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Background: effectiveness of cladribine tablets, an oral disease-modifying treatment (DMT) for multiple sclerosis (MS), was established in clinical trials and confirmed with real-world experience. Objectives: use real-world data to compare treatment patterns and clinical outcomes in people with MS (pwMS) treated with cladribine tablets versus other oral DMTs. Methods: retrospective treatment comparisons were based on data from the international MSBase registry. Eligible pwMS started treatment with cladribine, fingolimod, dimethyl fumarate, or teriflunomide tablets from 2018 to mid-2021 and were censored at treatment discontinuation/switch, death, loss to follow-up, pregnancy, or study period end. Treatment persistence was evaluated as time to discontinuation/switch; relapse outcomes included time to first relapse and annualized relapse rate (ARR). Results: cohorts included 633 pwMS receiving cladribine tablets, 1195 receiving fingolimod, 912 receiving dimethyl fumarate, and 735 receiving teriflunomide. Individuals treated with fingolimod, dimethyl fumarate, or teriflunomide switched treatment significantly more quickly than matched cladribine tablet cohorts (adjusted hazard ratio (95% confidence interval): 4.00 (2.54-6.32), 7.04 (4.16-11.93), and 6.52 (3.79-11.22), respectively). Cladribine tablet cohorts had significantly longer time-to-treatment discontinuation, time to first relapse, and lower ARR, compared with other oral DMT cohorts. Conclusion: cladribine tablets were associated with a significantly greater real-world treatment persistence and more favorable relapse outcomes than all oral DMT comparators., Financial support for this study was provided entirely by a contract with EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA (CrossRef Funder ID: 10.13039/100004755). The funding agreement ensured the authors’ independence in designing the study, interpreting the data, writing, and publishing the report. The following authors are employed by the sponsor: NT and SLW.

Objective: we aimed to measure the craniectomy area using three-dimensional (3D) anatomic area and volume calculations to demonstrate that it can be an effective criterion for evaluating survival and functional outcomes of patients with malignant middle cerebral artery (MCA) infarction. Material and methods: the patients diagnosed with malignant ischemic stroke between 2013 and 2018, for which they underwent surgery due to deterioration in their neurological function, were retrospectively reviewed. Radiological images of all patients were evaluated; total brain tissue volume, ischemic brain tissue volume, total calvarial bone area, and decompression bone area were measured using 3D anatomical area and volume calculations. Results: in total, 45 patients (27 males and 18 females) had been treated with decompressive craniectomy (DC). The removed bone area was found to be significantly related to the outcome in patients with MCA infarction. The average decompression bone area and mean bone removal rate for patients who died after DC were 112 ± 27 cm2and 20%, whereas these values for surviving patients were 149 ± 29 cm2and 26% (P = 0.001), respectively. At the 6-month follow-up, the average decompression bone area and mean bone removal rate for patients with severe disability were 126 ± 30 cm2and 22.2%, whereas these values for patients without severe disability were 159 cm2± 26 and 28.4% (P = 0.001), respectively. Conclusion: in patients with malignant MCA infarction, the decompression area is associated with favorable functional outcomes, first, survival and second, 6-month modified Rankin scale score distribution after craniectomy., NA

Objective: In this study, our aim is to define the cognitive profile specific to Huntington’s disease (HD) in comparison to Parkinson’s disease (PD) without any accompanying cognitive involvement and to search for its relationship with CAG repeat number. Materials and Methods: Demographic data and detailed cognitive test results of HD and PD patients were reviewed, analyzed retrospectively and were compared to results of healthy controls (HC). Cognitive test battery included minimental state examination (MMSE), Beck’s depression inventory, enhanced cued recall (ECR), semantic fluency, digit-span forwards and backwards, trail making part A (TMT A) and B, reciting months backwards, phonemic fluency, Stroop, clock drawing, Benton’s line orientation, Benton’s facial recognition and Hooper visual organization tests. Instrumental activities of daily living test (IADL) was given for evaluating independence of patients in daily life. The relationship between test results and CAG repeat number and CAP score (product of CAG repeat number and age) for HD were evaluated. Results: Age, disease duration and number of years of education were similar between HD and PD. All cognitive test results of HD group were significantly worse than those of HC. HD group also scored significantly worse than PD group in MMSE, ECR, semantic fluency, TMT A, reciting months backwards, phonemic fluency, Stroop 1-5, clock drawing, Hooper visual organization and Benton’s facial recognition tests. CAP score was significantly correlated with the results of Stroop part 3-4 and scores of IADL. Conclusion: This study showed that HD has a cognitive profile with certain particular features, which differentiates it from PD. We can also conclude that cognitive decline takes place earlier in the course of HD compared to PD and it is more severe. CAP score was found corelated with executive functions and ADL in HD, confirming that the severity of pathological involvement is directly related to the cognitive profile of patients as well as their life quality., NA

Aim: to evaluate the patients who had epilepsy surgery and pathologically proven focal cortical dysplasia (FCD) in order to further classify and discuss electroencephalography (EEG) findings in different pathological subtypes. Material and methods: this study included 19 refractory epilepsy patients who underwent surgery between 1999 and 2017 in the Istanbul Faculty of Medicine. Demographic data, preoperative examinations, scalp video EEGs, and postoperative outcomes were evaluated retrospectively. Results: In this study, 36.8% of the patients were female. The mean age was 21.89 ± 14.64 years. Rhythmic epileptiform discharges (RED) were observed in 31.6%. 37.5% of the patients with isolated intermittent spike/sharp waves were type I, 50% were type II, and 12.5% were type III. 100% of the patients with normal background activity were FCD type II. 67% of the patients with asymmetric slowing were FCD type I, 22% was FCD type II, 11% were FCD type III. 71% of the patients with symmetrical slowing were FCD type I, 29% were FCD type II. One patient had Frontal Intermittent Rhythmic Activity, one patient had Electrical Status Epilepticus in Slow Sleep, two patients had “burst suppression,” and one patient had a “switch of” sign. The frequency of focal epileptogenic activity was higher when there was an FCD lesion on magnetic resonance imaging. Conclusion: the findings obtained in this study did not reveal any distinctive electrophysiological features in FCD and subgroups of FCD. The incidence of REDs did not differ between types. The frequency of isolated intermittent sharp/spike waves was higher in type II than I. Intermittent and continuous EEG slowing was more commonly seen among FCD Type I patients., NA

Neuromyelitis optica spectrum disorders (NMOSD) are a group of autoimmune inflammatory conditions that primarily target the optic nerves, spinal cord, brainstem, and occasionally the cerebrum. NMOSD is characterized by recurrent attacks of visual, motor, and/or sensory dysfunction that often result in severe neurological deficits. In recent years, there has been a significant progress in relapse treatment and prevention but the residual disability per attack remains high. Although symptomatic and restorative research has been limited in NMOSD, some therapeutic approaches can be inferred from published case series and evidence from multiple sclerosis literature. In this review, we will discuss established and emerging therapeutic options for symptomatic treatment and restoration of function in NMOSD. We highlight NMOSD-specific considerations and identify potential areas for future research. The review covers pharmacologic, non-pharmacologic, and neuromodulatory approaches to neuropathic pain, tonic spasms, muscle tone abnormalities, sphincter dysfunction, motor and visual impairment, fatigue, sleep disorders, and neuropsychological symptoms. In addition, we briefly discuss remyelinating agents and mesenchymal stem cell transplantation in NMOSD., Open access funding provided by the Guthy-Jackson Charitable Foundation

