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BACKGROUND: The blink reflex excitability, assessed through paired electrical stimuli responses, has been modulated using traditional non-invasive neurostimulation techniques. Recently, transcranial Alternating Current Stimulation (tACS) emerged as a tool to modulate brain oscillations implicated in various motor, perceptual, and cognitive functions. This study aims to investigate the influence of 20-Hz and 10-Hz tACS sessions on the primary motor cortex and their impact on blink reflex excitability. MATERIALS AND METHODS: Fifteen healthy volunteers underwent 10-min tACS sessions (intensity 1 mA) with active/reference electrodes placed over C4/Pz, delivering 20-Hz, 10-Hz, and sham stimulation. The blink reflex recovery cycle (BRrc) was assessed using the R2 amplitude ratio at various interstimulus intervals (ISIs) before (T0), immediately after (T1), and 30 min post-tACS (T2). RESULTS: Both 10-Hz and 20-Hz tACS sessions significantly increased R2 ratio at T1 (10-Hz: p = 0.02; 20-Hz: p < 0.001) and T2 (10-Hz: p = 0.01; 20-Hz: p < 0.001) compared to baseline (T0). Notably, 20-Hz tACS induced a significantly greater increase in blink reflex excitability compared to sham at both T1 (p = 0.04) and T2 (p < 0.001). CONCLUSION: This study demonstrates the modulatory effect of tACS on trigemino-facial reflex circuits, with a lasting impact on BRrc. Beta-band frequency tACS exhibited a more pronounced effect than alpha-band frequency, highlighting the influential role of beta-band oscillations in the motor cortex on blink reflex excitability modulation.
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The co-occurrence of genetic myopathies with myasthenia gravis (MG) is extremely rare, however a few studies have been reported. We aim to explore the link between genetically inherited muscle disorders and immune-mediated neuromuscular junction conditions, taking into account the diagnostic and therapeutic implications posed by these combined conditions. We searched all English medical papers registered in Web of Knowledge, PubMed, Google Scholar, and Science Direct between January 1987 concerning the association between muscular dystrophies (MD) and MG, also adding three new cases to the series reported so far. Three new clinical cases in which MG concurs with oculopharyngeal muscular dystrophy (OPMD) or facioscapulohumeral muscular dystrophy (FSHD) or myotonic dystrophy type 2 (DM2) were reported. A comprehensive literature review showed that FSHD is the dystrophy most frequently associated with generalized MG. The AChR antibody titer is high and neurophysiologic tests prove to be an essential tool for the diagnosis. The association between MG and MD is rare but should not be underestimated. The presence of unusual clinical features suggest investigating additional overlapping condition, especially when a treatable disease like MG is suspected.
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OBJECTIVE: The sound-induced flash illusion (SIFI) is a valid paradigm to study multisensorial perception. In the "fission" SIFI, multiple flashes are perceived when observing a single flash paired with two or more beeps. SIFI is largely dependent on visual and acoustic cortex excitability; in migraine, dysfunctional cortical excitability affects SIFI perception. Since estrogen peak occurring during ovulation can increase neuronal excitability, the present study aims to verify whether cortical excitability shifts linked to the menstrual cycle could influence SIFI. METHODS: In a comparative prospective study, we tested the effect of estrogens on crossmodal perception using the SIFI. We recruited 27 females in reproductive age, including 16 healthy and 11 menstrually related migraine females, testing their proneness to SIFI on day 14 (high estradiol) and day 27 (low estradiol) of menstrual cycle. RESULTS: Women on day 14 reported less flashes than on day 27 (p = 0.02) in the fission illusion, suggesting a pro-excitatory effect of estradiol on visual cortex excitability during ovulation. Moreover, we confirmed that migraine women perceived less flashes (p = 0.001) than controls, independently from cycle phase. Non-migraineurs women significantly reported more flashes on day 27 than on day 14 (p = 0.04). CONCLUSIONS: This study suggests that estradiol may influence the multisensory perception due to changes of visual cortex excitability, with high estradiol peak leading to increased visual cortical sensitivity during ovulation in non-migraineurs. Visual cortex hyperresponsiveness, here reflected by reduced SIFI, is not influenced by estradiol fluctuations in migraine women, as shown by reduced fission effects on day 14 and 27.
