text:
The fashions, at their discretion, set the costs on videos. You can take pleasure in watching bought videos at any time you need. It is unlikely you each will reach the climax, maintaining silent. To begin talking to strangers in public chat, you have to create a free account. Sadly, your communication options finish at this point, and never every model permits chat free of charge members. However, when you flip right into a gold member (~$1.99) you should have a lot of the site features, together with non-public chat options, sharing your webcam with a model, adding new followers, and so on.
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Now you possibly can get pleasure from your gold membership, have personal chats with the fashions, share your webcam, and lots of different things obtainable for the premium members. What else can the intercourse business propose to you, you could wonder? Most probably, you'll be impressed to know that this toy can react to the room's surrounding sounds (music-driven vibrator).
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Members are constantly being prompted to buy tokens, together with other pop-ups throughout the location. When shopping model critiques of the location, most were negative. This implies that the vast majority of fashions set a token goal for his or her show that members tip in direction of if they need the present to advance. You can find nude intercourse reveals at their peak just by browsing via the assorted streams on Bongacams but who actually has time for that. Not to mention simply watching quite than directing the show is sorta boring.
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Camsoda Com
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You can type the chatrooms based on the variety of viewers and ensure that there are rooms with thousands of members vigorously exchanging messages with one another each second. Free chat rooms feature virtually all ranges of proclivities and many of the fashions perform in flesh for requests made by paying users. Couple rooms usually present the hosts performing all forms of reveals. That cam site of spygasm isn't even worth our or your time and so we're going to focus as an alternative on just bongacams as a end result of it's a a lot more frequented platform. Far and away, BongaCams is amongst the most popular webcam sex chat websites.
With girls, guys and chicks-with-dicks gracing the BongaCams chat rooms, your choice for chat hosts is solely top-class. In 'spy mode' you only get full spectating rights; any capacity to communicate with the model is restricted. Private chat is extra unique and these periods all have a set worth of 60 Tokens per minute.


text:
People's TonightSHOW ALL
Roque shrugs off criticism on joining int'l law body
PRESIDENTIAL Spokesperson Harry Roque has shrugged off as "bereft of legal merit" the criticism of a group of human rights lawyers opposing his nomination to be part of a United Nations (UN) expert panel that develops and codifies international law.
This, after the Free Legal Assistance Group (FLAG) wrote to the UN International Law Commission (ILC) in New York to voice their opposition to Roque's nomination, alleging he "does not possess the qualifications for a seat at the Commission".
"Wala po kasi desisyon naman 'yan ng mga estado. Kung pakikinggan sila ng estado, e di wala tayong magagawa," Roque said, when asked to react to FLAG's call for the rejection of his nomination.
Among other reasons, FLAG told to the ILC that Roque's pronouncements "defending extrajudicial killings and belittling the competence and jurisdiction of the International Criminal Court (ICC), and his cavalier disregard of the effects of domestic violations of human rights" as spokesperson of President Rodrigo Duterte makes him "ill-suited" to become a member of their panel.
Roque, however, said he has not ever shown blatant disrespect for the law and human rights as Duterte's spokesperson.
"That's absolutely bereft of legal merit po kasi kung mayroon 'yun, dapat may kaso na ako," he said.
Roque said his job of relaying information regarding issues and concerns related to the President is part of the freedom of information, which is also a human right.
"Naniniwala po ako na karamihan po, kung hindi po talaga malaking porsiyento ng ating mamamayan, ay nakikita naman po na ginagawa natin ng tama ang ating trabaho. FOI po or Freedom of Information ay isang karapatang pantao," he added.
He also said the ILC and ICC were two separate entities.
"Obviously gross ignorance of what the ILC is all about. Hiwalay po ang ILC sa ICC. Wala pong kinalaman ang ILC sa ICC," he said.
He said dozens of countries, including the Philippines, are not members of the ICC, including China, India, Russia, and even the United States (US).
"Kung ang kanilang dahilan ay dahil sa International Criminal Court, hindi po lahat ng bansa ay miyembro ng International Criminal Court. In fact, karamihan po ng boboto, hindi nga po sila miyembro ng International Criminal Court. Minorya po ng miyembro ng general assembly ang mga miyembro ng International Criminal Court," he added.
Roque's platform
Meanwhile, Roque revealed his platform should he be selected as among the 34 members of the ILC.
He said he will push for a treaty on "vaccine equality", emphasizing that it was "unacceptable" that nearly 85 percent of COVID-19 vaccines have gone to people in high-income countries.
"Kinakailangan po magkaroon tayo ng tratado kung saan ang lahat ng mga bansa sa daigdig ay magko-contribute sa isang pondo on the basis of ability to pay para bumili ng mga bakuna at ang mga bakunang ito naman ay ibibigay sa mga bansa depending on need," he said.
Roque will also pursue efforts to draft a treaty that recognizes ownership or jurisdiction over territories submerged in water as conclusive.
"Ang pangalawa ho nating tratado na sinasabi sa ating plataporma ay isang tratado kung saan kikilanin ng buong daigdig na yung mga teritoryong mawawala dahil po dun sa pagtaas ng ating karagatan dahil po sa global warming, dapat po yung teritoryo na lupa na nagbibigay din ng teritoryo sa ating karagatan ay maging conclusive, hindi na po dapat mabago miski malubog pa 'yan sa tubig," he added.
With his nomination, Roque has a chance of becoming one of eight nationals from Asia-Pacific states to sit for five years in the panel starting Jan 1, 2023.
Roque served as an associate professor at the University of the Philippines (UP) College of Law, teaching public international law and constitutional law for over 15 years.
He was admitted to practice before the UN War Crimes Tribunal for Rwanda in 2004 and was the first Asian admitted to practice before the International Criminal Court. Philippine News Agency