Background: biallelic pathogenic variants in the SCARB2 gene have been associated with action myoclonus-renal failure (AMRF) syndrome. Even though SCARB2 associated phenotype has been reported to include typical neurological characteristics, depending on the localization and the feature of the pathogenic variants, clinical course and the presentations have been shown to differ. Case presentation: whole exome sequencing (WES) analysis revealed a homozygous truncating variant (p.N45MfsX88) in SCARB2 gene in the index case, and subsequent sanger sequencing analysis validated the variant in all affected family members from a Turkish family with the clinical characteristics associated with AMRF and related disorders. Intrafamilial clinical heterogeneity with common features including dysarthria, tremor and proteinuria, and distinct features such as peripheral neuropathy (PNP), myoclonus and seizures between the affected cases, was observed in the family. In-depth literature review enabled the detailed investigation of the reported variants associated with AMRF and suggested that while the type of the variant did not have a major impact on the course of the clinical characteristics, only the C terminal localization of the pathogenic variant significantly affected the clinical presentation, particularly the age at onset (AO) of the disease. Conclusions: in this study we showed that biallelic SCARB2 pathogenic variants might cause a spectrum of common and distinct features associated with AMRF. Of those features while the common features include myoclonus (100%), ataxia (96%), tonic clonic seizures (82%), dysarthria (68%), tremor (65%), and renal impairment (62%), the uncommon features involve PNP (17%), hearing loss (6.8%), and cognitive impairment (13.7%). AO has been found to be significantly higher in the carriers of the p.G462DfsX34 pathogenic variant. SCARB2 pathogenic variants have not been only implicated in AMRF but also in the pathogenesis of Parkinson’s disease (PD) and Gaucher disease (GD), suggesting the importance of genetic and functional studies in the clinical and the diagnostic settings. Given the proven role of SCARB2 gene in the pathogenesis of AMRF, PD and GD with a wide spectrum of clinical symptoms, investigation of the possible modifiers, such as progranulin and HSP7, has a great importance., Deutsche Forschungsgemein?schaft (DFG)

Aim: to evaluate the role of posterior dynamic stabilization (PDS) with kyphoplasty (KP) in the surgical treatment of unstable osteoporotic compression fractures, which are common in the elderly population. Material and methods: this study included 25 patients with osteoporotic compression fractures. KP with PDS was performed on all patients. Radiological evaluation was performed with magnetic resonance imaging, computed tomography, and plain radiographs. The vertebral kyphosis angle (VKA), local kyphosis angle (LKA), and percentage of collapse were calculated. Clinical evaluation was performed with the visual analog scale and the Oswestry Disability Index (ODI). The preoperative and postoperative clinical and radiological data were compared. Results: the clinical and radiological parameters showed significant improvement following surgical treatment. The mean preoperative visual analog scale score of 7.78 decreased to 0.94 after 12 months. The mean preoperative ODI score of 70.33 decreased to 15.65 after 12 months. The mean preoperative VKA of 17.89° decreased to 9.22° after 12 months. The mean preoperative LKA of 9.61° decreased to 5.50° after 12 months. The mean preoperative percentage of collapse of 32.56% decreased to 19.00% after 12 months. There were no major complications. Conclusion: KP with the PDS method offered satisfactory outcomes in the surgical treatment of unstable osteoporotic compression fractures., NA

Background: little is known about changes of mental health during the COVID-19 pandemic in potentially disadvantaged groups. We investigated changes in anxiety and depression symptoms during the first year of the pandemic in six European countries and Australia by prior mental disorders and migration status. Methods: overall, 4674 adults answered a web-based survey in May-June 2020 and were followed by three repeated surveys up to February 2021. Information on psychosocial, financial and demographic, living conditions, prior mental disorders, depression and anxiety symptoms during the pandemic and migration status was collected. Weighted general estimation equations modelling was used to investigate the association between prior mental disorders, migration status, and symptoms over time. Results: most participants were, European Union (EU); Horizon 2020; Research and Innovation Programme Societal Challenges

Key points Massive irreparable rotator cuff tear was used as a model to study the impact of chronic pain and motor impairment on the motor systems of the human brain using magnetic resonance imaging.Patients show markers of lower grey/white matter integrity and lower functional connectivity compared with control participants in regions responsible for movement and the perception of visual movement and body shape.An independent cohort of patients showed relative deficits in the perception of visual motion and hand laterality compared with an age‐matched control group.These data support the hypothesis that the structure and function of the motor control system differs in patients who have experienced chronic motor impairment.This work also raises a new hypothesis, supported by neuroimaging and behaviour, that a loss of motor function could also be associated with off‐target effects, namely a reduced ability to perceive motion and body form. Abstract Changes in the way we move can induce changes in the brain, yet we know little of such plasticity in relation to musculoskeletal diseases. Here we use massive irreparable rotator cuff tear as a model to study the impact of chronic motor impairment and pain on the human brain. Cuff tear destabilises the shoulder, impairing upper‐limb function in overhead and load‐bearing tasks. We used neuroimaging and behavioural testing to investigate how brain structure and function differed in cuff tear patients and controls (imaging: 21 patients, age 76.3 ± 7.68; 18 controls, age 74.9 ± 6.59; behaviour: 13 patients, age 75.5 ± 10.2; 11 controls, age 73.4 ± 5.01). We observed lower grey matter density and cortical thickness in cuff tear patients in the postcentral gyrus, inferior parietal lobule, temporal‐parietal junction and the pulvinar – areas implicated in somatosensation, reach/grasp and body form perception. In patients we also observed lower functional connectivity between the motor network and the middle temporal visual cortex (MT), a region involved in visual motion perception. Lower white matter integrity was observed in patients in the inferior fronto‐occipital/longitudinal fasciculi. We investigated the cognitive domains associated with the brain regions identified. Patients exhibited relative impairment in visual body judgements and the perception of biological/global motion. These data support our initial hypothesis that cuff tear is associated with differences in the brain's motor control regions in comparison with unaffected individuals. Moreover, our combination of neuroimaging and behavioural data raises a new hypothesis that chronic motor impairment is associated with an altered perception of visual motion and body form., Key points Massive irreparable rotator cuff tear was used as a model to study the impact of chronic pain and motor impairment on the motor systems of the human brain using magnetic resonance imaging.Patients show markers of lower grey/white matter integrity and lower functional connectivity compared with control participants in regions responsible for movement and the perception of visual movement and body shape.An independent cohort of patients showed relative deficits in the perception of visual motion and hand laterality compared with an age‐matched control group.These data support the hypothesis that the structure and function of the motor control system differs in patients who have experienced chronic motor impairment.This work also raises a new hypothesis, supported by neuroimaging and behaviour, that a loss of motor function could also be associated with off‐target effects, namely a reduced ability to perceive motion and body form.