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Ilusões , Transtornos de Enxaqueca , Humanos , Feminino , Estudos Prospectivos , Percepção Auditiva/fisiologia , Estimulação Acústica , Percepção Visual/fisiologia , Estimulação LuminosaRESUMO
Congenital insensitivity to pain (CIP) is a rare autosomal recessive disorder presenting with a spectrum of clinical features caused by mutations in different genes. A 10-year-old girl with CIP, hyposmia and hypogeusia, and her unaffected twin and parents underwent next generation sequencing of SCN9A exons and flanking splice sites. Transcript analysis from whole blood successfully assayed the effect of the mutation on the mRNA splicing by polymerase chain reaction amplification on cDNA and Sanger sequencing. We identified the novel splicing variant c.1108-2A>G compound with the p.Arg896Gln (c.2687G>A) missense mutation previously described in a homozygous patient. The new intronic variant was predicted to induce exon 10 skipping. Conversely, SCN9A mRNA assay demonstrated its partial deletion with a loss of 46 nucleotides causing a premature stop codon in position p.Gln369 (NP_002968). Genetic analysis showed that the two variants were biallelic, being the mother and brother heterozygous carriers of the missense mutation, and the father heterozygous for the splicing mutation. Skin biopsy showed lack of Meissner's corpuscles, loss of epidermal nociceptors and normal autonomic organ innervation. We report a novel splicing mutation and provide clues on its pathogenic effect, broadening the spectrum of genotypes and phenotypes associated to CIP.
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Canal de Sódio Disparado por Voltagem NAV1.7/genética , Insensibilidade Congênita à Dor/genética , Criança , Feminino , Genótipo , Heterozigoto , Humanos , Mutação , FenótipoRESUMO
BACKGROUND AND OBJECTIVE: Neurophysiological studies in migraine have reported conflicting findings of either cortical hyper- or hypoexcitability. In migraine with aura (MwA) patients, we recently documented an inhibitory response to suprathreshold, high-frequency repetitive transcranial magnetic stimulation (hf-rTMS) trains applied to the primary motor cortex, which is in contrast with the facilitatory response observed in the healthy subjects. The aim of the present study was to support the hypothesis that in migraine, because of a condition of basal increased cortical responsivity, inhibitory homeostatic like mechanisms of cortical excitability could be induced by high magnitude stimulation. For this purpose, the hf-rTMS trains were preconditioned by transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique able to modulate the cortical excitability state. METHODS: Twenty-two MwA patients and 20 patients with migraine without aura (MwoA) underwent trains of 5-Hz repetitive transcranial magnetic stimulation at an intensity of 130% of the resting motor threshold, both at baseline and after conditioning by 15 minutes of cathodal or anodal tDCS. Motor cortical responses to the hf-rTMS trains were compared with those of 14 healthy subjects. RESULTS: We observed abnormal inhibitory responses to the hf-rTMS trains given at baseline in both MwA and MwoA patients as compared with the healthy subjects (P < .00001).The main result of the study was that cathodal tDCS, which reduces the cortical excitability level, but not anodal tDCS, which increases it, restored the normal facilitatory response to the hf-rTMS trains in both MwA and MwoA. CONCLUSIONS: The present findings strengthen the notion that, in migraine with and without aura, the threshold for inducing inhibitory mechanisms of cortical excitability might be lower in the interictal period. This could represent a protective mechanism counteracting cortical hyperresponsivity. Our results could be helpful to explain some conflicting neurophysiological findings in migraine and to get insight into the mechanisms underlying recurrence of the migraine attacks.
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Homeostase/fisiologia , Transtornos de Enxaqueca/fisiopatologia , Córtex Motor/fisiopatologia , Adulto , Potencial Evocado Motor/fisiologia , Feminino , Humanos , Masculino , Estimulação Transcraniana por Corrente Contínua , Estimulação Magnética TranscranianaRESUMO
Chronic migraine is a disease with a high burden on patients from both a working and quality of life point of view. The pathophysiology of this subtype of migraine is due to several factors, such as medication overuse. Nevertheless, the detrimental recurring of headache attacks with central and peripheral sensitization plays a central role and explains some additional symptoms complained about by these patients even in the interictal phase. OnabotulinumtoxinA is a therapy indicated for chronic migraine since it has proven to reduce peripheral sensitization, showing even efficacy on central symptoms. The aim of this narrative review is to present the current evidence regarding the effect of OnabotulinumtoxinA on sensitization and interictal symptoms.
