory nature of our study does not allow to draw definite conclusions on the possible implications of a vestibular dysfunction in migraine pathophysiology. Our results however suggest that NTG administration may lend itself to investigate vestibular dysfunction in migraine, at least in a subset of patients. The present findings represent a starting point for designing future ad hoc and well-powered studies.

Pearls & Oy-sters: Marionette walk in Parkinson's disease: a rare dyskinetic-dystonic gait pattern complication improved by visual cueing.

We report a case of a 60-year-old patient with a 10-year history of Parkinson's disease who developed a dyskinetic-dystonic gait pattern highly impacting his personal and social life. After multiple unsuccessful attempts to improve the clinical condition by adapting the pharmacological treatment, the patient underwent gait rehabilitation based on the use of visual cueing. This approach induced a relevant improvement in the dyskinetic-dystonic gait.Our case contributes to the phenotypic description of motor fluctuations in advanced Parkinson's disease and suggests an additional therapeutic option to mitigate their impact on motor performances.

Non-Invasive Neuromodulation in the Rehabilitation of Pisa Syndrome in Parkinson's Disease: A Randomized Controlled Trial.

Background: Pisa syndrome (PS) is a frequent postural complication of Parkinson's disease (PD). PS poorly responds to anti-parkinsonian drugs and the improvement achieved with neurorehabilitation tends to fade in 6 months or less. Transcranial direct current stimulation (t-DCS) is a non-invasive neuromodulation technique that showed promising results in improving specific symptoms in different movement disorders. Objectives: This study aimed to evaluate the role of bi-hemispheric t-DCS as an add-on to a standardized hospital rehabilitation program in the management of PS in PD. Methods: This study included 28 patients with PD and PS (21 men, aged 72.9 ± 5.1 years) who underwent a 4-week intensive neurorehabilitation treatment and were randomized to receive: i) t-DCS (t-DCS group, n = 13) for 5 daily sessions (20 min-2 mA) with bi-hemispheric stimulation over the primary motor cortex (M1), or ii) sham stimulation (sham group, n = 15) with the same duration and cadence. At baseline (T0), end of rehabilitation (T1), and 6 months later (T2) patients were evaluated with both trunk kinematic analysis and clinical scales, including UPDRS-III, Functional Independence Measure (FIM), and Numerical Rating Scale for lumbar pain. Results: When compared to the sham group, the t-DCS group achieved a more pronounced improvement in several variables: overall posture (p = 0.014), lateral trunk inclination (p = 0.013) during upright standing position, total range of motion of the trunk (p = 0.012), FIM score (p = 0.048), and lumbar pain intensity (p = 0.017). Conclusions: Our data support the use of neuromodulation with t-DCS as an add-on to neurorehabilitation for the treatment of patients affected by PS in PD.

Facial expressions modulate pain perception in patients with chronic migraine.

AIM: First, we investigated whether the exposure to different visual feedback conditions may modulate pain perception by means of visual induced analgesia in patients with chronic migraine. Second, to comprehend the way emotional face expressions could induce visual analgesia, we evaluated the degree of identification with the four experimental conditions. METHODS: In a 1 × 4 within-subject study design, 38 female chronic migraine patients were exposed to different visual stimuli - positive face, neutral face, negative face, and control (white screen) - during a migraine attack. Visual stimuli were presented 3 times in a randomized order (each condition lasted 40 seconds). Migraine pain ratings and identification scores were assessed immediately after the observation of each visual condition. RESULTS: We observed a significant difference in pain ratings between the positive (median: 30, 95% CI 26.69 to 38.20) and the negative (median: 30, 95% CI 33.09 to 44.13) (z = -4.46, p < 0.0001) facial expressions or the neutral facial expression (median: 30, 95% CI 31.89 to 42.41) (z = 3.41, p < 0.001). Participants identified more with the neutral face condition than with the other conditions. CONCLUSIONS: Observation of a positive emotional face resulted sufficient to modulate pain perception possibly via the mediation of emotion regulation for positive emotions. This study paves the way for the integration of new cognitive behavioural interventions based on the adoption of visual induced analgesia to further control pain perception in chronic migraine patients.

