The epigenetic component of the brain response to electromagnetic stimulation in Parkinson's Disease patients: A literature overview

Modulations of epigenetic machinery, namely DNA methylation pattern, histone modification, and non‐coding RNAs expression, have been recently included among the key determinants contributing to Parkinson's Disease (PD) aetiopathogenesis and response to therapy. Along this line of reasoning, a set of experimental findings are highlighting the epigenetic‐based response to electromagnetic (EM) therapies used to alleviate PD symptomatology, mainly Deep Brain Stimulation (DBS) and Transcranial Magnetic Stimulation (TMS). Notwithstanding the proven efficacy of EM therapies, the precise molecular mechanisms underlying the brain response to these types of stimulations are still far from being elucidated. In this review we provide an overview of the epigenetic changes triggered by DBS and TMS in both PD patients and neurons from different experimental animal models. Furthermore, we also propose a critical overview of the exposure modalities currently applied, in order to evaluate the technical robustness and dosimetric control of the stimulation, which are key issues to be carefully assessed when new molecular findings emerge from experimental studies. Bioelectromagnetics. 39:3–14, 2018. © 2017 Wiley Periodicals, Inc.     

Effects of chronic iTBS‐rTMS and enriched environment on visual cortex early critical period and visual pattern discrimination in dark‐reared rats

Early cortical critical period resembles a state of enhanced neuronal plasticity enabling the establishment of specific neuronal connections during first sensory experience. Visual performance with regard to pattern discrimination is impaired if the cortex is deprived from visual input during the critical period. We wondered how unspecific activation of the visual cortex before closure of the critical period using repetitive transcranial magnetic stimulation (rTMS) could affect the critical period and the visual performance of the experimental animals. Would it cause premature closure of the plastic state and thus worsen experience‐dependent visual performance, or would it be able to preserve plasticity? Effects of intermittent theta‐burst stimulation (iTBS) were compared with those of an enriched environment (EE) during dark‐rearing (DR) from birth. Rats dark‐reared in a standard cage showed poor improvement in a visual pattern discrimination task, while rats housed in EE or treated with iTBS showed a performance indistinguishable from rats reared in normal light/dark cycle. The behavioral effects were accompanied by correlated changes in the expression of brain‐derived neurotrophic factor (BDNF) and atypical PKC (PKCζ/PKMζ), two factors controlling stabilization of synaptic potentiation. It appears that not only nonvisual sensory activity and exercise but also cortical activation induced by rTMS has the potential to alleviate the effects of DR on cortical development, most likely due to stimulation of BDNF synthesis and release. As we showed previously, iTBS reduced the expression of parvalbumin in inhibitory cortical interneurons, indicating that modulation of the activity of fast‐spiking interneurons contributes to the observed effects of iTBS. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 19–33, 2016     

经颅磁刺激和经颅直流电刺激在调控大脑共情功能中的应用

共情可以帮助人们建立和谐的人际关系，更好地适应现实社会，是一种重要的社会认知功能。已有研究表明，诸多神经和精神类疾病的发生发展和复发与共情缺陷有关。非侵入性脑刺激技术（经颅磁刺激和经颅直流电刺激）可以通过调节大脑皮层兴奋性来调控个体的共情水平，缓解共情缺陷症状。针对健康群体使用该技术的现有证据显示：内侧前额叶、初级运动皮层、额下回、背外侧前额叶和颞顶交界处的活动有助于提升个体的认知共情水平，其中双侧背外侧前额叶的活动还有助于下调个体的情感共情水平，而右侧颞顶交界处的活动则可以增强自我表征从而支持个体在共情时进行自我和他人的区分。少数针对共情缺陷群体使用该技术的临床证据提示，增强左侧背外侧前额叶和内侧前额叶的活动可以分别提升精神疾病和神经退行性疾病患者的认知共情水平。未来的研究应探讨在统一的行为测量范式下针对不同刺激参数和刺激位点进行共情干预研究，通过融合其他神经生理技术进一步考察非侵入性脑刺激技术改善共情功能的作用机制，并考虑个体差异性对大脑共情功能干预效果的影响。     

Reduction in cortical parvalbumin expression due to intermittent theta‐burst stimulation correlates with maturation of the perineuronal nets in young rats