Predicting saliency in videos is a challenging problem due to complex modeling of interactions between spatial and temporal information, especially when ever-changing, dynamic nature of videos is considered. Recently, researchers have proposed large-scale data sets and models that take advantage of deep learning as a way to understand what is important for video saliency. These approaches, however, learn to combine spatial and temporal features in a static manner and do not adapt themselves much to the changes in the video content. In this article, we introduce the gated fusion network for dynamic saliency (GFSalNet), the first deep saliency model capable of making predictions in a dynamic way via the gated fusion mechanism. Moreover, our model also exploits spatial and channelwise attention within a multiscale architecture that further allows for highly accurate predictions. We evaluate the proposed approach on a number of data sets, and our experimental analysis demonstrates that it outperforms or is highly competitive with the state of the art. Importantly, we show that it has a good generalization ability, and moreover, exploits temporal information more effectively via its adaptive fusion scheme., Turkish Academy of Sciences; GEBIP 2018; Science Academy; BAGEP 2021

Katar, Salim (Balikesir Author), AIM: To assess and compare the antioxidant capacities of high-grade gliomas (HGG) according to their grades and the presence of isocitrate dehydrogenase 1 (IDH1) mutation using tissue thiol level measurement. MATERIAL and METHODS: Tissue thiol concentrations were measured in 41 HGG samples and 21 healthy brain tissues obtained from autopsy procedures, which were performed within the first 4 hours of death. All samples were stored at -80 degrees C, and a thiol quantification kit was used in evaluating tissue thiol levels. The Number Cruncher Statistical System was used for statistical analyses to detect the differences between the control group and the HGG group, which was also divided into subgroups according to their grade and IDH1 mutation presence. RESULTS: The tissue thiol levels of HGGs were found to be higher than the control group (p=0.001). Although the median thiol levels of Grade 4 gliomas were higher than those of Grade 3, no statistically significant difference was noted (p=0.076). When all tumors were compared according to the IDH1 mutation presence, IDH1-negative (IDH1-) HGGs had higher thiol contents than IDH1 mutant (IDH1+) HGGs (p=0.001). The thiol levels of Grade 4 IDH1- gliomas were statistically significantly higher than of Grade 3 gliomas (p=0.023), but no statistically significant difference between the thiol levels of Grade 3 and Grade 4 IDH1+ tumors was noted (p=0.459). CONCLUSION: We have demonstrated the higher thiol concentrations of HGGs, particularly IDH1- ones. The sulfhydryl contents of gliomas as an indicator of tumoral antioxidant capacity may be responsible for the treatment resistance of IDH1- gliomas, the mechanism of which is not clear. Thiols can be a novel target for treatment, considering the unsatisfactory results of current modalities for HGGs., Turkish Neurosurgical Society

Background: patients with anti-aquaporin-4 antibody seropositive (AQP4-IgG+) neuromyelitis optica spectrum disorders (NMOSDs) frequently suffer from optic neuritis (ON) leading to severe retinal neuroaxonal damage. Further, the relationship of this retinal damage to a primary astrocytopathy in NMOSD is uncertain. Primary astrocytopathy has been suggested to cause ON-independent retinal damage and contribute to changes particularly in the outer plexiform layer (OPL) and outer nuclear layer (ONL), as reported in some earlier studies. However, these were limited in their sample size and contradictory as to the localisation. This study assesses outer retinal layer changes using optical coherence tomography (OCT) in a multicentre cross-sectional cohort. Method: 197 patients who were AQP4-IgG+ and 32 myelin-oligodendrocyte-glycoprotein antibody seropositive (MOG-IgG+) patients were enrolled in this study along with 75 healthy controls. Participants underwent neurological examination and OCT with central postprocessing conducted at a single site. Results: no significant thinning of OPL (25.02 +/- 2.03 mu m) or ONL (61.63 +/- 7.04 mu m) were observed in patients who were AQP4-IgG+ compared with patients who were MOG-IgG+ with comparable neuroaxonal damage (OPL: 25.10 +/- 2.00 mu m; ONL: 64.71 +/- 7.87 mu m) or healthy controls (OPL: 24.58 +/- 1.64 mu m; ONL: 63.59 +/- 5.78 mu m). Eyes of patients who were AQP4-IgG+ (19.84 +/- 5.09 mu m, p=0.027) and MOG-IgG+ (19.82 +/- 4.78 mu m, p=0.004) with a history of ON showed parafoveal OPL thinning compared with healthy controls (20.99 +/- 5.14 mu m); this was not observed elsewhere. Conclusion: the results suggest that outer retinal layer loss is not a consistent component of retinal astrocytic damage in AQP4-IgG+ NMOSD. Longitudinal studies are necessary to determine if OPL and ONL are damaged in late disease due to retrograde trans-synaptic axonal degeneration and whether outer retinal dysfunction occurs despite any measurable structural correlates., Guthy Jackson Charitable Foundation (GJCF); German Research Foundation (DFG)

Introduction: we aimed to explore how physicians from different specialties approach the management of functional neurological symptom (conversion) and somatic symptom disorders in the emergency department compared with pulmonary embolism and how physicians’ professional and personal characteristics influence their diagnostic preferences. Methods: using a vignette methodology, and cross-sectional design, three emergency department case vignettes of possible functional neurological symptom, somatic symptom disorder, and pulmonary embolism were presented to physicians from internal medicine, emergency medicine, and psychiatry. A structured survey including questions on diagnosis and management of these cases, and physicians’ professional and personal characteristics (childhood trauma, attachment style) was conducted. Results: physicians from internal medicine and emergency medicine tended to consider functional neurological symptom disorder as ‘malingering’ while psychiatrists tended to diagnose the pulmonary embolism case as a psychiatric condition. Emergency medicine physicians preferred to manage functional neurological symptom disorder themselves, while other doctors endorsed recommending a psychiatric consultation. In the univariable model, being a physician from psychiatry, emergency medicine, or internal medicine; being a specialist, history of childhood sexual abuse, dismissive, and fearful attachment styles of doctors were significant predictors of diagnosing functional neurological symptom disorder as malingering. Being a psychiatrist stayed as the only significant predictor in the multivariable model. Conclusion: objectively-aberrant functional neurological symptoms and subjective somatic symptoms may be creating different reactions in physicians. In the emergency department, physicians’ diagnostic and treatment preferences of conversion disorder may be influenced by lack of training in conversion disorder, rather than their personal characteristics. / Amaç: farklı uzmanlık dallarından hekimlerin acil serviste fonksiyonel nörolojik (konversiyon) belirti bozukluğu ve bedensel belirti bozukluğunu yönetimini, pulmoner embolinin yönetimi ile karşılaştırarak incelemeyi ve hekimlerin mesleki ve kişisel özelliklerinin tanı tercihlerini nasıl etkilediğini araştırmayı amaçladık. Yöntem: vinyet yöntemi ve kesitsel tasarım kullanıldı. Olası fonksiyonel nörolojik belirti bozukluğu, bedensel belirti bozukluğu ve pulmoner emboli tanısı ile acil servise başvuran üç olgu, iç hastalıkları, acil tıp ve psikiyatri hekimlerine sunuldu. Bu olguların tanı ve tedavisine, ve hekimlerin mesleki ve kişisel özellikleri (çocukluk çağı travması, bağlanma biçimi) ne yönelik sorular içeren yapılandırılmış anket uygulandı. Bulgular: dahiliye ve acil tıp hekimleri, fonksiyonel nörolojik belirti bozukluğunu “temaruz” olarak görme eğilimindeyken, psikiyatristler pulmoner emboli vakasını psikiyatrik bir durum olarak görme eğilimindeydiler. Acil tıp hekimleri, fonksiyonel nörolojik belirti bozukluğunu kendileri yönetmeyi tercih ederken, diğer doktorlar psikiyatri konsültasyonu önerdi. Tek değişkenli modelde psikiyatri, acil tıp veya dahiliye hekimi olmak; uzman olmak, çocukluk çağı cinsel istismarı, kayıtsız ve korkulu bağlanma biçimleri, fonksiyonel nörolojik belirti bozukluğunu temaruz olarak tanımlamayı yordamaktaydı. Çok değişkenli modelde tek anlamlı yordayıcı psikiyatri uzmanlık dalıydı. Sonuç: nesnel olarak gözlenen anormal fonksiyonel nörolojik belirtiler ve öznel bedensel belirtiler hekimlerde farklı tepkilere yol açıyor olabilir. Acil serviste hekimlerin konversiyon bozukluğu tanı ve tedavi tercihleri, kişisel özelliklerinden ziyade konversiyon bozukluğu konusundaki eğitim eksikliğinden etkileniyor olabilir., NA

