High-frequency transcranial alternating current stimulation matching individual frequency of somatosensory evoked high-frequency oscillations can modulate the somatosensory system through thalamocortical pathway.

tACS (transcranial alternating current stimulation) is a technique for modulating brain activity through electrical current. Its effects depend on cortical entrainment, which is most effective when transcranial alternating current stimulation matches the brain's natural rhythm. High-frequency oscillations produced by external stimuli are useful for studying the somatosensory pathway. Our study aims to explore transcranial alternating current stimulation's impact on the somatosensory system when synchronized with individual high-frequency oscillation frequencies. We conducted a randomized, sham-controlled study with 14 healthy participants. The study had three phases: Individualized transcranial alternating current stimulation (matching the individual's high-frequency oscillation rhythm), Standard transcranial alternating current stimulation (600 Hz), and sham stimulation. We measured early and late HFO components after median nerve electrical stimulation at three time points: before (T0), immediately after (T1), and 10 min after transcranial alternating current stimulation (T2). Compared to Sham and Standard stimulation Individualized transcranial alternating current stimulation significantly enhanced high-frequency oscillations, especially the early component, immediately after stimulation and for at least 15 min. No other effects were observed for other high-frequency oscillation measures. In summary, our study provides initial evidence that transcranial alternating current stimulation synchronized with an individual's high-frequency oscillation frequency can precisely and time-specifically modulate thalamocortical activity. These insights may pave the way for innovative, personalized neuromodulation methods for the somatosensory system.

Transcranial direct current stimulation in semantic variant of primary progressive aphasia: a state-of-the-art review.

The semantic variant of primary progressive aphasia (svPPA), known also as "semantic dementia (SD)," is a neurodegenerative disorder that pertains to the frontotemporal lobar degeneration clinical syndromes. There is currently no approved pharmacological therapy for all frontotemporal dementia variants. Transcranial direct current stimulation (tDCS) is a promising non-invasive brain stimulation technique capable of modulating cortical excitability through a sub-threshold shift in neuronal resting potential. This technique has previously been applied as adjunct treatment in Alzheimer's disease, while data for frontotemporal dementia are controversial. In this scoped review, we summarize and critically appraise the currently available evidence regarding the use of tDCS for improving performance in naming and/or matching tasks in patients with svPPA. Clinical trials addressing this topic were identified through MEDLINE (accessed by PubMed) and Web of Science, as of November 2022, week 3. Clinical trials have been unable to show a significant benefit of tDCS in enhancing semantic performance in svPPA patients. The heterogeneity of the studies available in the literature might be a possible explanation. Nevertheless, the results of these studies are promising and may offer valuable insights into methodological differences and overlaps, raising interest among researchers in identifying new non-pharmacological strategies for treating svPPA patients. Further studies are therefore warranted to investigate the potential therapeutic role of tDCS in svPPA.

Individualized Prediction of Drug Resistance in People with Post-Stroke Epilepsy: A Retrospective Study.

BACKGROUND: The study aimed to develop a model and build a nomogram to predict the probability of drug resistance in people with post-stroke epilepsy (PSE). METHODS: Subjects with epilepsy secondary to ischemic stroke or spontaneous intracerebral hemorrhage were included. The study outcome was the occurrence of drug-resistant epilepsy defined according to International League Against Epilepsy criteria. RESULTS: One hundred and sixty-four subjects with PSE were included and 32 (19.5%) were found to be drug-resistant. Five variables were identified as independent predictors of drug resistance and were included in the nomogram: age at stroke onset (odds ratio (OR): 0.941, 95% confidence interval (CI) 0.907-0.977), intracerebral hemorrhage (OR: 6.292, 95% CI 1.957-20.233), severe stroke (OR: 4.727, 95% CI 1.573-14.203), latency of PSE (>12 months, reference; 7-12 months, OR: 4.509, 95% CI 1.335-15.228; 0-6 months, OR: 99.099, 95% CI 14.873-660.272), and status epilepticus at epilepsy onset (OR: 14.127, 95% CI 2.540-78.564). The area under the receiver operating characteristic curve of the nomogram was 0.893 (95% CI: 0.832-0.956). CONCLUSIONS: Great variability exists in the risk of drug resistance in people with PSE. A nomogram based on a set of readily available clinical variables may represent a practical tool for an individualized prediction of drug-resistant PSE.