We recently showed that intermittent theta‐burst stimulation (iTBS) using transcranial magnetic stimulation strongly reduces the number of rat neocortical interneurons expressing glutamic acid decarboxylase 67 kDa (GAD67) and parvalbumin (PV), indicating changed activity of fast‐spiking (FS) interneurons. In advance of in vitro studies intended to characterize changes in electrical properties of FS interneurons under these conditions, we tested whether the iTBS effect is age‐dependent. Conscious Sprague‐Dawley rats aged between 28 and 90 days received three blocks of iTBS at 15 min intervals. We found that iTBS‐related reduction in PV+ cells was absent up to an age of 32 days, then gradually increased, and approached a maximum of about 40% reduction at an age of about 40 days. The relative number of cells expressing PV (PV+, 8–9%) did not change with age in sham‐controls and also the increase in cortical c‐Fos expression induced by iTBS was not principally age‐dependent. However, a prominent growth of the perineuronal nets, typically surrounding the PV+ cells, exactly paralleled the increase in the iTBS effect. Based on these findings, we conclude that the functional development of the inhibitory network of PV+ interneurons with regard to intracortical synaptic connectivity is not sufficiently matured in rats younger than 35d to enable activity‐dependent modifications during iTBS. Outgrowth of the perineuronal nets and associated maturation of excitatory cortical inputs, as is characteristic for the critical cortical period, may take place before PV+ interneurons can be sufficiently activated via repetitive transcranial magnetic stimulation, allowing plastic changes of molecular phenotype and likely also synaptic plasticity. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 75: 1–11, 2015     

The impact of pharmacological and non‐pharmacological interventions to improve physical health outcomes in people with schizophrenia: a meta‐review of meta‐analyses of randomized controlled trials

We summarized and compared meta‐analyses of pharmacological and non‐pharmacological interventions targeting physical health outcomes among people with schizophrenia spectrum disorders. Major databases were searched until June 1, 2018. Of 3,709 search engine hits, 27 meta‐analyses were included, representing 128 meta‐analyzed trials and 47,231 study participants. While meta‐analyses were generally of adequate or high quality, meta‐analyzed studies were less so. The most effective weight reduction interventions were individual lifestyle counseling (standardized mean difference, SMD=–0.98) and exercise interventions (SMD=–0.96), followed by psychoeducation (SMD=–0.77), aripiprazole augmentation (SMD=–0.73), topiramate (SMD=–0.72), d‐fenfluramine (SMD=–0.54) and metformin (SMD=–0.53). Regarding waist circumference reduction, aripiprazole augmentation (SMD=–1.10) and topiramate (SMD=–0.69) demonstrated the best evidence, followed by dietary interventions (SMD=–0.39). Dietary interventions were the only to significantly improve (diastolic) blood pressure (SMD=–0.39). Switching from olanzapine to quetiapine or aripiprazole (SMD=–0.71) and metformin (SMD=–0.65) demonstrated best efficacy for reducing glucose levels, followed by glucagon‐like peptide‐1 receptor agonists (SMD=–0.39), dietary interventions (SMD=–0.37) and aripiprazole augmentation (SMD=–0.34), whereas insulin resistance improved the most with metformin (SMD=–0.75) and rosiglitazone (SMD=–0.44). Topiramate had the greatest efficacy for triglycerides (SMD=–0.68) and low‐density lipoprotein (LDL)‐cholesterol (SMD=–0.80), whereas metformin had the greatest beneficial effects on total cholesterol (SMD=–0.51) and high‐density lipoprotein (HDL)‐cholesterol (SMD=0.45). Lifestyle interventions yielded small effects for triglycerides, total cholesterol and LDL‐cholesterol (SMD=–0.35 to –0.37). Only exercise interventions increased exercise capacity (SMD=1.81). Despite frequent physical comorbidities and premature mortality mainly due to these increased physical health risks, the current evidence for pharmacological and non‐pharmacological interventions in people with schizophrenia to prevent and treat these conditions is still limited and more larger trials are urgently needed.     

