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Introduction Despite policies setting a minimum legal sales age, youth continue to access electronic cigarettes (ECs). Evidence of rising youth vaping prevalence in many countries suggests existing measures have serious loopholes and raise important questions about how youth source vaping products. Aims and Methods We explored how youth source ECs using in-depth interviews with 30 adolescents aged 16–17 who vaped at least once a month and lived in Aotearoa New Zealand. Our semistructured interview guide probed participants' vaping experiences and how they developed and used social, quasi-commercial, and commercial supply routes to access ECs. We used an inductive reflexive thematic analysis approach to interpret the data. Results Nearly all participants shared ECs with peers and sharing was the sole access route for some. Many used proxies, often older relatives or people they knew socially, to purchase ECs on their behalf; however, others recruited proxies by approaching previously unknown people they identified on social media. Participants also sourced ECs via quasi-commercial networks that existed within schools and on social media, and some purchased in their own right, usually from smaller retail outlets that did not ask for ID. Conclusions Disrupting social supply will be challenging, though reducing ECs' availability, appeal, and affordability could make social supply, including sharing and proxy purchasing, more difficult. Reports that youth purchase ECs from commercial retailers known to waive age verification suggest stronger monitoring and enforcement, along with escalating retailer penalties, are required. Implications Vaping access routes sit on a continuum from informal, spontaneous sharing to carefully planned commercial purchases. While supply via friends, siblings and other social contacts is an important means of access, nicotine dependence drives some to use riskier access routes, including approaching unknown people to act as proxy purchasers. Evidence young people identify noncompliant retailers suggests policy makers should monitor and enforce existing measures more stringently and consider additional penalties for recidivist underage suppliers. A more comprehensive response that reduces the appeal, addictiveness, affordability, and availability of vaping products would address factors fostering and maintaining youth vaping. [ABSTRACT FROM AUTHOR]

Non-invasive brain stimulation is designed to target accessible brain regions that underlie many psychiatric disorders. One such method, transcranial magnetic stimulation (TMS), is commonly used in patients with treatment-resistant depression (TRD). However, for non-responders, the choice of an alternative therapy is unclear and often decided empirically without detailed knowledge of precise circuit dysfunction. This is also true of invasive therapies, such as deep brain stimulation (DBS), in which responses in TRD patients are linked to circuit activity that varies in each individual. If the functional networks affected by these approaches were better understood, a theoretical basis for selection of interventions could be developed to guide psychiatric treatment pathways. The mechanistic understanding of TMS is that it promotes long-term potentiation of cortical targets, such as dorsolateral prefrontal cortex (DLPFC), which are attenuated in depression. DLPFC is highly interconnected with other networks related to mood and cognition, thus TMS likely alters activity remote from DLPFC, such as in the central executive, salience and default mode networks. When deeper structures such as subcallosal cingulate cortex (SCC) are targeted using DBS for TRD, response efficacy has depended on proximity to white matter pathways that similarly engage emotion regulation and reward. Many have begun to question whether these networks, targeted by different modalities, overlap or are, in fact, the same. A major goal of current functional and structural imaging in patients with TRD is to elucidate neuromodulatory effects on the aforementioned networks so that treatment of intractable psychiatric conditions may become more predictable and targeted using the optimal technique with fewer iterations. Here, we describe several therapeutic approaches to TRD and review clinical studies of functional imaging and tractography that identify the diverse loci of modulation. We discuss differentiating factors associated with responders and non-responders to these stimulation modalities, with a focus on mechanisms of action for non-invasive and intracranial stimulation modalities. We advance the hypothesis that non-invasive and invasive neuromodulation approaches for TRD are likely impacting shared networks and critical nodes important for alleviating symptoms associated with this disorder. We close by describing a therapeutic framework that leverages personalized connectome-guided target identification for a stepwise neuromodulation paradigm. [ABSTRACT FROM AUTHOR]

Non-invasive brain stimulation is designed to target accessible brain regions that underlie many psychiatric disorders. One such method, transcranial magnetic stimulation (TMS), is commonly used in patients with treatment-resistant depression (TRD). However, for non-responders, the choice of an alternative therapy is unclear and often decided empirically without detailed knowledge of precise circuit dysfunction. This is also true of invasive therapies, such as deep brain stimulation (DBS), in which responses in TRD patients are linked to circuit activity that varies in each individual. If the functional networks affected by these approaches were better understood, a theoretical basis for selection of interventions could be developed to guide psychiatric treatment pathways. The mechanistic understanding of TMS is that it promotes long-term potentiation of cortical targets, such as dorsolateral prefrontal cortex (DLPFC), which are attenuated in depression. DLPFC is highly interconnected with other networks related to mood and cognition, thus TMS likely alters activity remote from DLPFC, such as in the central executive, salience and default mode networks. When deeper structures such as subcallosal cingulate cortex (SCC) are targeted using DBS for TRD, response efficacy has depended on proximity to white matter pathways that similarly engage emotion regulation and reward. Many have begun to question whether these networks, targeted by different modalities, overlap or are, in fact, the same. A major goal of current functional and structural imaging in patients with TRD is to elucidate neuromodulatory effects on the aforementioned networks so that treatment of intractable psychiatric conditions may become more predictable and targeted using the optimal technique with fewer iterations. Here, we describe several therapeutic approaches to TRD and review clinical studies of functional imaging and tractography that identify the diverse loci of modulation. We discuss differentiating factors associated with responders and non-responders to these stimulation modalities, with a focus on mechanisms of action for non-invasive and intracranial stimulation modalities. We advance the hypothesis that non-invasive and invasive neuromodulation approaches for TRD are likely impacting shared networks and critical nodes important for alleviating symptoms associated with this disorder. We close by describing a therapeutic framework that leverages personalized connectome-guided target identification for a stepwise neuromodulation paradigm.