The role of glucagon-like peptide 1 (GLP-1) in insulin-dependent signaling is well-known; GLP-1 enhances glucose-dependent insulin secretion and lowers blood glucose in diabetes. GLP-1 receptors (GLP-1R) are also widely expressed in the brain, and in addition to its role in neuroprotection, it affects reward pathways. This systematic review aimed to analyze the studies on GLP-1 and reward pathways and its currently identified mechanisms. Methods: "Web of Science" and "Pubmed" were searched to identify relevant studies using GLP-1 as the keyword. Among the identified 26,539 studies, 30 clinical, and 71 preclinical studies were included. Data is presented by grouping rodent studies on palatable food intake, drugs of abuse, and studies on humans focusing on GLP-1 and reward systems. Results: GLP-1Rs are located in reward-related areas, and GLP-1, its agonists, and DPP-IV inhibitors are effective in decreasing palatable food intake, along with reducing cocaine, amphetamine, alcohol, and nicotine use in animals. GLP-1 modulates dopamine levels and glutamatergic neurotransmission, which results in observed behavioral changes. In humans, GLP-1 alters palatable food intake and improves activity deficits in the insula, hypothalamus, and orbitofrontal cortex (OFC). GLP-1 reduces food cravings partially by decreasing activity to the anticipation of food in the left insula of obese patients with diabetes and may inhibit overeating by increasing activity to the consumption of food in the right OFC of obese and left insula of obese with diabetes. Conclusion: current preclinical studies support the view that GLP-1 can be a target for reward system related disorders. More translational research is needed to evaluate its efficacy on human reward system related disorders., NA

Key Points Question What genetic variants are associated with juvenile amyotrophic lateral sclerosis (ALS)? Findings In this family-based genetic study, exome sequencing was performed in 3 patients diagnosed with juvenile ALS and failure to thrive; this identified de novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient). Variants in SPTLC1 are a known cause of hereditary sensory and autonomic neuropathy, type 1A, and these data extend the phenotype associated with this gene. Meaning De novo variants in the SPTLC1 gene are associated with juvenile ALS, a fatal neurological disorder., This genetic association study identifies genetic variants associated with juvenile amyotrophic lateral sclerosis., Importance Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective To identify the genetic variants associated with juvenile ALS. Design, Setting, and Participants In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. Main Outcomes and Measures De novo variants present only in the index case and not in unaffected family members. Results Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. Conclusions and Relevance These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

Introduction: high-grade gliomas (HGG), including Glioblastoma multiforme (GBM), account for the majority of primary brain tumors. Nevertheless, prognostic and diagnostic biomarkers are quite limited for HGG. The objective of this study was to investigate the prognostic value of sRANKL and sTREM2 levels in HGG patients. Methods: twelve consecutive patients with HGG, 14 patients with non-glial tumors (non-GT) and 20 age and gender-matched healthy controls were recruited. Overall survival duration of the patients was recorded. Pre-operative serum levels of sRANKL and sTREM2 were measured by ELISA. Tumors of HGG patients were analyzed by immunohistochemical staining for p53 and Ki67 and percentage scores were calculated. Results: patients with HGG and non-GT showed lower serum sRANKL and sTREM2 levels than healthy individuals. Levels of sRANKL were inversely correlated with the overall survival of patients (p=0.002, R=0.787), while sTREM2 levels were inversely correlated with p53 score (p=0.018, R=-0.666) but not survival. Conclusion: brain tumor patients show suppressed levels of filial activity biomarkers in the peripheral circulation. Serum sRANKL levels may serve as a potential prognostic biomarker for HGG. / Amaç: glioblastoma multiforme (GBM) dâhil olmak üzere yüksek dereceli gliomalar (YDG), birincil beyin tümörlerinin çoğunluğunu oluşturur. Bununla birlikte, tanısal ve prognostik biyobelirteçler YDG için oldukça sınırlıdır. Bu çalışmanın amacı, YDG hastalarında sRANKL vesTREM2 düzeylerinin prognostik değerini araştırmaktır. Yöntem: çalışmaya 12 YDG hastası, 14 tümörü glial (GT) kaynaklı olmayan hasta ile 20 yaş ve cinsiyet uyumlu sağlıklı kontrol dâhil edildi. Hastaların genel sağkalım süreleri kaydedildi. sRANKL ve sTREM2’ninoperasyon öncesi serum seviyeleri ELISA yöntemi ile ölçüldü. YDG hastalarının tümörleri p53 ve Ki67 için immünohistokimyasal boyama ile analiz edilerek yüzde skorları hesaplandı. Bulgular: YDG’si olan ve GT olmayan hastalar, sağlıklı bireylere göre daha düşük serum sRANKL ve sTREM2 seviyeleri gösterdi. sRANKL seviyeleri hastaların genel sağkalımı ile ters orantılıyken (p=0,002, R=-0,787),sTREM2 seviyelerinin ise p53 skoru ile ters orantılı olduğu saptandı(p=0,018, R=-0,666).Sonuç: beyin tümörü bulunan hastalarda, periferik dolaşımdaki glial aktivite biyobelirteçlerinin seviyeleri gösterilmiştir. Serum sRANKL seviyeleri, YDG hastaları için potansiyel bir prognostik biyobelirteç olabilir., NA