BoNT-A efficacy in high frequency migraine: an open label, single arm, exploratory study applying the PREEMPT paradigm.

INTRODUCTION: In this open label, single-arm trial we evaluated the efficacy of onabotulinum toxin-A in the prevention of high-frequency episodic migraine (8-14 migraine days/month). METHODS: We enrolled 32 high-frequency episodic migraine subjects (age 44.8 ± 11.9 years, 11.0 ± 2.2 migraine days, 11.5 ± 2.1 headache days, 7 females). After a 28-day baseline period, subjects underwent 4 subsequent onabotulinum toxin-A treatments according to the phase III research evaluating migraine prophylaxis therapy (PREEMPT) paradigm, 12-weeks apart. The primary outcome was the reduction of monthly migraine days from baseline in the 12-week period following the last onabotulinum toxin-A treatment. RESULTS: Onabotulinum toxin-A reduced monthly migraine days by 3.68 days (-33.1%, p < 0.01). Thirty-nine percent of the patients experienced a ≥50% reduction in monthly migraine days. Onabotulinum toxin-A also reduced the number of headache days (-33.9%, p < 0.01) and the intake of acute medications (-22.9%, p = 0.03). Disability and quality of life (QoL) scores improved markedly (migraine disability assessment (MIDAS) -41.7%; migraine specific questionnaire (MSQ) -31.7%, p < 0.01). CONCLUSIONS: The findings suggest that, when administered according to the PREEMPT paradigm, onabotulinum toxin-A is effective in the prevention of high-frequency episodic migraine.Trial Registration: NCT04578782.

Validity of the Severity of Dependence Scale for detecting dependence behaviours in chronic migraine with medication overuse.

AIMS: In this study, we tested the validity of the Severity of Dependence Scale in detecting dependence behaviours in patients with chronic migraine and medication overuse (CM + MO) using the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the Leeds Dependence Questionnaire as gold standard measures. METHODS: Four hundred and fifty-four patients with CM + MO filled in the Severity of Dependence Scale and the Leeds Dependence Questionnaire and underwent a psychological evaluation for the diagnosis of substance dependence according to the DSM-IV criteria. RESULTS: Sixty-nine percent of subjects (n = 313) presented substance dependence according to the DSM-IV criteria. These patients scored significantly higher than those without substance dependence in Severity of Dependence Scale total score (Z = -3.29, p = 0.001), and in items 1 (Z = -2.44, p = 0.015), 2 (Z = -2.50, p = 0.012), 4 (Z = -2.05, p = 0.04), and 5 (Z = -3.39, p = 0.001). Severity of Dependence Scale total score (ß = 0.13, SE = 0.04, z = 3.49, p < 0.001) was a significant predictor for substance dependence. Receiver Operating Characteristic (ROC) curves showed that Severity of Dependence Scale discriminated patients with or without substance dependence. CONCLUSION: Severity of Dependence Scale could represent an interesting screening tool for dependency-like behaviors in CM + MO patients.

Psychological predictors of negative treatment outcome with Erenumab in chronic migraine: data from an open label long-term prospective study.