Background: Longitudinal studies report associations between use of electronic cigarettes (ECs) and cigarettes over time among young people, but do not distinguish within- from between-person effects, which complicates interpretation of findings. Further, the role of shared risk factors, such as substance use and mental health, in explaining longitudinal associations between EC and cigarette use remains unclear. This study used within- and between-person analyses to assess longitudinal associations between youths' EC and cigarette use and shared risk factors.Methods: Between 2015 and 2017, 2039 youths completed three Web-based surveys, allowing us to model EC and cigarette use from ages 16 to 20. Auto-regressive latent growth models with structured residuals (ALT-SR) examined both between-person and within-person associations between past-month frequency of EC use, cigarette use, and third variables (alcohol and marijuana use, mental health symptoms) over time.Results: Models revealed robust reciprocal associations between EC and cigarette use, such that more frequent EC use at one time predicted more frequent cigarette use at the subsequent time, and vice versa. Between-person analyses showed associations between shared risk factors and both EC and cigarette use. However, shared risk factors did not predict frequency of subsequent EC and cigarette use in within-person analyses.Conclusions: Findings add to a growing body of research suggesting that EC use among youth is prospectively associated with progression toward greater cigarette use. Shared risk factors may help explain differences in EC and cigarette use patterns between young people, but do not appear to influence longitudinal trajectories of EC and cigarette use within individuals.Implications: This study examined within- and between-person associations between e-cigarette use, cigarette use, and shared risk factors (alcohol use, marijuana use, mental health symptoms) in a longitudinal cohort of youths. Within- and between-person analyses revealed reciprocal prospective associations between e-cigarette and cigarette use, suggesting a progression toward more frequent use of both products over time. The shared risk factors examined here did not affect escalations in e-cigarette or cigarette use over time within individuals, but likely influence which youths use these products. Findings add to a growing body of evidence suggesting that e-cigarette use increases subsequent cigarette use in young people. [ABSTRACT FROM AUTHOR]

Introduction: Electronic cigarettes (ECs) seem to be a less harmful alternative for conventional cigarettes. This study aimed to assess whether the generated aerosols from ECs contain lower amount of cadmium (Cd) and lead (Pb) than cigarette smoke and to detect any changes in exposure to Cd and Pb among cigarette smokers who switched completely or partially to EC.Methods: EC aerosols and cigarette smoke were generated, and the determination of Cd and Pb in trapped samples and e-liquids was performed by the electrothermal atomic absorption spectrometry method. A cross-sectional, group-based survey was carried out using 156 volunteers classified into groups of nonsmokers, EC-only users, dual EC users-cigarette smokers, and cigarette-only smokers. Using electrothermal atomic absorption spectrometry, blood Cd and Pb levels were measured, and the results were compared by analysis of covariance.Results: Transfer of Cd and Pb to EC aerosol was found to be minimal, although the metals were present in the remaining e-liquid from tanks used for vapor generation. The geometric mean blood Cd concentration adjusted for age and sex was 0.44 (95% confidence interval = 0.37 to 0.52) µg/L in the EC-only users, which was significantly lower than those in the smokers of 1.44 (1.16 to 1.78) and dual users of 1.38 (1.11 to 1.72). The blood Pb geometric mean differed significantly only between nonsmokers of 11.9 (10.6 to 13.3) and smokers of 15.9 (13.6 to 18.6).Conclusion: The study revealed that smokers who completely switched to ECs and quit smoking conventional cigarettes may significantly reduce their exposure to Cd and probably Pb.Implications: Switching to EC use is associated with a rapid and substantial decrease in the exposure to carcinogenic Cd. Exposure to Pb is probably also decreased but may be overshadowed by other factors. The study provides empirical data based not only on the analysis of generated aerosol but also on biological indicators of recent exposure-that is, the concentrations of Cd and Pb in blood, indicating EC as a potential harm-reduction device, especially regarding Cd exposure. However, in this case, dual EC use-cigarette smoking provides doubtful benefits. [ABSTRACT FROM AUTHOR]

Introduction: The aerosol composition of electronic cigarettes (ECs) suggests that exposure to toxicants during use is greatly reduced compared to exposure from combustible cigarettes (CCs).Methods: This randomized, parallel-group, clinical study enrolled smokers to switch to Vuse Solo (VS) Digital Vapor Cigarettes (Original or Menthol) or Nicorette 4 mg nicotine gum (NG) in a controlled setting. Subjects who smoked CCs ad libitum for 2 days during a baseline period were then randomized to ad libitum use of either VS or NG for 5 days. Biomarkers of 23 toxicants were measured in 24-hour urine samples and blood collected at baseline and following product switch.Results: A total of 153 subjects completed the study. Total nicotine equivalents decreased in all groups, but higher levels were observed in the VS groups compared to the NG groups, with decreases of 38% and 60%-67%, respectively. All other biomarkers were significantly decreased in subjects switched to VS, and the magnitude of biomarker decreases was similar to subjects switched to NG. Decreases ranged from 30% to greater than 85% for constituents such as benzene and acrylonitrile.Conclusions: These results indicate that exposure to toxicants when using VS is significantly reduced compared to CC smoking, and these reductions are similar to those observed with use of NG. Although statistically significantly decreased, nicotine exposure is maintained closer to CC smoking with VS use compared to NG use. This research suggests that use of VS exposes consumers to fewer and lower levels of smoke toxicants than CCs while still providing nicotine to the consumer.Implications: This is the first study to report changes in nicotine delivery and biomarkers of tobacco exposure following a short-term product switch from CCs to either an EC or NG in a controlled environment. The study shows that nicotine exposure decreased in both groups but was maintained closer to CC smoking with the EC groups. Biomarkers of tobacco combustion decreased to similar levels in both EC and gum groups. [ABSTRACT FROM AUTHOR]