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Toxinas Botulínicas Tipo A , Transtornos de Enxaqueca , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Toxinas Botulínicas Tipo A/uso terapêutico , Doença CrônicaRESUMO
Migraine is a burdensome neurological disorder that still lacks clear and easily accessible diagnostic biomarkers. Furthermore, a straightforward pathway is hard to find for migraineurs' management, so the search for response predictors has become urgent. Nowadays, artificial intelligence (AI) has pervaded almost every aspect of our lives, and medicine has not been missed. Its applications are nearly limitless, and the ability to use machine learning approaches has given researchers a chance to give huge amounts of data new insights. When it comes to migraine, AI may play a fundamental role, helping clinicians and patients in many ways. For example, AI-based models can increase diagnostic accuracy, especially for non-headache specialists, and may help in correctly classifying the different groups of patients. Moreover, AI models analysing brain imaging studies reveal promising results in identifying disease biomarkers. Regarding migraine management, AI applications showed value in identifying outcome measures, the best treatment choices, and therapy response prediction. In the present review, the authors introduce the various and most recent clinical applications of AI regarding migraine.
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The pathophysiological mechanisms underlying migraine are more difficult to investigate in children than in the adult population. Abnormal cortical excitability turns out to be one of the most peculiar aspects of migraine, accounting for the manifestations of migraine attacks. Recently, visual cortical excitability has been explored effectively in adult migraineurs with a technique based on cross-modal audio-visual illusions (with sound-induced flash illusions (SIFIs) being reduced in migraineurs compared to non-migraineur subjects). On such a basis, in this study, we investigated visual cortical excitability in children with migraine using SIFIs using combinations of visual and sound stimuli presented randomly. We evaluated 26 children with migraine without aura and 16 healthy children. Migraineurs did not differ from the age-matched healthy subjects regarding fission or fusion illusions but perceived more flashes in trials of multiple flashes with or without beeps. The higher number of SIFIs in migraineur children compared to adults may be due to a greater propensity of visual stimulation to be driven by auditory stimuli (i.e., acoustic dominance). The increased ability to perceive flashes reveals a hyperfunctional visual cortex, demonstrating that the use of SIFIs is a valid tool for assessing visual cortical responsiveness even in pediatric migraine.
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The cluster headache is a primary headache characterized by attacks of unilateral pain associated with ipsilateral cranial autonomic features. These attacks recur in clusters during the years alternating with periods of complete remission, and their onset is often during the night. This annual and nocturnal periodicity hides a strong and mysterious link among CH, sleep, chronobiology and circadian rhythm. Behind this relationship, there may be the influence of genetic components or of anatomical structures such as the hypothalamus, which are both involved in regulating the biological clock and contributing even to the periodicity of cluster headaches. The bidirectional relationship manifests itself also with the presence of sleep disturbances in patients affected by cluster headaches. What if the key to studying the physiopathology of such disease could rely on the mechanisms of chronobiology? The purpose of this review is to analyze this link in order to interpret the pathophysiology of cluster headaches and the possible therapeutic implications.
