A novel tDCS sham approach based on model-driven controlled shunting

BackgroundTranscranial direct current stimulation (tDCS), a non-invasive brain stimulation technique able to transiently modulate brain activity, is surging as one of the most promising therapeutic solutions in many neurological and psychiatric disorders. However, profound limitations exist in current placebo (sham) protocols that limit single- and double-blinding, especially in non-naïve subjects.ObjectiveTo ensure better blinding and strengthen reliability of tDCS studies and trials, we tested a new optimization algorithm aimed at creating an “active” sham tDCS condition (ActiSham hereafter) capable of inducing the same scalp sensations perceived during real stimulation while preventing currents from reaching the cortex and cause changes in brain excitability.MethodsA novel model-based multielectrode technique — optimizing the location and currents of a set of small electrodes placed on the scalp — was used to control the relative amount of current delivered transcranially in real and placebo multichannel tDCS conditions. The presence, intensity and localization of scalp sensations during tDCS was evaluated by means of a specifically designed questionnaire administered to the participants. We compared blinding ratings by directly addressing subjects’ ability to discriminate across conditions for both traditional (Bifocal-tDCS and Sham, using sponge electrodes) and our novel multifocal approach (both real Multifocal-tDCS and ActiSham). Changes in corticospinal excitability were monitored based on Motor Evoked Potentials (MEPs) recorded via concurrent Transcranial Magnetic Stimulation (TMS) and electromyography (EMG).ResultsParticipants perceived Multifocal-tDCS and ActiSham similarly in terms of both localization and intensity of scalp sensations, whereas traditional Bifocal stimulation was rated as more painful and annoying compared to its Sham counterpart. Additionally, differences in scalp localization were reported for active/sham Bifocal-tDCS, with Sham tDCS inducing more widespread itching and burning sensations. As for MEPs amplitude, a main effect of stimulation was found when comparing Bifocal-Sham and ActiSham (F_(1,13) = 6.67, p = .023), with higher MEPs amplitudes after the application of Bifocal-Sham.ConclusionsCompared to traditional Bifocal-tDCS, ActiSham offers better participants’ blinding by inducing very similar scalp sensations to those of real Multifocal tDCS both in terms of intensity and localization, while not affecting corticospinal excitability.     

Relationship between Neurological Deterioration and Blood Pressure/Heart Rate Variability in Patients with Acute Cerebral Infarction

ObjectivesNeurological deterioration (ND) during hospitalization is an independent predictor of poor prognosis after stroke. Risk factors affecting early ND within 48 h post stroke have been intensively investigated, while few data are available on those for late ND after transfer to a wheelchair. Therefore, it was investigated whether hemodynamic factors may affect the late ND during hospitalization.Materials and methodsA retrospective study was conducted on 135 patients with atherothrombotic or cardiogenic cerebral infarction who were admitted to our hospital between April 1st, 2014 and July 31st, 2017. During hospitalization, average, maximum, and minimum values were determined for systolic blood pressure (sBP), diastolic BP (dBP), and heart rate (HR), respectively.135 patients were classified into two groups; ND (+) group, in which modified Barthel index score at the time of transfer to a wheelchair showed five points or more decrease between wheelchair transfer and discharge, and ND (?) group, which did not. Vital indices were compared between the two groups and subjected to ROC-curve analysis.ResultsThe ND (+) group included 32 patients, and the ND (?) 103. Significant differences were found between the groups in four items; sBPmin (p = 0.029), dBPmin (p = 0.019), HRave (p = 0.028), and HRmax (p < 0.01). The ND (+) group showed lower sBPmin and dBPmin, and higher HRave and HRmax than the ND (?) group.ConclusionsLate ND after transfer to a wheelchair is related to the vital indices during hospitalization and should be cautiously managed to prevent late ND     

Associations of Neutrophil-Lymphocyte Ratios with Reperfusion and Functional Outcomes in Ischemic Stroke after Endovascular Therapy

ObjectivesTreatment of ischemic stroke with endovascular thrombectomy (EVT) leads to improved outcomes compared to IV tPA. The neutrophil-lymphocyte ratio (NLR), a marker of inflammation, has been proposed to predict outcomes in ischemic stroke patients and may be used to identify patients at risk for poor outcomes after EVT.Materials and MethodsThis was a retrospective study of adult ischemic stroke patients undergoing EVT between 1/1/2018 and 12/31/2020. Outcomes were successful reperfusion (TICI score ≥2B), favorable discharge NIHSS (≤4), favorable discharge and 3-month mRS (≤2), and symptomatic intracranial hemorrhage (sICH). The primary exposure was NLR, measured pre- and post-EVT. Other variables collected included demographics and timing of stroke onset, arrival, groin puncture, tPA, and recanalization.ResultsA total of 592 patients were included. The most common vessel involved was the middle cerebral artery (73%). Lower admission NLR was associated with favorable discharge NIHSS and favorable discharge and 3-month mRS (all P < 0.01). NLRs measured after EVT were associated with all the primary outcomes. Improvements in NLR after EVT were associated with favorable discharge (P = 0.02) and 3-month mRS (P = 0.02) and lower incidence of sICH (P = 0.01).ConclusionsBecause of the long-term functional deficits that can persist after ischemic stroke, it is vital to identify patients with higher probability for these outcomes. The results from this study showed that favorable NLR measures, as well as favorable trends in NLR over time, are associated with improved outcomes, indicating that NLR is a useful marker to identify patients at risk for poor functional outcomes.     