Introduction: The demand for alternative nicotine/tobacco products is not well established. This paper uses a behavioral economic approach to test whether smokers have differential demand for conventional factory-made, electronic, and very low nicotine content cigarettes (FMCs/ECs/VLNCs) and uses the prospective cohort design to test the predictive validity of demand indices on subsequent use of commercially available FMCs and ECs.Methods: Daily smokers (≥16 years) from the Netherlands completed an online survey in April 2014 (N = 1215). Purchase tasks were completed for FMCs, ECs, and VLNCs. Participants indicated the number of cigarettes they would consume in 24 h, across a range of prices (0-30 euro). The relationship between consumption and price was quantified into four indices of demand (intensity, Pmax, breakpoint, and essential value). A follow-up survey in July 2015 measured FMC and EC use.Results: At baseline, greater demand was observed for FMCs relative to ECs and VLNCs across all demand indices, with no difference between ECs and VLNCs. At follow-up, greater baseline FMC demand (intensity, essential value) was associated with lower quit rates and higher relapse. EC demand (Pmax, breakpoint, essential value) was positively associated with any EC use between survey waves, past 30 day EC use, and EC purchase between waves.Conclusions: Smokers valued FMCs more than ECs or VLNCs, and FMCs were less sensitive to price increases. Demand indices predicted use of commercially available products over a 15 month period. To serve as viable substitutes for FMCs, ECs and VLNCs will need to be priced lower than FMCs.Implications: Purchase tasks can be adapted for novel nicotine/tobacco products as a means to efficiently quantify demand and predict use. Among current daily smokers, the demand for ECs and VLNCs is lower than FMCs. [ABSTRACT FROM AUTHOR]

Given the increasing popularity of electronic cigarettes (ECs) and a lack of regulation of EC advertising, this study aimed to analyse online videos promoting ECs to assess the main marketing messages that could influence consumers' perceptions of associated risks and benefits. A web search of EC advertising videos was performed on YouTube by using keywords related to EC promotion. An evaluation grid was used to analyse promotional messages contained in each video. The most frequent promotional messages were related to health benefits (67.7%) and to the possibility of quitting smoking (57.4%). Messages that could also be appealing to adolescents and young adults, such as those promoting the multiple flavors available and the technological improvement of ECs, were present in 41.2% and 42.7% of the videos respectively. ECs similar to traditional cigarettes in appearance were included in 52.9% of the videos. EC promotional videos address messages not only to smokers who want to quit or decrease tobacco consumption but also to nonsmokers, especially young people. The use of ECs similar to traditional cigarettes may be a gateway to tobacco cigarette use. Since EC use may represent an important public health concern, regulatory policies on EC advertising should be established. [ABSTRACT FROM AUTHOR]

The use of electronic cigarettes (ECs) has been on the rise with increased number of battery explosions causing burns. This study is a retrospective review of patients who presented with burns caused by EC explosions.Here, we present a case series of eight patients sustaining burns from EC explosions, within a year, to elucidate the pattern of such burns and to provide a treatment guideline.All of them were males. Five patients had partial-thickness burns and three had full-thickness burns. TBSA ranged from 4 to 16% (burns to lower extremity [n = 7], hand [n =3], scrotum/penis [n =2], chest [n = 1]). None had inhalation injuries. Two patients (29%) required skin grafting. EC explosion is predominantly attributed to its lithium-ion battery. Several types of injuries can occur, including chemical and thermal burns, inhalation injuries, metal poisoning, etc. There are currently no specific guidelines on the management of burns due to lithium-ion battery exposure. Herein, we recommend the following: Initial assessment of injuries should accompany the Advanced Trauma Life Support guidelines; serum levels of lithium, cobalt, and manganese should be checked and elevated levels should be monitored; patients should be monitored for signs of metal toxicity; wound should be extensively debrided and irrigated to remove any residual materials; and litmus test should be performed to check for alkali pH prior to irrigation with water or other aqueous solutions. [ABSTRACT FROM AUTHOR]