The EEG pen-on-paper sound: History and recent advances.

The electroencephalogram (EEG) is one of the most useful technologies for brain research and clinical neurology, characterized by non-invasiveness and high time resolution. The acquired traces are visibly displayed, but various studies investigate the translation of brain waves in sound (i.e., a process called sonification). Several articles have been published since 1934 about the sonification of EEG traces, in the attempt to identify the "brain-sound." However, for a long time this sonification technique was not used for clinical purposes. The analog EEG was in fact already equipped with an auditory output, although rarely mentioned in scientific papers: the pen-on-paper noise made by the writer unit. EEG technologists often relied on the sound that pens made on paper to facilitate the diagnosis. This article provides a sample of analog video-EEG recordings with audio support representing the strengths of a combined visual-and-auditory detection of different types of seizures. The purpose of the present article is to illustrate how the analog EEG "sounded," as well as to highlight the advantages of this pen-writing noise. It was considered so useful that early digital EEG devices could be equipped with special software to duplicate it digitally. Even in the present days, the sonification can be considered as an attempt to modify the EEG practice using auditory neurofeedback with applications in therapeutic interventions, cognitive improvement, and basic research.

Liver fibrosis-4 score predicts outcome of patients with ischemic stroke undergoing intravenous thrombolysis.

Some evidence suggests a possible influence of liver disease on stroke prognosis. We investigated the association between fibrosis-4 (FIB-4) score, a marker of liver disease, and the 3-month outcome in patients with ischemic stroke undergoing intravenous thrombolysis. We also evaluated the rate of symptomatic intracranial hemorrhage after thrombolysis. In this prospective cohort study, we enrolled consecutive patients with ischemic stroke treated with thrombolysis who had a 3-month follow-up. The FIB-4 score was calculated and the validated cut-off values were used to indicate high/low risk of advanced liver fibrosis. The primary outcome was 3-month poor prognosis estimated as a modified Rankin scale score ≥3. Of the 264 included patients, 131 (49.62%) had a 3-month mRS ≥3, with a significantly higher FIB-4 score, compared to those with a mRS <3 score (adjp <0.001). When adjusted for possible confounders by multivariate logistic regression, FIB-4 score remained a significant predictor of poor outcome (OR 1.894, p = 0.011), along with history of atrial fibrillation (OR 3.488, p = 0.017), admission NIHSS score (OR 1.305, p < 0.001), and low values of hemoglobin (OR 0.730, p < 0.001). Mechanical thrombectomy had a favorable effect on patients' outcome (OR 0.201, p = 0.005). The risk of poor 3-month outcome was significantly higher among the 32 patients (12.1%) with high risk of severe fibrosis (p = 0.007). FIB-4 score values were also related to symptomatic intracranial hemorrhage (p = 0.004), specifically among patients with high probability of advanced hepatic fibrosis (p = 0.037). FIB-4 score can be considered as a promising independent predictor of poor prognosis in patients with acute ischemic stroke undergoing intravenous thrombolysis.

Frequency and Correlates of Mild Cognitive Impairment in Myasthenia Gravis.