The synchronization of astrocytes via gap junctions (GJ) is a crucial mechanism in epileptic conditions, contributing to the synchronization of the neuronal networks. Little is known about the endogenous response of GJ in genetic absence epileptic animal models. We evaluated and quantified astrocyte GJ protein connexin (Cx) 30 and 43 in the somatosensory cortex (SSCx), ventrobasal (VB), centromedian (CM), lateral geniculate (LGN) and thalamic reticular (TRN) nuclei of thalamus of genetic absence epilepsy rats from Strasbourg (GAERS), Wistar albino glaxo rats from Rijswijk (WAG/Rij) and control Wistar animals using immunohistochemistry and Western Blot. The Cx30 and Cx43 immunopositive astrocytes per unit area were quantified for each region of the three animal strains. Furthermore, Cx30 and Cx43 Western Blot was applied to the tissue samples from the same regions of the three strain. The number of Cx30 immunopositive astrocytes showed significant increase in both GAERS and WAG/Rij compared to control Wistar in all brain regions studied except LGN of WAG/Rij animals. Furthermore, Cx43 in both GAERS and WAG/Rij showed significant increase in SSCx, VB and TRN. The protein expression was increased in both Cx30 and Cx43 in the two epileptic strains compared to control Wistar animals. The significant increase in the astrocytic GJ proteins Cx30 and Cx43 and the differences in the co-expression of Cx30 and Cx43 in the genetically absence epileptic strains compared to control Wistar animals may suggest that astrocytic Cx's may be involved in the mechanism of absence epilepsy. Increased number of astrocytic Cx's in GAERS and WAG/Rij may represent a compensatory response of the thalamocortical circuitry to the absence seizures or may be related to the production and/or development of absence seizures., NA

Background: genetic stratification of Parkinson's disease (PD) patients facilitates gene-tailored research studies and clinical trials. The objective of this study was to describe the design of and the initial data from the Rostock International Parkinson's Disease (ROPAD) study, an epidemiological observational study aiming to genetically characterize similar to 10,000 participants. Methods: recruitment criteria included (1) clinical diagnosis of PD, (2) relative of participant with a reportable LRRK2 variant, or (3) North African Berber or Ashkenazi Jew. DNA analysis involved up to 3 successive steps: (1) variant (LRRK2) and gene (GBA) screening, (2) panel sequencing of 68 PD-linked genes, and (3) genome sequencing. Results: initial data based on the first 1360 participants indicated that the ROPAD enrollment strategy revealed a genetic diagnostic yield of similar to 14% among a PD cohort from tertiary referral centers. Conclusions: the ROPAD screening protocol is feasible for high-throughput genetic characterization of PD participants and subsequent prioritization for gene-focused research efforts and clinical trials., Denali Therapeutics Inc. (South San Francisco, CA) partially funded laboratory testing services.

It has been demonstrated that intrinsic auricular muscles zone stimulation (IAMZS) can improve the motor symptoms of Parkinson's disease (PD) patients who are examined with the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores. In the present pilot study, using motion capture technology, we aimed to investigate the efficacy of IAMZS compared to medication alone or in combination with medication. Ten PD patients (mean age: 54.8 ± 10.1 years) were enrolled. Each participant participated in three different sessions: sole medication, sole stimulation-20 min of IAMZS, and combined IAMZS (20 min) and medication. Each session was performed on different days but at the same time to be aligned with patients' drug intake. Motion capture recording sessions took place at baseline, 20, 40, and 60 min. Statistical analysis was conducted using one-way repeated measures ANOVA. Bonferroni correction was implemented for pairwise comparisons. The sole medication was ineffective to improve gait-related parameters of stride length, stride velocity, stance, swing, and turning speed. In the sole-stimulation group, pace-related gait parameters were significantly increased at 20 and 40 min. These improvements were observed in stride length at 20 (p = 0.0498) and 40 (p = 0.03) min, and also in the normalized stride velocity at 40 min (p-value = 0.02). Stride velocity also tended to be significant at 20 min (p = 0.06) in the sole-stimulation group. Combined IAMZS and medication demonstrated significant improvements in all the time segments for pace-related gait parameters [stride length: 20 min (p = 0.04), 40 min (p = 0.01), and 60 min (p < 0.01); stride velocity: 20 min (p < 0.01), 40 min (p = 0.01), and 60 min (p < 0.01)]. These findings demonstrated the fast action of the IAMZS on PD motor symptoms. Moreover, following the termination of IAMZS, a prolonged improvement in symptoms was observed at 40 min. The combined use of IAMZS with medication showed the most profound improvements. The IAMZS may be particularly useful during medication off periods and may also postpone the long-term side effects of high-dose levodopa. A large scale multicentric trial is required to validate the results obtained from this pilot study., Koç Holding; Koç University

Background: Sialidosis is a rare autosomal recessive disease caused by NEU1 mutations, leading to neuraminidase deficiency and accumulation of sialic acid-containing oligosaccharides and glycopeptides into the tissues. Sialidosis is divided into two clinical entities, depending on residual enzyme activity, and can be distinguished according to age of onset, clinical features, and progression. Type 1 sialidosis is the milder, late-onset form, also known as non-dysmorphic sialidosis. It is commonly characterized by progressive myoclonus, ataxia, and a macular cherry-red spot. As a rare condition, the diagnosis is often only made after few years from onset, and the clinical management might prove difficult. Furthermore, the information in the literature on the long-term course is scarce. Case presentations: we describe a comprehensive clinical, neuroradiological, ophthalmological, and electrophysiological history of four unrelated patients affected by type 1 sialidosis. The long-term care and novel clinical and neuroradiological insights are discussed. Discussion and conclusions: we report the longest follow-up (up to 30 years) ever described in patients with type 1 sialidosis. During the course, we observed a high degree of motor and speech disability with preserved cognitive functions. Among the newest antiseizure medication, perampanel (PER) was proven to be effective in controlling myoclonus and tonic–clonic seizures, confirming it is a valid therapeutic option for these patients. Brain magnetic resonance imaging (MRI) disclosed new findings, including bilateral gliosis of cerebellar folia and of the occipital white matter. In addition, a newly reported variant (c.914G > A) is described., Istanbul University Research Fund

Anorexia nervosa, with the highest mortality rate among psychiatric diseases, is characterized by low body mass index, fear of weight gain, and disturbed body image. Even though multiple drugs have been proposed for the treatment of anorexia nervosa, current treatment modalities include nutritional support and psychotherapy. In this study, our aim is to analyze the efficiency and possible adverse effects of olanzapine, an atypical anti-psychotic drug, in the treatment of anorexia nervosa. The studies investigating the efficiency and possible adverse effects of olanzapine in anorexia nervosa have been searched by using 3 databases (Embase, PubMed, and Cochrane Library). DerSimonian-Laird random effects meta-analyses have been used in the statistical analysis. Effect of olanzapine treatment in accordance with the duration and dosage of drug have been analyzed by the determination of 95% confidence intervals (p value < 0.05 is considered as statistically significant). Despite the presence of some contradictory studies, olanzapine treatment has been found beneficial in anorexia nervosa. In addition, analysis reveals that statistically significant beneficial effect of olanzapine treatment is used at high doses and for short duration. Possible side effects include neuroleptic malignant syndrome, hypoglycemia, and heart block in patients suffering from anorexia nervosa. Even though there is obvious need for more comprehensive further studies, current literature favors olanzapine treatment. The efficiency of olanzapine is considered to be related to changes in dopaminergic and serotonergic system in anorexic patients both in terms of neurotransmitter levels and receptor activity., NA

Patients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis., National Health and Medical Research Council of Australia; Roche; Merck; Biogen; Novartis; Bayer Schering; Sanofi Genzyme; Teva