Introduction: The purpose was to measure nicotine levels to the tobacco and levels emitted to the aerosol of a heat-not-burn product (HnB, IQOS) compared to e-cigarettes (ECs) and a tobacco cigarette.Methods: The HnB device and regular and menthol sticks were purchased from Italy. Three types of ECs (ciga-like, eGo-style, and variable wattage) and a commercially-available tobacco cigarette were also tested. A custom-made liquid containing 2% nicotine was used with ECs. Products were tested using Health Canada Intense puffing regime while HnB and ECs were additionally tested using a 4-second puff duration regime while maintaining the same puff volume.Results: Nicotine content in HnB regular and menthol tobacco sticks was 15.2 ± 1.1 mg/g and 15.6 ± 1.7 mg/g tobacco respectively. The levels of nicotine to the aerosol were similar for regular and menthol HnB products (1.40 ± 0.16 and 1.38 ± 0.11 mg/12 puffs respectively) and did not change significantly with prolonged puff duration. The tobacco cigarette delivered the highest level of nicotine (1.99 ± 0.20 mg/cigarette), with levels being higher than HnB and ECs under Health Canada Intense regime but similar to eGo-style and variable wattage ECs at prolonged puff duration regime.Conclusions: The HnB product delivers nicotine to the aerosol at levels higher than ECs but lower than a tobacco cigarette when tested using Health Canada Intense puffing regime. No change in HnB nicotine delivery was observed at prolonged puff duration with the same puff volume, unlike ECs which deliver more nicotine with longer puff duration.Implications: Nicotine delivery to the smoker is expected to play an important role in the ability of any harm-reduction product to successfully substitute smoking. This study evaluated the content and nicotine delivery to the aerosol of a heat-not-burn tobacco product (IQOS) in comparison with e-cigarettes and a tobacco cigarette. The main findings were that the heat-not-burn tobacco sticks contained similar nicotine concentration to tobacco cigarettes, and that the levels of nicotine delivered to the aerosol of the heat-not-burn products were lower than tobacco cigarette, higher than e-cigarettes at low puff duration but lower than high-power e-cigarettes at longer puff duration. [ABSTRACT FROM AUTHOR]

Background: Electronic cigarettes (ECs) can influence nicotine addiction by delivering aerosolized nicotine. We investigated if nicotine from ECs is delivered to the brain β2*-nicotinic acetylcholine receptors (β2*-nAChR) and how this relates to the behavioral effects and nicotine delivery from cigarettes.Methods: Seven nicotine users participated in positron emission tomography (PET) studies with (-)-[18F]Flubatine before and after nicotine challenge with 0, 8, and 36 mg/ml nicotine in a 3.3 Volt, 1.5 Ohm EC or a standard tobacco cigarette. Craving was evaluated before and after product use.Results: Average β2*-nAChR occupancy was higher after 36 mg/ml EC challenge compared to 8 mg/ml EC at trend level. Average β2*-nAChR occupancy after tobacco cigarette smoking was 68 ± 18% and was not different compared with 8 mg/ml (64 ± 17%,) or 36 mg/ml (84 ± 3%) nicotine in EC users. Area under the curve (AUC) of blood nicotine level was higher in the cigarette smoking group compared with the 8mg/ml group (p = 0.03), but similar compared with the 36 mg/ml EC (p = 0.29). Drug craving was reduced after use of the tobacco cigarette, 8 mg/ml EC, and 36 mg/ml EC.Conclusions: In this novel investigation of EC effects at β2*-nAChRs, we show that average β2*-nAChR occupancy was higher after 36 mg/ml EC challenge compared with 8 mg/ml EC. Receptor occupancy and arterial blood nicotine levels after cigarette smoking were similar to 36 mg/ml EC use under controlled conditions. These findings suggest that the ECs studied here have abuse liability and may provide an adequate alternative nicotine delivery system for cigarette smokers.Implications: This is the first study to directly determine the neurologic effects of electronic cigarettes on human brain beta-2 nicotinic acetylcholine receptors using PET neuroimaging with (-)-[18F]Flubatine, a novel radiotracer. Our findings suggest that the e-cigarettes studied here have abuse liability and may provide an adequate alternative nicotine delivery system for cigarette smokers. [ABSTRACT FROM AUTHOR]

Background: There is considerable debate about the benefits and risks of electronic cigarettes (ECs). To better understand the risk-benefit ratio of ECs, more information is needed about net nicotine consumption and toxicant exposure of cigarette smokers switching to ECs.Methods: Forty cigarette smokers (≥1 year of smoking) interested in switching to ECs but not necessarily quitting smoking were enrolled in a 4-week observational study and provided an e-Go C non-variable battery and refillable atomizers and choice of eight flavors in 12 or 24 mg nicotine dosage. Measurement of urinary cotinine (metabolite of nicotine), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL; a pulmonary carcinogen), and eight volatile organic compounds (VOCs) that are toxic tobacco smoke constituents was conducted at baseline and week 4.Results: All participants with follow-up data (92.5%) reported using the study EC. Of the 40 smokers, 16 reported no cigarettes at week 2 (40%) and six continued to report no cigarettes at week 4 (15%). Change in nicotine intake over the 4 weeks was non-significant (p = .90). Carbon monoxide (p < .001), NNAL (p < .01) and metabolites of benzene (p < .01) and acrylonitrile (p = .001) were significantly decreased in the study sample. Smokers switching exclusively to ECs for at least half of the study period demonstrated significant reductions in metabolites of ethylene oxide (p = .03) and acrylamide (p < .01).Conclusion: Smokers using ECs over 4 weeks maintained cotinine levels and experienced significant reductions in carbon monoxide, NNAL, and two out of eight measured VOC metabolites. Those who switched exclusively to ECs for at least half of the study period significantly reduced two additional VOCs.Implications: This study extends current literature by measuring change in smoking dependence and disease-associated biomarkers, NNAL and a panel of eight common VOCs that are toxic tobacco smoke constituents in smokers who switch to ECs. The findings support the idea of harm reduction, however some levels of toxicant exposure are still of clinical concern, particularly for dual users. Extrapolation of these results must be careful to separate the different toxic exposure results for exclusive switchers versus dual cigarette + EC users, and not to equate harm reduction with the idea that using ECs is harmless. [ABSTRACT FROM AUTHOR]