BACKGROUND: Antibodies against acetylcholine receptors (AChRs) can also target nicotinic AChRs that are present throughout the central nervous system, thus leading to cognitive dysfunctions in patients with myasthenia gravis (MG). However, the presence of cognitive impairment in MG is controversial, and the factors that may influence this risk are almost completely unknown. In this study, the frequency of mild cognitive impairment (MCI) in MG, as well as the clinical, immunological, and behavioral correlates of MCI in MG were evaluated. METHODS: A total of 52 patients with MG underwent a comprehensive assessment including motor and functional scales, serological testing, and neuropsychological and behavioral evaluation. RESULTS: The frequency of MCI was 53.8%, and the most impaired cognitive domains were, in order, visuoconstructive/visuospatial skills, memory, and attention. After multivariate analysis, only pyridostigmine use was inversely associated with the presence of MCI, while a trend toward a positive association between MCI and disease severity and arms/legs hyposthenia was found. Correlation analyses showed that daily doses of prednisone and azathioprine significantly correlated with depressive symptomatology, while disease severity significantly correlated with depressive symptomatology and sleep disturbance. CONCLUSIONS: The presence of MCI is rather frequent in MG and is characterized by multidomain amnestic impairment. Such preliminary data need further confirmation on larger case series.

Immunological Aspects of Von Hippel-Lindau Disease: A Focus on Neuro-Oncology and Myasthenia Gravis.

Von Hippel-Lindau (VHL) disease is an autosomal dominant condition that predisposes affected individuals to a variety of malignant and benign neoplasms. The pathogenetic turning point of this illness is the accumulation of hypoxia-inducible factor (HIF)-1α, a transcription factor of several genes involved in oncogenesis, angiogenesis, tissue regeneration, metabolic regulation, hematopoiesis, and inflammatory responses. From an oncological perspective, increased awareness of the molecular pathways underlying this disease is bringing us closer to the development of specific and targeted therapies. Meanwhile, on the surgical side, improved understanding can help to better identify the patients to be treated and the surgical timing. Overall, pathogenesis research is crucial for developing patient-tailored therapies. One of the actual key topics of interest is the link between the VHL/HIF axis and inflammation. The present study aims to outline the fundamental mechanisms that link VHL disease and immune disorders, as well as to explore the details of the overlap between VHL disease and myasthenia gravis (MG) pathogenetic pathways. As a result, MG becomes a paradigm for autoimmune disorders that might be related with VHL disease.

Neutrophil-to-Lymphocyte Ratio Predicts Early Neurological Deterioration after Endovascular Treatment in Patients with Ischemic Stroke.

The worsening of neurological status that occurs early after acute ischemic stroke (AIS) remains a serious issue, and the inflammatory response plays a key role in stroke pathobiology. Recently, endovascular treatment (EVT) has revolutionized the management and outcome of patients with AIS due to either extracranial carotid disease or intracranial disease. The neutrophil-to-lymphocyte ratio (NLR) represents an easily available inflammatory biomarker. The aim of the study was to assess the relationship between the NLR at admission and the occurrence of early neurological deterioration (END) in patients with AIS who underwent EVT. Patients with AIS and proximal arterial occlusion in the anterior circulation undergoing EVT were retrospectively identified. Absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) were collected from admission blood work to calculate the NLR. The study outcome was END defined as an increase in at least 4 points in NIHSS score or death between baseline and 24 h after the ischemic event. Patients included were 211, and END occurred in 30 (14.2%). Patients with older age (OR = 1.07, 95% CI: 1.02−1.13), higher serum glucose (OR = 1.01, 95% CI: 1.01−1.02), and higher NLR (OR = 1.011, 95% CI: 1.04−1.18) had an increased risk of END. The best predictive cut-off value of NLR was 6.4, and END occurred in 24.1% and 3.9% of the patients with NLR ≥ 6.4 and <6.4, respectively (p < 0.001). In patients with AIS undergoing EVT, higher NLR values predicted a higher risk of END. Biomarkers able to identify inflammatory mechanisms might identify novel treatment targets and enhance proof-of-concept trials of immunomodulation in stroke.

Latency of poststroke epilepsy can predict drug resistance.