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OBJECTIVE: Nearly half of people with epilepsy (PWE) are expected to develop seizure clusters (SC), with the subsequent risk of hospitalization. The aim of the present study was to evaluate the use, effectiveness and safety of intravenous (IV) brivaracetam (BRV) in the treatment of SC. METHODS: Retrospective multicentric study of patients with SC (≥ 2 seizures/24 h) who received IV BRV. Data collection occurred from January 2019 to April 2022 in 25 Italian neurology units. Primary efficacy outcome was seizure freedom up to 24 h from BRV administration. We also evaluated the risk of evolution into Status Epilepticus (SE) at 6, 12 and 24 h after treatment initiation. A Cox regression model was used to identify outcome predictors. RESULTS: 97 patients were included (mean age 62 years), 74 (76%) of whom had a history of epilepsy (with drug resistant seizures in 49% of cases). BRV was administered as first line treatment in 16% of the episodes, while it was used as first or second drug after benzodiazepines failure in 49% and 35% of episodes, respectively. On the one hand, 58% patients were seizure free at 24 h after BRV administration and no other rescue medications were used in 75 out of 97 cases (77%) On the other hand, SC evolved into SE in 17% of cases. A higher probability of seizure relapse and/or evolution into SE was observed in patients without a prior history of epilepsy (HR 2.0; 95% CI 1.03 - 4.1) and in case of BRV administration as second/third line drug (HR 3.2; 95% CI 1.1 - 9.7). No severe treatment emergent adverse events were observed. SIGNIFICANCE: In our cohort, IV BRV resulted to be well tolerated for the treatment of SC and it could be considered as a treatment option, particularly in case of in-hospital onset. However, the underlying etiology seems to be the main outcome predictor.
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Epilepsia Generalizada , Epilepsia , Estado Epiléptico , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Anticonvulsivantes/efeitos adversos , Resultado do Tratamento , Epilepsia/tratamento farmacológico , Epilepsia Generalizada/tratamento farmacológico , Pirrolidinonas/efeitos adversos , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/induzido quimicamente , Quimioterapia CombinadaRESUMO
Chronic migraine is a burdensome disease presenting with episodic pain and several symptoms that may persist even among headache attacks. Multisensory integration is modified in migraine, as assessed by the level of the perception of sound-induced flash illusions, a simple paradigm reflecting changes in cortical excitability which reveals to be altered in migraineurs. OnabotulinumtoxinA is an effective preventive therapy for chronic migraineurs, reducing peripheral and central sensitization, and may influence cortical excitability. Patients affected by chronic migraine who started onabotulinumtoxinA preventive therapy were included. Clinical effects (headache diaries and migraine related questionnaires) were assessed at the beginning of the therapy and after 12 weeks. Contextually, patients underwent the evaluation of multisensory perception by means of the sound-induced flash illusions. OnabotulinumtoxinA showed effectiveness both in migraine prevention and in reducing headache burden. Even one session of therapy was able to restore, at least partially, multisensory processing, as shown by patients' susceptibility to the sound-induced flash illusion. OnabotulinumtoxinA could influence migraineurs cortical excitability concurrently to the beneficial effects in headache prevention.
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Toxinas Botulínicas Tipo A , Ilusões , Transtornos de Enxaqueca , Humanos , Toxinas Botulínicas Tipo A/uso terapêutico , Doença Crônica , Transtornos de Enxaqueca/prevenção & controle , Cefaleia/tratamento farmacológico , Resultado do TratamentoRESUMO
Multisensory processing can be assessed by measuring susceptibility to crossmodal illusions such as the Sound-Induced Flash Illusion (SIFI). When a single flash is accompanied by 2 or more beeps, it is perceived as multiple flashes (fission illusion); conversely, a fusion illusion is experienced when more flashes are matched with a single beep, leading to the perception of a single flash. Such illusory perceptions are associated to crossmodal changes in visual cortical excitability. Indeed, increasing occipital cortical excitability, by means of transcranial electrical currents, disrupts the SIFI (ie, fission illusion). Similarly, a reduced fission illusion was shown in patients with episodic migraine, especially during the attack, in agreement with the pathophysiological model of cortical hyperexcitability of this disease. If episodic migraine patients present with reduced SIFI especially during the attack, we hypothesize that chronic migraine (CM) patients should consistently report less illusory effects than healthy controls; drugs intake could also affect SIFI. On such a basis, we studied the proneness to SIFI in CM patients (nâ¯=â¯63), including 52 patients with Medication Overuse Headache (MOH), compared to 24 healthy controls. All migraine patients showed reduced fission phenomena than controls (P < .0001). Triptan MOH patients (nâ¯=â¯23) presented significantly less fission effects than other CM groups (Pâ¯=â¯.008). This exploratory study suggests that CM - both with and without medication overuse - is associated to a higher visual cortical responsiveness which causes deficit of multisensorial processing, as assessed by the SIFI. PERSPECTIVE: This observational study shows reduced susceptibility to the SIFI in CM, confirming and extending previous results in episodic migraine. MOH contributes to this phenomenon, especially in case of triptans.