Intratumoral heterogeneity greatly hinders efficiency of target therapy in glioblastoma (GBM). To decipher the underlying mechanisms of heterogeneity, patient-derived adult GBM cells were separately isolated from margins of T1 gadolinium enhancing tumor lesions (PNCs) and T1 gadolinium enhancing core lesions (ECs). Single clone culture was conducted in ECs and U87MG cell line to screen clones with distinct biological phenotypes. Single cell clones with diverse phenotypes were simultaneously separated from ECs and U87 cell line. PNCs, GCs(H) and U87(H) exhibited longer cellular protrusion than ECs, GCs(L) and U87(L), respectively. Cell strains with longer protrusion exhibited higher invasive ability and lower sensitivity to temozolomide (TMZ) and radiation. Subsequently, TPD52L2 was verified as the functional protein to regulate the cellular heterogeneity by the proteomics analysis. Downregulation of TPD52L2 enhanced cell invasion whereas inhibited cell proliferation rate and sensitivity to chemotherapy in vivo and in vitro, this condition was reversed when TPD52L2 was overexpressed. The invasiveness was facilitated by up-regulating CTNNB1/β-catenin and SNAI1/Snail mediated EMT process. In addition, the clinical data of 88 GBM cases in our neurosurgery center was analyzed to reveal the influence of TPD52L2 in the prognosis of GBM. Low expression of TPD52L2 exacerbated prognosis of GBM patients received standard radiotherapy plus concomitant and adjuvant TMZ (Stupp strategy). Taken together, TPD52L2 is an important biomarker influencing GBM prognosis. [ABSTRACT FROM AUTHOR]

Cortical stimulation mapping is a valuable tool to test the functional organization of the motor cortex in both basic neurophysiology (e.g., elucidating the process of motor plasticity) and clinical practice (e.g., before resecting brain tumors involving the motor cortex). However, compilation of motor maps based on the motor threshold (MT) requires a large number of cortical stimulations and is therefore time consuming. Shortening the time for mapping may reduce stress on the subjects and unveil short-term plasticity mechanisms. In this study, we aimed to establish a cortical stimulation mapping procedure in which the time needed to identify a motor area is reduced to the order of minutes without compromising reliability. We developed an automatic motor mapping system that applies epidural cortical surface stimulations (CSSs) through one-by-one of 32 micro-electrocorticographic electrodes while examining the muscles represented in a cortical region. The next stimulus intensity was selected according to previously evoked electromyographic responses in a closed-loop fashion. CSS was repeated at 4 Hz and electromyographic responses were submitted to a newly proposed algorithm estimating the MT with smaller number of stimuli with respect to traditional approaches. The results showed that in all tested rats (n = 12) the motor area maps identified by our novel mapping procedure (novel MT algorithm and 4-Hz CSS) significantly correlated with the maps achieved by the conventional MT algorithm with 1-Hz CSS. The reliability of the both mapping methods was very high (intraclass correlation coefficients ≧0.8), while the time needed for the mapping was one-twelfth shorter with the novel method. Furthermore, the motor maps assessed by intracortical microstimulation and the novel CSS mapping procedure in two rats were compared and were also significantly correlated. Our novel mapping procedure that determined a cortical motor area within a few minutes could help to study the functional significance of short-term plasticity in motor learning and recovery from brain injuries. Besides this advantage, particularly in the case of human patients or experimental animals that are less trained to remain at rest, shorter mapping time is physically and mentally less demanding and might allow the evaluation of motor maps in awake individuals as well.

Ultrasound (US) is known to non-invasively stimulate and modulate brain function; however, the mechanism of action is poorly understood. This study tested US stimulation of rat motor cortex (100 W/cm2, 200 kHz) in combination with epidural cortical stimulation. US directly evoked hindlimb movement. This response occurred even with short US bursts (3 ms) and had short latency (10 ms) and long refractory (3 s) periods. Unexpectedly, the epidural cortical stimulation hindlimb response was not altered during the 3-s refractory period of the US hindlimb response. This finding suggests that the US refractory period is not a general suppression of motor cortex, but rather the recovery time of a US-specific mechanism. [ABSTRACT FROM AUTHOR]

Stroke leads to serious long-term disability. Electrical epidural cortical stimulation has made significant improvements in stroke rehabilitation therapy. We developed a preliminary wireless implantable passive interface, which consists of a stimulating surface electrode, receiving coil, and single flexible passive demodulated circuit printed by flexible printed circuit (FPC) technique and output pulse voltage stimulus by inductively coupling an external circuit. The wireless implantable board was implanted in cats' unilateral epidural space for electrical stimulation of the primary visual cortex (V1) while the evoked responses were recorded on the contralateral V1 using a needle electrode. The wireless implantable board output stable monophasic voltage stimuli. The amplitude of the monophasic voltage output could be adjusted by controlling the voltage of the transmitter circuit within a range of 5-20 V. In acute experiment, cortico-cortical evoked potential (CCEP) response was recorded on the contralateral V1. The amplitude of N2 in CCEP was modulated by adjusting the stimulation intensity of the wireless interface. These results demonstrated that a wireless interface based on a microcoil array can offer a valuable tool for researchers to explore electrical stimulation in research and the dura mater-electrode interface can effectively transmit electrical stimulation. [ABSTRACT FROM AUTHOR]