BACKGROUND AND PURPOSE: The progressive nature of epileptogenesis raises the question of whether the latent period may already carry information about the characteristics of the subsequent epilepsy. This study aimed to explore whether the time from stroke to epilepsy onset was related to the risk of drug resistance in patients with poststroke epilepsy (PSE). METHODS: Patients with epilepsy secondary to cerebral infarct or spontaneous intracerebral hemorrhage were included. Study outcome was the occurrence of drug resistance defined as failure of adequate trials of two tolerated and appropriately chosen and used antiseizure medication schedules to achieve sustained seizure freedom. RESULTS: One hundred fifty-nine patients with PSE and a median follow-up of 5 (interquartile range [IQR] = 3-9) years were included. In the study cohort, 29 (18.2%) participants were drug resistant. The median length of the time interval between stroke and PSE onset was 13 (IQR = 7-15) months in drug-resistant patients and 19 (IQR = 14-42) months (p < 0.001) in patients with seizure control. According to multivariable regression analysis, the time from stroke to PSE was an independent predictor of drug resistance (p < 0.001). The risk of drug resistance was highest when the onset of PSE occurred within the first months from stroke and decreased progressively with a steeper decline over the first 12 months. CONCLUSIONS: Substantial variability may exist in the pathways leading to PSE and distinguish patients with a variable risk of drug resistance.

A critical assessment of the current pharmacotherapy for the treatment of embolic strokes of undetermined source.

INTRODUCTION: 'Embolic stroke of undetermined source' (ESUS) is a term coined to identify non-lacunar stroke whose mechanism is likely to be embolic, and the source remains unidentified. The best antithrombotic treatment for preventing stroke recurrence in this population has not been delineated. AREAS COVERED: The authors summarize and critically appraise the currently available evidence about the antithrombotic treatment for preventing stroke recurrence in patients with ESUS. Randomized trials addressing this topic were identified through MEDLINE (accessed by PubMed, as of November 2021, week 4). EXPERT OPINION: Recent randomized trials have failed to demonstrate a significant benefit of direct oral anticoagulants over aspirin in reducing the recurrence of cerebral infarctions in unselected cohorts of patients with ESUS. The heterogeneity and often overlap of embolic sources may be possible explanations for the overall absence of a benefit of oral anticoagulants in ESUS as a single homogeneous entity. The results of these trials and their subgroup analyses have provided important cues to understand the pathophysiology of ESUS. They have, furthermore, increased in the interest in researchers in identifying distinct etiological phenotypes within this stroke population. There is a good rationale for ongoing and future investigations in order to tailor antithrombotic treatment according to individual features of patients with ESUS.

Camillo Negro (1861-1927) and his method for eliciting the extensor toe sign.

The "toe phenomenon", or extensor toe sign, is characterized by the extension (dorsiflexion) of the great toe elicited by plantar stimulation, and indicates pyramidal tract dysfunction. This phenomenon was first extensively described and studied by Joseph Jules François Félix Babinski (1857-1932), who introduced it in clinical practice. In 1912, the famous Italian neurologist Camillo Negro (1861-1927) proposed a new method of eliciting the extensor toe sign by inviting the patient, lying in bed in dorsal decubitus position, to raise the paretic limb with the leg extended on the thigh. This sign appeared during voluntary effort and could not be elicited by raising the unaffected lower limb. Negro was also the first to investigate the influence of cold upon the appearance of the "toe phenomenon" and to propose the use of (faradic) electrical stimulation to evoke it.

Patisiran Enhances Muscle Mass after Nine Months of Treatment in ATTRv Amyloidosis: A Study with Bioelectrical Impedance Analysis and Handgrip Strength.