Aim: to investigate the relationship between clinical features and prognosis of the hippocampal sclerosis (HS) cases and International League Against Epilepsy (ILAE) histopathology classification. Material and methods: a hundred patients with refractory epilepsy who were operated with the diagnosis of the Mesial Temporal Lobe Epilepsy were included in the study. Socio-demographic characteristics, clinical and family histories, post-operative ILAE and Engel epilepsy scores and diagnostic tests were recorded. At the same time, all of the pathological specimens were classified according to the new semi-quantitative ILAE classification. A significant statistical relationship was investigated between clinical data and HS-ILAE groups. RESULTS: There were 36 male 64 female patients. The mean follow-up period was 6.5 years. 75% of the cases were HS-ILAE type 1, 19% HS-ILAE type 2, 6% were unidentifiable. FCD3A was detected in 3 patients. The HS-ILAE Type 2 ratio was high on the right-sided cases. In addition, HS-ILAE Type 1 ratio was high in patients with early seizure onset and long duration of epilepsy. There was no significant relationship between long-term ILAE and Engel epilepsy outcome scores and HS-ILAE types. Conclusion: resection of mesiotemporal structures in hippocampal sclerosis provides seizure control in at least two-thirds of cases. Histopathological findings may help us understand the epileptogenicity-prognosis of HS. The relationship between ILAE histopathology classification and clinical factors will become more obvious in the future. According to our study, there was a relationship between onset age of epilepsy, epilepsy duration, lesion side and HS-ILAE types. The reinforcement of these relationships with larger series will benefit clinicians., NA

Purpose: Daytime sleepiness, a frequent symptom of obstructive sleep apnea (OSA), can impact functional status. In patients with coronary artery disease (CAD) and concomitant OSA, the distinction between sleep-related functional impairment from underlying CAD versus OSA is unclear. This study evaluated the impact of OSA on sleep-related functional impairment in patients with CAD and compared the effect of 1-year continuous positive airway pressure (CPAP) use on change in impairment between those with and without excessive daytime sleepiness (EDS) and OSA. We hypothesized that sleep-related functional impairment is impacted by EDS independent of OSA in patients with CAD. Methods: One hundred five CAD patients without OSA and 105 with moderate-to-severe OSA from the RICCADSA trial were matched on disease severity and included in the current substudy. Of those with OSA, 80 were allocated to CPAP. Functional Outcomes of Sleep Questionnaire (FOSQ) score < 17.9 corresponded to sleep-related functional impairment. Results: Following revascularization, CAD patients with and without OSA frequently report sleep-related functional impairment (35% and 27.3%, respectively; p = .29). Moderate-to-severe OSA was not related to baseline FOSQ scores < 17.9 in regression analyses; EDS was (OR 4.82, 95% CI 2.12-11.0; p < .001). CPAP use significantly improved FOSQ scores from baseline to 1-year follow-up in OSA patients with EDS (17.2 +/- 2.0 to 18.15 +/- 1.7, p = .002) despite suboptimal adherence. Conclusions: Sleep-related functional impairment may be reflective of persistent EDS, independent of OSA. Diagnosing OSA and initiating treatment are worthwhile in individuals with CAD and EDS, as both are important to guide appropriate therapy in patients with CAD., National Institute of Health Heart Lung and Blood Institute

In this paper, we analyze the role of hidden bias in representational efficiency of the Gaussian-Bipolar Restricted Boltzmann Machines (GBPRBMs), which are similar to the widely used Gaussian-Bernoulli RBMs. Our experiments show that hidden bias plays an important role in shaping of the probability density function of the visible units. We define hidden entropy and propose it as a measure of representational efficiency of the model. By using this measure, we investigate the effect of hidden bias on the hidden entropy and provide a full analysis of the hidden entropy as function of the hidden bias for small models with up to three hidden units. We also provide an insight into understanding of the representational efficiency of the larger scale models. Furthermore, we introduce Normalized Empirical Hidden Entropy (NEHE) as an alternative to hidden entropy that can be computed for large models. Experiments on the MNIST, CIFAR-10 and Faces data sets show that NEHE can serve as measure of representational efficiency and gives an insight on minimum number of hidden units required to represent the data., NA

Brain damage is associated with linguistic deficits and might alter co-speech gesture production. Gesture production after focal brain injury has been mainly investigated with respect to intrasentential rather than discourse-level linguistic processing. In this study, we examined 1) spontaneous gesture production patterns of people with left hemisphere damage (LHD) or right hemisphere damage (RHD) in a narrative setting, 2) the neural structures associated with deviations in spontaneous gesture production in these groups, and 3) the relationship between spontaneous gesture production and discourse level linguistic processes (narrative complexity and evaluation competence). Individuals with LHD or RHD (17 people in each group) and neurotypical controls (n = 13) narrated a story from a picture book. Results showed that increase in gesture production for LHD individuals was associated with less complex narratives and lesions of individuals who produced more gestures than neurotypical individuals overlapped in frontal-temporal structures and basal ganglia. Co-speech gesture production of RHD individuals positively correlated with their evaluation competence in narrative. Lesions of RHD individuals who produced more gestures overlapped in the superior temporal gyrus and the inferior parietal lobule. Overall, LHD individuals produced more gestures than neurotypical individuals. The groups did not differ in their use of different gesture forms except that LHD individuals produced more deictic gestures per utterance than RHD individuals and controls. Our findings are consistent with the hypothesis that co-speech gesture production interacts with macro-linguistic levels of discourse and this interaction is affected by the hemispheric lateralization of discourse abilities., NIH; National Science Foundation

How interval timing is affected by aging constitutes one of the contemporary research questions. There is however a limited number of studies that investigate this research question in animal models of aging. The current study investigated how temporal decision-making is affected by aging. Initially, we trained young (2-3 month-old) and old C57BL/6J male mice (18-19 month-old) independently with short (3 s) and long (9 s) intervals by signaling, in each trial, the hopper associated with the interval that is in effect in that trial. The probability of short and long trials was manipulated (0.25 or 0.75) for different animals in each age group. During testing, both hoppers were illuminated, and thus active trial type was not differentiated. We expected mice to spontaneously combine the independently acquired time interval-location-probability information to adaptively guide their timing behavior in test trials. This adaptive ability and the resultant timing behavior were analyzed and compared between the age groups. Both young and old mice indeed adjusted their timing behavior in an abrupt fashion based on the independently acquired temporal-spatial-probabilistic information. The core timing ability of old mice was also intact. However, old mice had difficulty in terminating an ongoing timed response when the probability for the short trial was higher and this difference disappeared in the group that was exposed to a lower probability of short trials. These results suggest an inhibition problem in old mice as reflected through the threshold modulation process in timed decisions, which is cognitively penetrable to the probabilistic information., Scientific and Technological Research Council of Turkey (TÜBİTAK); Scientific and Technological Research Council of Turkey (TÜBİTAK) National Scholarship Program; Turkish Academy of Sciences GEBIP-2015 award; Suna Kıraç Library