Background Epidural prefrontal cortical stimulation (EpCS) represents a novel therapeutic approach with many unique benefits that can be used for treatment-resistant depression (TRD). Objective To examine the long-term safety and efficacy of EpCS of the frontopolar cortex (FPC) and dorsolateral prefrontal cortex (DLPFC) for treatment of TRD. Methods Adults ( N  = 5) who were 21–80 years old with severe TRD [failure to respond to adequate courses of at least 4 antidepressant medications, psychotherapy and ≥20 on the Hamilton Rating Scale for Depression (HRSD24)] were recruited. Participants were implanted with bilateral EpCS over the FPC and DLPFC and received constant, chronic stimulation throughout the five years with Medtronic IPGs. They were followed for 5 years (2/1/2008–10/14/2013). Efficacy of EpCS was assessed with the HRSD24 in an open-label design as the primary outcome measure at five years. Results All 5 patients continued to tolerate the therapy. The mean improvements from pre-implant baseline on the HRSD24 were [7 months] 54.9% (±37.7), [1 year] 41.2% (±36.6), [2 years] 53.8% (±21.7), and [5 years] 45% (±47). Three of 5 (60%) subjects continued to be in remission at 5 years. There were 5 serious adverse events: 1 electrode ‘paddle’ infection and 4 device malfunctions, all resulting in suicidal ideation and/or hospitalization. Conclusion These results suggest that chronic bilateral EpCS over the FPC and DLPFC is a promising and potentially durable new technology for treating TRD, both acutely and over 5 years. [ABSTRACT FROM AUTHOR]

Stroke is a leading cause of disability, and the number of stroke survivors continues to rise. Traditional neurorehabilitation strategies aimed at restoring function to weakened limbs provide only modest benefit. New brain stimulation techniques designed to augment traditional neurorehabilitation hold promise for reducing the burden of stroke-related disability. Investigators discovered that repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and epidural cortical stimulation (ECS) can enhance neural plasticity in the motor cortex post-stroke. Improved outcomes may be obtained with activity-dependent stimulation, in which brain stimulation is contingent on neural or muscular activity during normal behavior. We review the evidence for improved motor function in stroke patients treated with rTMS, tDCS, and ECS and discuss the mediating physiological mechanisms. We compare these techniques to activity-dependent stimulation, discuss the advantages of this newer strategy for stroke rehabilitation, and suggest future applications for activity-dependent brain stimulation. [ABSTRACT FROM AUTHOR]

Background: Treatment-resistant depression presents a serious challenge to both patients and clinicians. The anterior and midlateral prefrontal cortices play complementary roles in integrating emotional and cognitive experiences and in modulating subcortical regions. Both regions offer a distinct opportunity for targeted antidepressant treatments. We chose to pilot the safety and therapeutic benefits of chronic and intermittent epidural prefrontal cortical stimulation (EpCS) in patients with treatment-resistant depression. Methods: We enrolled five adults with an average of 5.8 failed antidepressant treatments in their current depressive episode. All subjects underwent comprehensive clinical assessments, detailed neuropsychological testing, and presurgical magnetic resonance imaging. Four cortical stimulation paddle leads were stereotactically placed bilaterally over the anterior frontal poles and midlateral prefrontal cortex. We also acquired a postsurgical computed tomography scan and repeatedly assessed clinical outcomes over time of EpCS as an adjunctive treatment to constant medications. Results: All patients tolerated the therapy. At 7-month follow-up, the average improvement from preimplant baseline on the Hamilton Rating Scale for Depression and the Inventory of Depressive Symptoms—Self-Report were 54.9% (± 37.7) and 60.1% (± 34.1), respectively. Three implanted subjects reached remission. One patient''s left hemisphere leads were explanted 12 weeks postsurgery because of a scalp infection. Conclusions: Bilateral EpCS over anterior and midlateral frontal cortex is a promising new technology for treatment-resistant depression. Future double-blind studies are warranted. [Copyright &y& Elsevier]

Summary: In the nineties, epidural cortical stimulation (ECS) of precentral region has been performed to treat drug-resistant neuropathic pain and repetitive transcranial magnetic stimulation (rTMS) of prefrontal region has shown antidepressant effects in episodes of major depression. These were among the first attempts to treat neurological or psychiatric disorders with cortical stimulation. Actually, a variety of invasive and noninvasive techniques of cortical stimulation could serve therapeutic purpose, including ECS, rTMS, but also transcranial electrical stimulation using pulsed currents (TCES) or direct currents (tDCS). This review presents the methods of therapeutic cortical stimulation that are currently applicable and some of their principles. In particular, it must be emphasized that the site(s) of action can be distant from the site of stimulation because axons with remote projections are more prone to be activated than local cell bodies. Hence, cortical stimulation may activate, inhibit or otherwise interfere with the activity of various cortico-subcortical networks, depending on stimulus frequency and intensity, current polarity, and the configuration of the induced electric field. Functional and clinical effects occur during or beyond the time of stimulation. The existence of after-effects relates to processes of synaptic plasticity induced by the stimulation. Cortical stimulation may also have neuroprotective effects against disease-related excitotoxic phenomena. Considering the multiple techniques and the various potential clinical indications, it is a challenge to determine the place of cortical stimulation in the treatment of neurological and psychiatric diseases, in particular by the side of deep brain stimulation. [Copyright &y& Elsevier]