BACKGROUND: Monoclonal antibodies (mABs) targeting the calcitonin gene-related peptide (CGRP) pathway represent the first disease-specific preventive migraine therapy. Growing evidence suggests that they are effective in the preventive treatment of difficult-to-treat patients. In this study, we evaluated the psychological predictors of the outcome of treatment with the anti-CGRP monoclonal antibody erenumab in patients with chronic migraine (CM). METHODS: Seventy-five patients with CM who had already failed at least 3 preventive therapies received erenumab every 28 days for a period of 12 months. Before the first administration, patients received a full psychological evaluation using The Structured Clinical Interview for DSM-5 Clinician Version (SCID-5-CV) to assess personality disturbances (primary outcome), mood and anxiety disorders, and as well specific questionnaires to evaluate alexithymia traits, childhood traumas, and current stressors (secondary outcomes). RESULTS: After 12 months of treatment, 53 patients reported a reduction of at least 50% in headache days/per month (Responders), whereas 22 did not (Non Responders). When compared to Responders, Non Responders were characterized by a higher prevalence of personality disorders belonging to Cluster C (avoidant, dependent, and obsessive-compulsive) (77% vs 37%, p = .001). Non Responders were also characterized by a higher prevalence of anxiety disorders (90% vs 60%, p = 0.007), showed more alexithymic traits (51.7 ± 13.7 vs 42.9 ± 14.3, p = 0.017), and reported a higher number of 'at least serious' current stressors (3.2 ± 4.0 vs 0.8 ± 1.4, p < .0001) than Responders. At the multivariate analysis, higher prevalence of Cluster C personality disorders (OR 3.697; p = 0.05) and higher number of 'at least serious' life events (OR 1.382; p = 0.017) arose as prognostic factors of erenumab failure. CONCLUSIONS: Erenumab confirmed its effectiveness in a population of difficult-to-treat migraine. The presence of "anxious-fearful" personality together with current stressors and anxiety represent negative predictors of treatment outcome. TRIAL REGISTRATION: The study protocol was registered at clinicaltrials.gov ( NCT04361721 ).

The Effects of Intensive Neurorehabilitation on Sequence Effect in Parkinson's Disease Patients With and Without Freezing of Gait.

Background: The sequence effect (SE), defined as a reduction in amplitude of repetitive movements, is a common clinical feature of Parkinson's disease (PD) and is supposed to be a major contributor to freezing of gait (FOG). During walking, SE manifests as a step-by-step reduction in step length when approaching a turning point or gait destination, resulting in the so-called destination sequence effect (dSE). Previous studies explored the therapeutic effects of several strategies on SE, but none of them evaluated the role of an intensive rehabilitative program. Objectives: Here we aim to study the effects of a 4-week rehabilitative program on dSE in patients with PD with and without FOG. Methods: Forty-three patients (30 males, 70.6 ± 7.5 years old) with idiopathic PD were enrolled. The subjects were divided into two groups: patients with (PD + FOG, n = 23) and without FOG (PD - FOG, n = 20). All patients underwent a standardized 4-week intensive rehabilitation in-hospital program. At hospital admission (T0) and discharge (T1), all subjects were evaluated with an inertial gait analysis for dSE recording. Results: At T0, the dSE was more negative in the PD + FOG group (-0.80 ± 0.6) when compared to the PD - FOG group (-0.39 ± 0.3) (p = 0.007), even when controlling for several clinical and demographic features. At T1, the dSE was reduced in the overall study population (p = 0.001), with a more pronounced improvement in the PD + FOG group (T0: -0.80 ± 0.6; T1: -0.23 ± 0.4) when compared to the PD - FOG group (T0: -0.39 ± 0.3; T1: -0.22 ± 0.5) (p = 0.012). At T1, we described in the overall study population an improvement in speed, cadence, stride duration, and stride length (p = 0.001 for all variables). Conclusions: dSE is a core feature of PD gait dysfunction, specifically in patients with FOG. A 4-week intensive rehabilitative program improved dSE in PD patients, exerting a more notable beneficial effect in the PD + FOG group.

High perceived isolation and reduced social support affect headache impact levels in migraine after the Covid-19 outbreak: A cross sectional survey on chronic and episodic patients.