NMDA receptor-dependent synaptic plasticity has been proposed to be important for encoding of memories. Consistent with this hypothesis, the non-competitive NMDA receptor antagonist, MK-801, has been found to impair performance on tests of memory. Interpretation of some of these findings has, however, been complicated by the fact that the drug-state of animals has differed during encoding and tests of memory. Therefore, it is possible that MK-801 may result in state-dependent retrieval or expression of memory rather than actually impairing encoding itself. We tested this hypothesis in mice using tests of object recognition memory with a 24 hour delay between the encoding and test phase. Mice received injections of either vehicle or MK-801 prior to the encoding phase and the test phase. In Experiment 1, a low dose of MK-801 (0.01 mg/kg) impaired performance when the drug-state (vehicle or MK-801) of mice changed between encoding and test, but there was no significant effect of MK-801 on encoding. In Experiment 2, a higher dose of MK-801 (0.1 mg/kg) failed to impair object recognition memory when mice received the drug prior to both encoding and test compared to mice that received vehicle. MK-801 did not affect object exploration, but it did induce locomotor hyperactivity at the higher dose. These results suggest that some previous demonstrations of MK-801 effects may reflect a failure to express or retrieve memory due to the state-dependency of memory rather than impaired encoding of memory., National Centre for the 3Rs; CRACK IT Solution; BBSRC

Erector spinae plane block (ESPB) is a newly described interfascial plane block, and the number of Journal articles on the bilateral application of ESPB is increasing in the literature. In this paper, in addition to analyzing bilateral ESPB cases and studies published so far, we aimed to review the relevant anatomy, describe the mechanism of spread of the injectant, demonstrate varying approaches to ESPB, and summarize case reports and clinical trials, as well as provide current insight on this emerging and popular block. Randomized controlled studies, comparative studies of ESPB versus other methods, and pharmacokinetic studies of bilateral applications must be the next step in clearly understanding bilateral ESPB., NA

An acoustic stimulus elicits an electroencephalographic response called auditory event-related potential (ERP). When some members of a stream of standard auditory stimuli are replaced randomly by a deviant stimulus and this stream is presented to a subject who ignores the stimuli, two different ERPs to deviant and standard stimuli are recorded. If the ERP to standard stimuli is subtracted from the ERP to deviant stimuli, the difference potential (DP) waveform typically exhibits a series of negative-positive-negative deflections called mismatch negativity (MMN), P3a, and reorienting negativity (RON), which are associated with pre-attentive change detection, involuntary attention switching, and reorienting of attention, respectively. The aim of the present study was to investigate how these pre-attentive processes are affected if the change occurs earlier than its usual timing implied by isochronous standard stimuli. In the MMN paradigm employed, 15% of the standards were randomly replaced by deviant stimuli which differed either in their pitch, their earlier onset time, or in both. Event-related responses to these three deviants [timely pitch change (RTP), earlier onset (REO), earlier pitch change (REP)] and to standards (RS) were recorded from 10 reading subjects. To maintain identical stimulation histories for the responses subtracted from each other, “deviant-standard” difference potentials (DP) for “timely” and “early” pitch deviances were derived as follows: DPTP = RTP − RS and DPEP = REP − REO. Interestingly, the MMN components of the DPs to timely and early pitch deviances had similar amplitudes, indicating that regularity of stimulus timing does not provide any benefit for the pre-attentive auditory change detection mechanism. However, different scalp current density (SCD) dynamics of the MMN/P3a complexes, elicited by timely and early pitch deviances, suggested that an auditory change in a stimulus occurring earlier-than-usual initiates a faster and more effective call-for-attention and causes stronger attention switching than a timely change. SCD results also indicated that the temporal, frontal, and parietal MMN components are simultaneously present rather than emerging sequentially in time, supporting the MMN models based on parallel deviance processing in the respective cortices. Similarity of the RONs to timely and early pitch deviances indicated that reorienting of attention is of the same strength in two cases., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Science Academy, Turkey

Many organisms can time intervals flexibly on average with high accuracy but substantial variability between the trials. One of the core psychophysical features of interval timing functions relates to the signatures of this timing variability; for a given individual, the standard deviation of timed responses/time estimates is nearly proportional to their central tendency (scalar property). Many studies have aimed at elucidating the neural basis of interval timing based on the neurocomputational principles in a fashion that would explain the scalar property. Recent experimental evidence shows that there is indeed a specialized neural system for timekeeping. This system, referred to as the “time cells,” is composed of a group of neurons that fire sequentially as a function of elapsed time. Importantly, the time interval between consecutively firing time cell ensembles has been shown to increase with more elapsed time. However, when the subjective time is calculated by adding the distributions of time intervals between these sequentially firing time cell ensembles, the standard deviation would be compressed by the square root function. In light of this information the question becomes, “How should the signaling between the sequentially firing time cell ensembles be for the resulting variability to increase linearly with time as required by the scalar property?” We developed a simplified model of time cells that offers a mechanism for the synaptic communication of the sequentially firing neurons to address this ubiquitous property of interval timing. The model is composed of a single layer of time cells formulated in the form of integrate-and-fire neurons with feed-forward excitatory connections. The resulting behavior is simple neural wave activity. When this model is simulated with noisy conductances, the standard deviation of the time cell spike times increases proportionally to the mean of the spike-times. We demonstrate that this statistical property of the model outcomes is robustly observed even when the values of the key model parameters are varied., American University of the Middle East

The role of cerebellum in coordination of somatic motor activity has been studied in detailed in various species. However, experimental and clinical studies have shown the involvement of the cerebellum with various visceral and cognitive functions via its vast connections with the central nervous system. The present study aims to define the cortical and subcortical and brain stem connections of the cerebellum via the superior (SCP) and middle (MCP) cerebellar peduncle using biotinylated dextran amine (BDA) and Fluoro-Gold (FG) tracer in Wistar albino rats. 14 male albino rats received 20-50-n1 pressure injections of either FG or BDA tracer into the SCP and MCP. Following 7-10 days of survival period, the animals were processed according to the related protocol for two tracers. Labelled cells and axons were documented using light and fluorescence microscope. The SCP connects cerebellum to the insular and infralimbic cortices whereas, MCP addition to the insular cortex, it also connects cerebellum to the rhinal, primary sensory, piriform and auditory cortices. Both SCP and MCP connected the cerebellum to the ventral, lateral, posterior and central, thalamic nuclei. Additionally, SCP also connects parafasicular thalamic nucleus to the cerebellum. The SCP connects cerebellum to basal ganglia (ventral pallidum and clastrum) and limbic structures (amygdaloidal nuclei and bed nucleus of stria terminalis), however, the MCP have no connections with basal ganglia or limbic structures. Both the SCP and MCP densely connects cerebellum to various brainstem structures. Attaining the knowledge of the connections of the SCP and MCP is important for the diagnosis of lesions in the MCP and SCP and would deepen current understanding of the neuronal circuit of various diseases or lesions involving the SCP and MCP., NA