Abstract: Among the alternatives to drugs in the treatment of neurological and psychiatric disorders, neuromodulation techniques, including brain stimulation, have been used increasingly this past decade. Cortical targets are especially appealing, because they are easily accessible by noninvasive or invasive methods. Applicable techniques include repetitive transcranial magnetic stimulation (rTMS), transcranial electrical stimulation using pulsed or direct current, and epidural cortical stimulation (ECS) with surgically implanted electrodes. In contrast to deep brain stimulation in movement disorders or electroconvulsive therapy in depression, the efficacy of cortical stimulation to treat neurological or psychiatric disorders has not been yet clearly demonstrated. However, encouraging results have been reported in neuropathic pain (for ECS) and depression (for rTMS). In this review, we will consider some principles and mechanisms of action of these methods. First, it must be noted that fibers of intracortical or cortico-subcortical networks are more prone to be activated by the stimulation than cell bodies of local cortical neurons. Hence, the site(s) of action may be distant from the site of stimulation. In addition, various parameters of stimulation (such as stimulation frequency, intensity, or electrode polarity) and the configuration of the induced electrical field greatly influence the nature of the recruited circuits, and therefore, the overall efficacy. Finally, clinical changes may be delayed and prolonged beyond the time of stimulation, complicating programming algorithms in the case of implanted stimulation device. All these features need to be taken into account when considering cortical stimulation as a method of treatment. [Copyright &y& Elsevier]

Repetitive transcranial magnetic stimulation (rTMS) of the cerebral cortex is a noninvasive strategy that could have the potential to relieve severe chronic pain, at least partially and transiently. The most studied target of stimulation is the precentral (motor) cortex, but other targets, such as the dorsolateral prefrontal cortex or the parietal cortex, could be of interest. Analgesic effects have been produced by rTMS in patients with neuropathic pain, fibromyalgia or visceral pain. Therapeutic applications of rTMS in pain syndromes are limited by the short duration of the induced effects, but prolonged pain relief can be obtained by performing rTMS sessions every day for several weeks. In patients who respond to rTMS but relapse, surgical implantation of epidural cortical electrodes and a pulse generator can be proposed to make clinical effects more permanent. The rate of improvement produced by rTMS may be predictive for the outcome of the implanted procedure. The place of rTMS as a therapeutic tool in the management of chronic pain remains to be determined. [ABSTRACT FROM AUTHOR]

Motor cortex stimulation, either non-invasively or with implanted electrodes, has been applied worldwide as a treatment for intractable neuropathic pain syndromes. Although computer simulations of non-invasive brain stimulation have been investigated largely to optimize protocols and improve our understanding of underlying mechanisms using a realistic head model, computational studies of invasive cortical stimulation are rare and limited to very simplified cortical models. In this paper, we present an anatomically realistic head model for epidural cortical stimulation that includes the most sophisticated epidural electrodes with an insulating paddle. The head model predicted the stimulus-induced field strengths according to two different stimulation techniques, bipolar and monopolar stimulations. We found that the stimulus-induced field focused on the precentral and postcentral gyri because of the epidural lead's invasiveness. Different stimulation configurations influenced the shape of the field markedly, and complex patterns of inward and outward directions of the radial field were observed in bipolar stimulation compared to those in monopolar stimulation. The spatial distributions of field strength showed that the optimal stimulation varied according to the target areas. In conclusion, we proposed an anatomically realistic head model and a sophisticated epidural lead to simulate epidural cortical stimulation-induced field strengths and identified the importance of such detailed modeling for epidural cortical stimulation because of the current's shunting through the cerebrospinal fluid., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Neurological diseases severely affect the quality of life of patients. Although existing treatments including rehabilitative therapy aim to facilitate the recovery of motor function, achieving complete recovery remains a challenge. In recent years, regenerative therapy has been considered as a potential candidate that could yield complete functional recovery. However, to achieve desirable results, integration of transplanted cells into neural networks and generation of appropriate microenvironments are essential. Furthermore, considering the nascent state of research in this area, we must understand certain aspects about regenerative therapy, including specific effects, nature of interaction when administered in combination with rehabilitative therapy (regenerative rehabilitation), and optimal conditions. Herein, we review the current status of research in the field of regenerative therapy, discuss the findings that could hold the key to resolving the challenges associated with regenerative rehabilitation, and outline the challenges to be addressed with future studies. The current state of research emphasizes the importance of determining the independent effect of regenerative and rehabilitative therapies before exploring their combined effects. Furthermore, the current review highlights the progression in the treatment perspective from a state of compensation of lost function to that of a possibility of complete functional recovery. [ABSTRACT FROM AUTHOR]