BACKGROUND AND AIMS: Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv) is caused by mutations in the TTR gene, leading to misfolded monomers that aggregate generating amyloid fibrils. The clinical phenotype is heterogeneous, characterized by a multisystemic disease affecting the sensorimotor, autonomic functions along with other organs. Patisiran is a small interfering RNA acting as a TTR silencer approved for the treatment of ATTRv. Punctual and detailed instrumental biomarkers are on demand for ATTRv to measure the severity of the disease and monitor progression and response to treatment. METHODS: Fifteen patients affected by ATTRv amyloidosis (66.4 ± 7.8 years, six males) were evaluated before the start of therapy with patisiran and after 9-months of follow-up. The clinical and instrumental evaluation included body weight and height; Coutinho stage; Neuropathy Impairment Score (NIS); Karnofsky performance status (KPS); Norfolk QOL Questionnaire; Six-minute walking test (6 MWT); nerve conduction studies; handgrip strength (HGS); and bioimpedance analysis (BIA). RESULTS: Body composition significantly changed following the 9-months pharmacological treatment. In particular, the patients exhibited an increase in fat free mass, body cell mass, and body weight with a decrease in fat mass. A significant increase after 9 months of treatment was observed for the 6 MWT. Coutinho stage, KPS, NIS, NIS-W, nerve conduction studies, Norfolk, COMPASS-31 scale, and HGS remained unchanged. CONCLUSIONS: BIA might represent a useful tool to assess the effects of multiorgan damage in ATTRv and to monitor disease progression and response to treatments. More evidence is still needed for HGS. Patisiran stabilizes polyneuropathy and preserves motor strength by increasing muscle mass after 9 months of treatment.

Systemic Inflammatory Response Index and Futile Recanalization in Patients with Ischemic Stroke Undergoing Endovascular Treatment.

Futile recanalization remains a significant challenge for endovascular treatment (EVT) of acute ischemic stroke (AIS). The inflammatory response that occurs after cerebral infarct plays a central role in stroke pathobiology that can influence the outcome of a recanalization procedure. The aim of this study was to evaluate the relationship between the systemic inflammatory response index (SIRI) and futile recanalization in patients with AIS. We retrospectively identified consecutive patients with ischemic stroke due to proximal arterial occlusion in the anterior circulation, who were treated with EVT and achieved near-complete or complete recanalization. Absolute neutrophil count (ANC), absolute monocyte count (AMC), and absolute lymphocyte count (ALC) were collected from admission blood work to calculate SIRI as ANC × AMC/ALC. The study outcome was futile recanalization, defined as poor functional status [modified Rankin scale (mRS) score ≥ 3] at 3 months despite complete or near-complete recanalization. A total of 184 patients were included. Futile recanalization was observed in 110 (59.8%) patients. Older patients (odds ratio (OR) = 1.07, 95% confidence interval (CI): 1.04-1.10, p < 0.001), higher admission National Institutes of Health stroke scale score (OR = 1.10, 95% CI: 1.02-1.19, p = 0.013), and higher admission SIRI (OR = 1.08, 95% CI: 1.01-1.17, p = 0.028) increased the risk of the poor outcome at 3 months despite complete or near-complete recanalization.

Predictors of Pharmaco-Resistance in Patients with Post-Stroke Epilepsy.

OBJECTIVES: The study aimed to explore the clinical predictors of pharmaco-resistance in patients with post-stroke epilepsy (PSE). METHODS: Patients with epilepsy secondary to cerebral infarct or spontaneous intracerebral hemorrhage were included. The study outcome was the occurrence of pharmaco-resistance defined as the failure of adequate trials of two tolerated and appropriately chosen and used antiseizure medication schedules, whether as monotherapies or in combination, to achieve sustained seizure freedom. RESULTS: One-hundred and fifty-nine patients with PSE and a median follow-up of 5 (3-9) years were included. The mean age of the patients at stroke onset was 56.7 (14.9) years, and 104 (65.4%) were males. In the study cohort, 29 participants were pharmaco-resistant. Age at stroke onset [odds ratio (OR) 0.97, 95% confidence interval (CI) 0.93-0.99; p = 0.044], history of intracerebral hemorrhage (OR 2.95, 95% CI 1.06-8.24; p = 0.039), severe stroke (OR 5.43, 95% CI 1.82-16.16; p = 0.002), status epilepticus as initial presentation of PSE (OR 7.90, 1.66-37.55; p = 0.009), and focal to bilateral tonic-clonic seizures (OR 3.19, 95% CI 1.16-8.79; p = 0.025) were independent predictors of treatment refractoriness. CONCLUSIONS: Pharmaco-resistance developed in approximately 20% of patients with PSE and was associated with younger age at stroke onset, stroke type and severity, status epilepticus occurrence, and seizure types.