This study investigates whether spinal manipulation leads to changes in motor control by measuring the recruitment pattern of motor units in both an upper and lower limb muscle and to see whether such changes may at least in part occur at the cortical level by recording movement related cortical potential (MRCP) amplitudes. In experiment one, transcranial magnetic stimulation input-output (TMS I/O) curves for an upper limb muscle (abductor pollicus brevis; APB) were recorded, along with F waves before and after either spinal manipulation or a control intervention for the same subjects on two different days. During two separate days, lower limb TMS I/O curves and MRCPs were recorded from tibialis anterior muscle (TA) pre and post spinal manipulation. Dependent measures were compared with repeated measures analysis of variance, with p set at 0.05. Spinal manipulation resulted in a 54.5% +/- 93.1% increase in maximum motor evoked potential (MEPmax) for APB and a 44.6% +/- 69.6% increase in MEPmax for TA. For the MRCP data following spinal manipulation there were significant difference for amplitude of early bereitschafts-potential (EBP), late bereitschafts potential (LBP) and also for peak negativity (PN). The results of this study show that spinal manipulation leads to changes in cortical excitability, as measured by significantly larger MEPmax for TMS induced input-output curves for both an upper and lower limb muscle, and with larger amplitudes of MRCP component post manipulation. No changes in spinal measures (i.e., F wave amplitudes or persistence) were observed, and no changes were shown following the control condition. These results are consistent with previous findings that have suggested increases in strength following spinal manipulation were due to descending cortical drive and could not be explained by changes at the level of the spinal cord. Spinal manipulation may therefore be indicated for the patients who have lost tonus of their muscle and/or are recovering from muscle degrading dysfunctions such as stroke or orthopaedic operations and/or may also be of interest to sports performers. These findings should be followed up in the relevant populations., Australian Spinal Research Foundation; Hamblin Chiropractic Research Fund Trust; New Zealand College of Chiropractic; Koç University

WOS: 000389088600005, PubMed ID: 27690351, Background: Decision-making in Obsessive Compulsive Disorder has typically been investigated in the adult population. Computational approaches have recently started to get integrated into these studies. However, decision-making research in pediatric OCD populations is scarce. Methods: We investigated latent decision processes in 21 medication-free pediatric OCD patients and 23 healthy control participants. We hypothesized that OCD patients would be more cautious and less efficient in evidence accumulation than controls in a two alternative forced choice (2AFC) task. Results: Pediatric OCD patients were less efficient than controls in accumulating perceptual evidence and showed a tendency to be more cautious. In comparison to post-correct decisions, OCD patients increased decision thresholds after erroneous decisions, whereas healthy controls decreased decision thresholds. These changes were coupled with weaker evidence accumulation after errors in both groups. Limitations: The small sample size limited the power of the study. Conclusions: Our results demonstrate poorer decision-making performance in pediatric OCD patients at the level of latent processes, specifically in terms of evidence accumulation. (C) 2016 Elsevier B.V. All rights reserved., Turkish Academy of Sciences, We would like to thank Hakan Karsilar for his help on the DMDT code; Elif Akin for her help in recruiting participants; Aysu Hazar for her help with data collection. This work was supported by the Turkish Academy of Sciences under grant GEBIP 2015 to Fuat Balci. The sponsor had no role, in study design; in the collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

International audience; Phosphorylation by serine/threonine kinases has been described as a new mechanism for regulating the effects of insecticides on insect neuronal receptors and channels. Although insect GABA receptors are commercially important targets for insecticides (e.g. fipronil), their modulation by kinases is poorly understood and the influence of phosphorylation on insecticide sensitivity is unknown. Using the whole-cell patch-clamp technique, we investigated the modulatory effect of PKC and CaMKinase II on GABA receptor subtypes (GABAR1 and GABAR2) in DUM neurons isolated from the terminal abdominal ganglion (TAG) of Periplaneta americana. Chloride currents through GABAR2 were selectively abolished by PMA and PDBu (the PKC activators) and potentiated by Gö6983, an inhibitor of PKC. Furthermore, using KN-62, a specific CaMKinase II inhibitor, we demonstrated that CaMKinase II activation was also involved in the regulation of GABAR2 function. In addition, using CdCl(2) (the calcium channel blocker) and LOE-908, a blocker of TRPγ, we revealed that calcium influx through TRPγ played an important role in kinase activations. Comparative studies performed with CACA, a selective agonist of GABAR1 in DUM neurons confirmed the involvement of these kinases in the specific regulation of GABAR2. Furthermore, our study reported that GABAR1 was less sensitive than GABAR2 to fipronil. This was demonstrated by the biphasic concentration-response curve and the current-voltage relationship established with both GABA and CACA. Finally, we demonstrated that GABAR2 was 10-fold less sensitive to fipronil following inhibition of PKC, whereas inhibition of CaMKinase II did not alter the effect of fipronil.

International audience; Maternal malnutrition results in learning deficits and predisposition to anxiety and depression in the offspring that extend into adulthood. At the cellular level, learning and memory rely on the production of new neurons in the dentate gyrus (DG) of the hippocampus, and hippocampal neurogenesis has been associated with the etiology and treatment of depression, but whether adult neurogenesis is affected by malnutrition during early life is not known. To investigate the effects of perinatal undernutrition on neurogenesis at adulthood, pregnant Sprague Dawley rats were fed either ad libitum (C) or were undernourished by reducing their daily food intake by 50% in relation to the C group during gestation and lactation (FR/FR). At birth, one subset of control pups was cross-fostered to food-restricted dams to constitute a third group of animals that were undernourished during the lactation period only (AdLib/FR). At 90 days of age, pups were injected with bromodeoxyuridine (BrdU) and sacrificed 2 h, week, or 3 weeks later. The number of BrdU-labeled cells in the DG was significantly reduced in the offspring of FR/FR dams in relation to controls at all the time points examined. However, the proportion of new cells exhibiting a neuronal phenotype was higher in FR/FR rats than in controls as revealed by the colabeling at 3 weeks of the BrdU-labeled cells with neuron-specific nuclear protein (NeuN). AdLib/FR animals exhibited also reduced BrdU labeling at 2 h and 1 week. Nevertheless, we found no significant differences at 3 weeks in either the number of BrdU-labeled cells or in the proportion of new neurons between controls and AdLib/FR rats. These results indicate that the decreased number of hippocampal neurons in perinatally undernourished rats is due to the deleterious effects of early nutrient restriction on cell proliferation but not on the neuronal differentiation process of the new generated cells.

We report a case of a 27-year-old man who presented with a clinical history of swelling on the left side of his head. MRI scan showed a left frontal meningioma. The patient underwent a macroscopically complete resection. The histological diagnosis was malignant meningioma. Ten months after the initial diagnosis, multiple distant metastases were detected. Risk factors leading to metastasis in this case are discussed with a review of the literature.

We designed this study to determine whether serum free and phospholipid-bound choline concentrations change after surgery or methylprednisolone treatment in dogs and rats. In dogs, serum free and phospholipid-bound choline concentrations were decreased by 29% and 17% immediately after abdominal-pelvic surgery under xylasine + ketamine anesthesia, respectively, and both remained low for 24 h. Serum cortisol was elevated after surgery. The elevation in serum cortisol was inversely correlated with the decreases in free (r = -0.737; P < 0.001) and phospholipid-bound (r = -0.771; P < 0.001) choline concentrations. After methyprednisolone administration (5-20 mg/kg) free and phospholipid-bound choline concentrations decreased in a dose- and time-dependent manner. In rats, either surgery or methylprednisolone failed to alter serum free choline concentrations while phospholipid-bound choline decreased after surgery. These data show that the decrease in serum choline after surgery results from the increase in circulating glucocorticoids.

Two cases of cerebello-pontine angle epidermoid tumour presented with the clinical findings of brain stem stroke. Preoperative imaging showed stretching of branches of the basilar artery. Brain stem stroke as a presenting feature of cerebello-pontine angle epidermoid tumour has not been reported before.