Cortical stimulation mapping is a valuable tool to test the functional organization of the motor cortex in both basic neurophysiology (e.g., elucidating the process of motor plasticity) and clinical practice (e.g., before resecting brain tumors involving the motor cortex). However, compilation of motor maps based on the motor threshold (MT) requires a large number of cortical stimulations and is therefore time consuming. Shortening the time for mapping may reduce stress on the subjects and unveil short-term plasticity mechanisms. In this study, we aimed to establish a cortical stimulation mapping procedure in which the time needed to identify a motor area is reduced to the order of minutes without compromising reliability. We developed an automatic motor mapping system that applies epidural cortical surface stimulations (CSSs) through one-by-one of 32 micro-electrocorticographic electrodes while examining the muscles represented in a cortical region. The next stimulus intensity was selected according to previously evoked electromyographic responses in a closed-loop fashion. CSS was repeated at 4 Hz and electromyographic responses were submitted to a newly proposed algorithm estimating the MT with smaller number of stimuli with respect to traditional approaches. The results showed that in all tested rats ( n = 12) the motor area maps identified by our novel mapping procedure (novel MT algorithm and 4-Hz CSS) significantly correlated with the maps achieved by the conventional MT algorithm with 1-Hz CSS. The reliability of the both mapping methods was very high (intraclass correlation coefficients ≧0.8), while the time needed for the mapping was one-twelfth shorter with the novel method. Furthermore, the motor maps assessed by intracortical microstimulation and the novel CSS mapping procedure in two rats were compared and were also significantly correlated. Our novel mapping procedure that determined a cortical motor area within a few minutes could help to study the functional significance of short-term plasticity in motor learning and recovery from brain injuries. Besides this advantage, particularly in the case of human patients or experimental animals that are less trained to remain at rest, shorter mapping time is physically and mentally less demanding and might allow the evaluation of motor maps in awake individuals as well.

Stroke leads to serious long-term disability. Electrical epidural cortical stimulation has made significant improvements in stroke rehabilitation therapy. We developed a preliminary wireless implantable passive interface, which consists of a stimulating surface electrode, receiving coil, and single flexible passive demodulated circuit printed by flexible printed circuit (FPC) technique and output pulse voltage stimulus by inductively coupling an external circuit. The wireless implantable board was implanted in cats' unilateral epidural space for electrical stimulation of the primary visual cortex (V1) while the evoked responses were recorded on the contralateral V1 using a needle electrode. The wireless implantable board output stable monophasic voltage stimuli. The amplitude of the monophasic voltage output could be adjusted by controlling the voltage of the transmitter circuit within a range of 5-20 V. In acute experiment, cortico-cortical evoked potential (CCEP) response was recorded on the contralateral V1. The amplitude of N2 in CCEP was modulated by adjusting the stimulation intensity of the wireless interface. These results demonstrated that a wireless interface based on a microcoil array can offer a valuable tool for researchers to explore electrical stimulation in research and the dura mater-electrode interface can effectively transmit electrical stimulation.

Background: Nearly 15 million people suffer from stroke every year worldwide, with about 20% of the survivors retaining chronic aphasic symptoms. Spontaneous recovery is limited to 3 to 6 months. Cortical stimulation techniques have been proposed to enhance the recovery process., Objective: The goal of this study was to evaluate the benefit of epidural cortical stimulation for the treatment of poststroke aphasia, based on a systematic review of the literature., Methods: An extensive PubMed search was performed for English language articles published from 1990 to 2014 with the keywords (cortical OR epidural) AND stimulation AND stroke AND (aphasia OR language OR speech). The criteria analyzed included the type of study, epidemiology of patients, stroke, aphasia, stimulation protocol, concurrent rehabilitation therapies, language evaluations, results observed, and follow-up., Results: Seven cases were reported to date (3 case reports, 1 randomized controlled trial). All patients experienced nonfluent aphasia following an ischemic stroke. All four studies reported encouraging effects of the stimulation with improved lexical access and fluency for all patients. The effects were specific, independent of the motor recovery or of the pain reported by the patients, and they were linked to the stimulation parameters., Conclusions: Due to the small number of existing cases in the literature, the strength of the evidence is still low. Two main hypotheses of neurobiological mechanisms have been explored: either using continuous stimulation to modify cortical perilesional inhibition or using intermittent stimulation during the speech and language therapy sessions to explore synaptic plasticity and long-term potentiation or depression. To establish the role of epidural stimulation and the relevant stimulation protocols and parameters, large randomized controlled trials are mandatory. We suggest avenues of investigation., (© The Author(s) 2015.)

Invasive stimulation of the motor (precentral) cortex using surgically implanted epidural electrodes is indicated for the treatment of neuropathic pain that is refractory to medical treatment. Controlled trials have demonstrated the efficacy of epidural motor cortex stimulation (MCS), but MCS outcome remains variable and validated criteria for selecting good candidates for implantation are lacking. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive approach that could be used as a preoperative tool to predict MCS outcome and also could serve as a therapeutic procedure in itself to treat pain disorders. This requires repeated rTMS sessions and a maintenance protocol. Other studies have also demonstrated the efficacy of transcranial direct current stimulation (tDCS) in relieving chronic pain syndromes. The most studied target is the precentral cortex, but other targets, such as the prefrontal and parietal cortices, could be of interest. The analgesic effects of cortical stimulation relate to the activation of various circuits modulating neural activities in remote structures, such as the thalamus, limbic cortex, insula, or descending inhibitory controls. In addition to the treatment of refractory neuropathic pain by epidural MCS, new developments of this type of strategy are ongoing, for other types of pain syndrome and stimulation techniques., (© 2013 Elsevier B.V. All rights reserved.)