Predictive value of EFHC1 variants for the long-term seizure outcome in juvenile myoclonic epilepsy

ObjectiveThis study aimed to determine the contribution of EFHC1 variants to the phenotypic variability of juvenile myoclonic epilepsy (JME) and to evaluate their diagnostic value regarding previously identified clinical long-term seizure outcome predictors in a consecutive cohort of patients with JME.MethodsThirty-eight probands and three family members affected with JME were studied at a tertiary epilepsy center with a review of their medical records and a subsequent face-to-face interview. All coding EFHC1 exons and adjacent exon/intron boundaries were directly sequenced.ResultsThe previously reported EFHC1 mutation F229L was found in two cases who presented with early generalized tonic–clonic seizure (GTCS) onset and appeared to be associated with milder subtypes of JME. Variant R294H was identified in two further probands who had a subtype of JME developing from childhood absence epilepsy. However, segregation of the phenotype with this variant could not be confirmed in one family.ConclusionsOur findings corroborate the heterogeneity of JME as an electroclinical epilepsy syndrome and provide evidence that genetic factors may influence and help predict the long-term seizure outcome in patients with JME.     

Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer's disease

Alzheimer's disease is an irreversible, progressive neurodegenerative disorder. Various therapeutic approaches are being used to improve the cholinergic neurotransmission, but their role in AD pathogenesis is still unknown. Although, an increase in tau protein concentration in CSF has been described in AD, but several issues remains unclear. Extensive and accurate analysis of CSF could be helpful to define presence of tau proteins in physiological conditions, or released during the progression of neurodegenerative disease. The amyloid cascade hypothesis postulates that the neurodegeneration in AD caused by abnormal accumulation of amyloid beta (Aβ) plaques in various areas of the brain. The amyloid hypothesis has continued to gain support over the last two decades, particularly from genetic studies. Therefore, current research progress in several areas of therapies shall provide an effective treatment to cure this devastating disease. This review critically evaluates general biochemical and physiological functions of Aβ directed therapeutics and their relevance.     

Hereditary transthyretin amyloidosis in multi-ethnic Malaysians

We report the clinical and genetic characteristics of hereditary transthyretin amyloidosis in the multi-ethnic Malaysian population. Subjects with genetically confirmed transthyretin amyloidosis seen between 2001 till August 2020 were included. There were 30 patients and 14 asymptomatic carriers, of which 26 (59.1%) were men. The majority (86.7%) were ethnic Chinese while two (6.7%) each were Malay and Sri Lankan Tamil ethnicity respectively. Among patients, mean age of symptom-onset was 55.9 ± 9.8 years with mean duration from symptom-onset to diagnosis of 3.2 ± 2.5 years. Common presenting symptoms were sensory symptoms of upper limbs (43.3%), symmetric sensory symptoms of both lower limbs (16.7%) and autonomic symptoms (16.7%). Nerve conduction studies showed sensorimotor polyneuropathy in 25 (83.3%) patients (22, axonal). Abnormal echocardiograms were seen in 24 (80%) patients, although 15 were asymptomatic. Of six different TTR mutations found, Ala97Ser was the commonest, and found exclusively in 84.6% of Chinese patients. Other mutations among Chinese patients were Val30Met, Ala25Thr and Asp39Val. Our Malay and Tamil patients had Glu54Lys and Gly47Val mutations respectively. In conclusion, TTR Ala97Ser is the commonest mutation among ethnic Chinese Malaysians which presented with late-onset progressive sensorimotor polyneuropathy, autonomic dysfunction and subclinical cardiac involvement.     

First Japanese autopsy case showing LRRK2 mutation G2019S and TDP-43 proteinopathy

This is the first Japanese autopsy case of Leucine-rich repeat kinase 2 (LRRK2) G2019S mutation with atypical TDP43 proteinopathy. Our case is important that presented clinically dysphagia and pathologically TDP-43 proteinopathy. TDP43 may play an important role of clinical presentation with LRRK2 G2019S mutation carriers.