Biological and molecular profile of fracture non‐union tissue: current insights

Delayed bone healing and non‐union occur in approximately 10% of long bone fractures. Despite intense investigations and progress in understanding the processes governing bone healing, the specific pathophysiological characteristics of the local microenvironment leading to non‐union remain obscure. The clinical findings and radiographic features remain the two important landmarks of diagnosing non‐unions and even when the diagnosis is established there is debate on the ideal timing and mode of intervention. In an attempt to understand better the pathophysiological processes involved in the development of fracture non‐union, a number of studies have endeavoured to investigate the biological profile of tissue obtained from the non‐union site and analyse any differences or similarities of tissue obtained from different types of non‐unions. In the herein study, we present the existing evidence of the biological and molecular profile of fracture non‐union tissue.     

Frequency‐dependent and montage‐based differences in phosphene perception thresholds via transcranial alternating current stimulation

It is well known that applying transcranial alternating current stimulation (tACS) to the scalp can generate artefactual visual perceptions of flashing or shimmering light known as phosphenes. The thresholds for generating these phosphenes have been used by international standards bodies to provide conservative estimates of the field strength required to interfere with human neural functioning and set safety limits accordingly. However, the precise relationship between electric currents and phosphene perception thresholds remains uncertain. The present study used tACS to systematically investigate the effects of the location and the frequency of stimulation on phosphene perception thresholds. These thresholds were obtained from 24 participants using a within‐subject design as a function of scalp stimulation sites (FPz‐Cz versus Oz‐Cz) and stimulation frequency (2–30 Hz in steps of 2 Hz). Phosphene perception thresholds were consistently lower for FPz‐Cz stimulation, and regardless of tACS location were lowest for 16 Hz stimulation. Threshold variation between participants was very small, which is meaningful when setting standards based on phosphenes. Bioelectromagnetics. 2019;40:365–374. © 2019 Bioelectromagnetics Society.     

Fine needle aspiration of non‐small cell lung cancer: current state and future perspective

A. Fassina, R. Cappellesso, F. Simonato, C. Lanza, A. Marzari and M. Fassan Fine needle aspiration of non‐small cell lung cancer: current state and future perspective The emerging treatment revolution determined by the advent of new targeted therapies requires accurate tumour subtyping as a mandatory step in the clinical workup of patients with non‐small cell lung carcinoma (NSCLC). As a result of advanced and inoperable disease or poor performance status, in many patients, minimally invasive procedures must be employed to obtain diagnostic material. Fine needle aspiration (FNA) is a valid and widely employed alternative to either tru‐cut or open‐sky biopsy. Indeed, cytological specimens are suitable for techniques such as immunocytochemistry, mutation and microRNA analysis, and may present advantages over small biopsies especially if cell blocks are prepared and attention is paid to cytomorphology and pre‐analytic management of specimens at the time they are collected. These will allow the adequate stratification of patients into different diagnostic and prognostic classes.     

Insight and the no‐self in deep brain stimulation

Ethical analyses of the effects of neural interventions commonly focus on changes to personality and behavior, interpreting these changes in terms of authenticity and identity. These phenomena have led to debate among ethicists about the meaning of these terms for ethical analysis of such interventions. While these theoretical approaches have different criteria for ethical significance, they agree that patients’ reports are concerning because a sense of self is valuable. In this paper, I question this assumption. I propose that the Buddhist theory of no‐self offers a novel approach to making ethical sense of patients’ claims following deep brain stimulation. This alternative approach is based on the value of insight into patterns of cause and effect among mental states and actions.     

Quantification of non‐specific binding of magnetic micro‐ and nanoparticles using cell tracking velocimetry: Implication for magnetic cell separation and detection

The maturation of magnetic cell separation technology places increasing demands on magnetic cell separation performance. While a number of factors can cause sub‐optimal performance, one of the major challenges can be non‐specific binding of magnetic nano‐ or microparticles to non‐targeted cells. Depending on the type of separation, this non‐specific binding can have a negative effect on the final purity, the recovery of the targeted cells, or both. In this work, we quantitatively demonstrate that non‐specific binding of magnetic nanoparticles can impart a magnetization to cells such that these cells can be retained in a separation column and thus negatively impact the purity of the final product and the recovery of the desired cells. Through experimental data and theoretical arguments, we demonstrate that the number of MACS magnetic particles needed to impart a magnetization that is sufficient to cause non‐targeted cells to be retained in the column to be on the order of 500–1,000 nanoparticles. This number of non‐specifically bound particles was demonstrated experimentally with an instrument, cell tracking velocimeter, CTV, and it is demonstrated that the sensitivity of the CTV instrument for Fe atoms contained in magnetic nanoparticles on the order of 1 × 10^?15 g/mL of Fe. Biotechnol. Bioeng. 2010;105: 1078–1093. © 2009 Wiley Periodicals, Inc.     