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Percepção Auditiva/fisiologia , Excitabilidade Cortical/fisiologia , Transtornos da Cefaleia Secundários/fisiopatologia , Ilusões/fisiologia , Transtornos de Enxaqueca/fisiopatologia , Uso Excessivo de Medicamentos Prescritos , Percepção Visual/fisiologia , Adulto , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Desempenho Psicomotor/fisiologia , Adulto JovemRESUMO
Migraine is a highly disabling disease characterized by recurrent pain. Despite an intensive effort, mechanisms of migraine pathophysiology still represent an unsolved issue. Evidence from both animal and human studies suggests that migraine is characterized by hyperresponsivity or hyperexcitability of sensory cortices, especially the visual cortex. This phenomenon, in turn, may affect multisensory processing. Indeed, migraineurs present with an abnormal, reduced, perception of the Sound-induced Flash Illusion (SiFI), a crossmodal illusion that relies on optimal integration of visual and auditory stimuli by the occipital visual cortex. Decreasing visual cortical excitability with transcranial direct current stimulation (tDCS) can increase the SiFI in healthy subjects. Moving away from these issues, we applied cathodal tDCS over the visual cortex of migraineurs, with and without aura, in order to decrease cortical excitability and thus physiologically restoring the perception of a reliable SiFI. Differently from our expectations, tDCS was unable to reliably modulate SiFI in migraine. The chronic, relatively excessive, visual cortex hyperexcitability, featuring the migraineur brain, may render tDCS ineffective for restoring multisensory processing in this disease.
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OBJECTIVE: Sound-induced flash illusions depend on visual cortical excitability. In this study, we explored whether sound-induced flash illusions are perceived differently in migraine, a condition associated with pathologic cortical hyperexcitability. METHODS: Sound-induced flash illusions were examined in 59 migraine patients (mean age = 32 ± 16 years; 36 females), 32 without aura and 27 with aura, and in 24 healthy controls (mean age = 42 ± 17 years; 16 females). Patients were studied during attacks and interictally. Visual stimuli (flashes) accompanied by sounds (beeps) were presented in different combinations: a single flash with multiple beeps was given to induce the perception of multiple flashes ("fission" illusion), and multiple flashes with a single beep were used to reduce the number of perceived flashes ("fusion" illusion). RESULTS: For migraineurs, the fission illusion was reduced, especially during the attack, and almost abolished when a single flash was combined with 2 beeps (except for those without aura tested interictally); the fusion illusion was less consistently reported in both migraine groups, but not completely disrupted. CONCLUSIONS: Results from this study add novel clues to our understanding of visual cortex hyperexcitability in migraine, especially migraine with aura. Furthermore, these analyses underscore how pathologic changes in cortical excitability affect multisensory interactions. Cross-modal illusions represent a valid tool for exploration of functional connectivity between sensory areas, which likely has an important role in the pathophysiology of migraine.
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Ilusões/fisiologia , Enxaqueca com Aura/fisiopatologia , Enxaqueca sem Aura/fisiopatologia , Córtex Visual/fisiopatologia , Percepção Visual/fisiologia , Estimulação Acústica , Adulto , Feminino , Humanos , Masculino , Estimulação LuminosaRESUMO
Several studies have shown that transcranial direct current stimulation (tDCS) is able to enhance performances on verbal and visual working memory (WM) tasks. Available evidence points to the right dorsolateral prefrontal cortex (DLPFC) as a critical area in visual WM, but to date direct comparisons of the effects obtained by stimulating the left versus the right DLPFC in the same subject are lacking. Our aim was to determine whether tDCS over the right DLPFC can differently affect performance as compared with left DLPFC stimulation. Ten healthy subjects performed a memory-guided visuospatial task in three conditions: baseline, during anodal stimulation applied over the right and during anodal stimulation applied over the left DLPFC. All the subjects also underwent a sham stimulation as control. Our results show that only active stimulation over the right DLPFC is able to increase performance when compared to the other conditions. Our findings confirm the crucial role played by the right DLPFC in spatial WM tasks.