subset: commoncrawl


text:
Book Title: Biblische Figuren des Alten vnd Newen Testaments : gantz künstlich gerissen / durch den weitberhümpten Vergilium Solis zu Nürnberg
Author: Solis, Virgil, 1514-1562
Image Title: David and Bathsheba
Scripture Reference:
Description: As David looks down from a palace balcony, Bathsheba bathes in a pool, accompanied by her attendants. The artist, Virgil Solis (1514-1562), has placed his monogram in the lower left corner of the woodcut.
Click here for additional images available from this book.
This image is made available by the generous contribution of E. Rhodes and Leona B. Carpenter Foundation.
Request a high-resolution file (fees apply)
Rights Statement: The online edition of this work in the public domain, i.e., not protected by copyright, has been produced by Pitts Theology Library, Emory University.
Rights Status: No Copyright - United States
Pitts Theology Library provides copyright information as a courtesy and makes no representation about copyright or other legal status of materials in the Digital Image Archive.


text:
Starry Romance™
A match made in heaven! The stars will align when they receive this breathtaking display. Send a gift of love that's beautifully designed to get their heart racing. There's no better way to let them know you care.
Oriental lilies, gladiolus, solidago, lush tropical leaves, and more are arranged in a square vase.
Product ID UFN1305
Approximately 14" W x 28" H
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(C75) [Number2 (たくじ)] たくじ本 [英訳]
18 pages - Uploaded
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text:
To be announced
BITX monetizes knowledge with immutable track record and client-side AI.
IMPORTANT: By investing in this business you agree to ourDisclaimer. All information including our rating, is provided merely for informational purposes. CryptoTotem does not provide investment advice.
What is BITX
BITX uses blockchain technology to restructure its FinTech services to provide monetizable knowledge based on smart contracts, hence to meet the urgent market demand for the performance-based content backend payment. Both the achievements and track records of information, knowledge, data and content created by consumers/ producers will be immutably managed in a distributed storage. With BITXs exclusive AI engine for universal stochastic learning, the goal of providing the intelligent feed flow of the user, for the user and by the user (OFBU) is achieved. The client-side AI technology is able to realize the decentralization of censorship and to protect the user data privacy.
DetailsPublic sales: Jul 11, 2018 - TBA
Token supply: 40,000,000
Hard cap: 2,777,250 USD(fiat)
Raised: 8,969,807 USD
LegalBlockchain Platform: Ethereum
Registration country: Hong Kong
Token infoTicker: BITX
Type: Utility-token
Token distribution:
30% incentives for supporting teams (research and development/ outsourcing/ maintenance/ marketing, etc.). T
25% used as the exchange tool in the ecosystem for reports, information and contents with data insights. (10% for the first three years, with a decrease of 50% per three years thereafter)
20% ICO project.
20% early cornerstone investors.
5% to public or allocated within the ecosystem according to the principle of transparency and the rule of verification for the purposes of incentives and sustainable maintenance.
BITX Roadmap
Small scope release of the initial version of the ICO Whitepaper;
Confirmation of cornerstone investors.
Launch of ICO project.
Launch of the new iOS APP as the start of the DAPP evolution.
Restructure of the ecological chain of the Bitex products with BITX under the integration of paid reports and content.
Launch of the Global Sentiment Visualization System for Alpha Test.
Commercialization of the initial Robo-advisory System.
Launch of the Initial system model for intelligent content analysis/filtering/search/publishing based on NLP and technology.
Launch of the universal machine learning system (eligible formvisualization, interpretability, interactive intervention and local deployment).