BACKGROUND: Psychosocial variables are key factors influencing psycho-physical equilibrium in migraine patients. Social isolation and vulnerability to stressors may prevent efficient psychological adjustment negatively affecting adaptation to life changes, as that imposed during Covid-19 lockdown. Here, we explored psychosocial dimensions and changes in clinical condition during Covid-19 lockdown in migraine patients, with regard to migraine type and headache impact. METHODS: Sixty-four migraine patients (32 episodic and 32 chronic) and 64 healthy control subjects were included in a case-control cross-sectional study. A two-step clustering procedure split patients into two clusters, based on the Headache Impact Test. Perceived global distress, loneliness, empathy, and coping levels were compared in groups, as well as changes in clinical condition. RESULTS: Migraine patients reported higher general loneliness and lower social support compared to healthy control subjects. Emotional loneliness was more marked in patients with higher headache impact. This subgroup of patients more frequently reported changes in the therapeutic and care paths as the perceived cause of the occurrence of motor or extra-motor symptomatology. CONCLUSIONS: Migraine patients, especially those more severely affected, proved more vulnerable than healthy control subjects to Covid-19 lockdown. Long-lasting interruption of social interactions may be detrimental in fragile patients that are in need of structured support interventions to maintain psycho-physical wellbeing.

Spinal nociceptive sensitization and plasma palmitoylethanolamide levels during experimentally induced migraine attacks.

ABSTRACT: Migraine pathophysiology has been suggested to include dysregulation of the endocannabinoid system (ES). We simultaneously evaluated plasma anandamide (AEA) and palmitoylethanolamide (PEA) levels and spinal sensitization in a validated human model of migraine based on systemic nitroglycerin (NTG) administration. Twenty-four subjects with episodic migraine (MIG) and 19 healthy controls (HC) underwent blood sampling and investigation of nociceptive withdrawal reflex thresholds (RTh: single-stimulus threshold; TST: temporal summation threshold) before and 30 (T30), 60 (T60), and 120 (T120) minutes after sublingual NTG administration (0.9 mg). At baseline, the MIG and HC groups were comparable for plasma AEA (P = 0.822) and PEA (P = 0.182) levels, and for RTh (P = 0.142) and TST values (P = 0.150). Anandamide levels increased after NTG administration (P = 0.022) in both groups, without differences between them (P = 0.779). By contrast, after NTG administration, PEA levels increased in the MIG group at T120 (P = 0.004), while remaining stable in the HC group. Nitroglycerin administration induced central sensitization in the MIG group, which was recorded as reductions in RTh (P = 0.046) at T30 and T120, and in TST (P = 0.001) at all time points. In the HC group, we observed increases in RTh (P = 0.001) and TST (P = 0.008), which suggest the occurrence of habituation. We found no significant correlations between the ES and neurophysiological parameters. Our findings suggest a role for PEA in the ictal phase of episodic migraine. The ES does not seem to be directly involved in the modulation of NTG-induced central sensitization, which suggests that the observed PEA increase and spinal sensitization are parallel, probably unrelated, phenomena.

Thalamocortical Connectivity in Experimentally-Induced Migraine Attacks: A Pilot Study.

In this study we used nitroglycerin (NTG)-induced migraine attacks as a translational human disease model. Static and dynamic functional connectivity (FC) analyses were applied to study the associated functional brain changes. A spontaneous migraine-like attack was induced in five episodic migraine (EM) patients using a NTG challenge. Four task-free functional magnetic resonance imaging (fMRI) scans were acquired over the study: baseline, prodromal, full-blown, and recovery. Seed-based correlation analysis (SCA) was applied to fMRI data to assess static FC changes between the thalamus and the rest of the brain. Wavelet coherence analysis (WCA) was applied to test time-varying phase-coherence changes between the thalamus and salience networks (SNs). SCA results showed significantly FC changes between the right thalamus and areas involved in the pain circuits (insula, pons, cerebellum) during the prodromal phase, reaching its maximal alteration during the full-blown phase. WCA showed instead a loss of synchronisation between thalami and SN, mainly occurring during the prodrome and full-blown phases. These findings further support the idea that a temporal change in thalamic function occurs over the experimentally induced phases of NTG-induced headache in migraine patients. Correlation of FC changes with true clinical phases in spontaneous migraine would validate the utility of this model.