Effects of the beta‐adrenergic receptor antagonist Propranolol on dyskinesia and L‐DOPA‐induced striatal DA efflux in the hemi‐parkinsonian rat

Dopamine (DA) replacement therapy with L‐DOPA continues to be the primary treatment of Parkinson's disease; however, long‐term therapy is accompanied by L‐DOPA‐induced dyskinesias (LID). Several experimental and clinical studies have established that Propranolol, a β‐adrenergic receptor antagonist, reduces LID without affecting L‐DOPA's efficacy. However, the exact mechanisms underlying these effects remain to be elucidated. The aim of this study was to evaluate the anti‐dyskinetic profile of Propranolol against a panel of DA replacement strategies, as well as elucidate the underlying neurochemical mechanisms. Results indicated that Propranolol, in a dose‐dependent manner, reduced LID, without affecting motor performance. Propranolol failed to alter dyskinesia produced by the D₁ receptor agonist, SKF81297 (0.08 mg/kg, sc), or the D₂ receptor agonist, Quinpirole (0.05 mg/kg, sc). These findings suggested a pre‐synaptic mechanism for Propranolol's anti‐dyskinetic effects, possibly through modulating L‐DOPA‐mediated DA efflux. To evaluate this possibility, microdialysis studies were carried out in the DA‐lesioned striatum of dyskinetic rats and results indicated that co‐administration of Propranolol (20 mg/kg, ip) was able to attenuate L‐DOPA‐ (6 mg/kg, sc) induced DA efflux. Therefore, Propranolol's anti‐dyskinetic properties appear to be mediated via attenuation of L‐DOPA‐induced extraphysiological efflux of DA.

     

Long non‐coding RNAs in non‐small cell lung cancer as biomarkers and therapeutic targets

Lung cancer‐associated mortality is the most common cause of cancer death worldwide. Non‐coding RNAs (ncRNAs), with no protein‐coding ability, have multiple biological roles. Long non‐coding RNAs (lncRNAs) are a recently characterized class of ncRNAs that are over 200 nucleotides in length. Many lncRNAs have the ability of facilitating or inhibiting the development and progression of tumours, including non‐small cell lung cancer (NSCLC). Because of their fundamental roles in regulating gene expression, along with their involvement in the biological mechanisms underlying tumourigenesis, they are a promising class of tissue‐ and/or blood‐based cancer biomarkers. In this review, we highlight the emerging roles of lncRNAs in NSCLC, and discuss their potential clinical applications as diagnostic and prognostic markers and as therapeutic targets.     

The α2 adrenoceptor antagonist idazoxan alleviates l‐DOPA‐induced dyskinesia by reduction of striatal dopamine levels: an in vivo microdialysis study in 6‐hydroxydopamine‐lesioned rats

l ‐DOPA‐induced dyskinesia is characterised by debilitating involuntary movement, which limits quality of life in patients suffering from Parkinson’s disease. Here, we investigate effects of the α₂ adrenoceptor antagonist idazoxan on l ‐DOPA‐induced dyskinesia as well as on alterations of extracellular l ‐DOPA and dopamine (DA) levels in the striatum in dyskinetic rats. Male Wistar rats were unilaterally lesioned with 6‐hydroxydopamine and subsequently treated with l ‐DOPA/benserazide to induce stable dyskinetic movements. Administration of idazoxan [(9 mg/kg, intraperitoneal (i.p.)] significantly alleviated l ‐DOPA‐induced dyskinesia, whereas idazoxan (3 mg/kg, i.p.) did not affect dyskinetic behaviour. Bilateral in vivo microdialysis revealed that idazoxan 9 mg/kg reduces extracellular peak l ‐DOPA levels in the lesioned and intact striatum as well as DA levels in the lesioned striatum. In parallel, the exposure to idazoxan in the striatum was monitored. Furthermore, no idazoxan and l ‐DOPA drug–drug interaction was found in plasma, brain tissue and CSF. In conclusion, the decrease of l ‐DOPA‐derived extracellular DA levels in the lesioned striatum significantly contributes to the anti‐dyskinetic effect of idazoxan.