text:
Side Effects Movie Quotes
"Side Effects" movie quotes follow the twists and turns of this psychological thriller in which one woman commits murder after being prescribed anxiety medication by her psychiatrist. The film was written by Scott Z. Burns and directed by Academy Award winner Steven Soderbergh who previously saw success with the "Traffic," "Erin Brockovich," the "Oceans Eleven" series, "Contagion" and "Magic Mike." Previously titled "The Bitter Pill," "Side Effects" opened in US theaters on February 8, 2013.
In "Side Effects," Rooney Mara portrays young wife Emily Taylor, a woman who fell in love with her husband, Martin (Channing Tatum), then fell into a deep depression after he was sent to jail. Upon his release, she consults successful psychiatrist Dr. Jonathan Banks (Jude Law) for help getting back to normal. After consulting with Emily's former shrink, Dr. Victoria Siebert (Catherine Zeta-Jones), Dr. Banks decides to put Emily on a new drug, Abixa.
Initially, Abixa seems to be the miracle drug for Emily as she feels much better while taking it however strange things begin to happen, such as Emily sleepwalking. This gets real serious real fast when one morning Emily awakes to a murder scene in her home. Claiming to have no idea what happened, Emily brings in Dr. Banks, rather than an attorney, to the criminal proceedings leading everyone to wonder if Emily is to blame for the murder, the drug or the medical care she received from Dr. Banks."Side Effects" is sure to make moviegoers think but it's not the only one on the minds of movie fans with other movies also getting attention such as "Django Unchained," "Killing Them Softly," "Hitchcock," "Skyfall," "Lincoln," "Flight," "Playing for Keeps," "Silver Linings Playbook," "Anna Karenina," "This Must Be the Place," "Cloud Atlas," "Wreck-It Ralph," "Nobody Walks," "The Sessions," "Red Dawn," "Chasing Mavericks," "Rise of the Guardians," "Argo," and "Looper."
How Are Things Going?
Dr. Jonathan Banks: "How are things going for you?"After taking the Ablixa for some time, Emily reports back to Dr. Banks on how her life has improved as a result. As far as anyone can see right now, all is going well now with this drug regimen.
Emily: "I can finally sleep. I have some energy. We had sex."
Maybe She's a Candidate
Dr. Victoria Siebert: "Prozac, Welbutrin, Effexor… Maybe she's a candidate for one of these newer meds, Ablixa."As Dr. Banks and Dr. Siebert discuss Emily's treatment, Dr. Siebert suggests that Emily may see results with a specific new drug that is being tested. It's this quick mention that sets off a chain of events no one could have predicted.
Someone's Been Murdered
911 Operator: "911, what's your emergency?"Upon waking up to blood all over her home and a dead body, Emily phones 911 to report a murder. At that point, she does not appear to have any memory of the crime though the evidence points toward her as the suspect.
Emily: "I need help. Someone's been murdered."
Whoever Makes This Drug
Martin: "Whoever makes this drug is going to be rich."Following what appears to be a pleasurable session in the sack for Martin and Emily, Martin comments on how great Emily's new depression drug, Ablixa, is for both of them. It's almost as if it's too good to be true.
Who Can See The Lies?
Dr. Victoria Siebert: "A number of years ago I had a patient who was having an affair, came in here every week like he was going to confession, cried, repented, didn't stop. Then one day he comes in and says it's over, finally got a handle on his issues like some great epiphany. It was about six or seven years later his wife turns up and says he has a whole other family in another state. He'd been lying to her and he was lying to me. The kids blamed me. The wife blamed me. Even the patient blamed me. There were times I blamed me. The point is, the cardiologist could see it coming from the tests. It's in the blood. But who can see the lies?"Dr. Jonathan Banks seeks advice from Dr. Victoria Siebert after he is blamed in part for the murder Emily is accused of. Dr. Siebert tells of a similar instance where she was not at fault but was blamed anyway in hopes that it can provided a parallel to Dr. Banks' situation.
I'm Glad She's Seeing a Man
Dr. Victoria Siebert: "I saw her four years ago for a little over nine months. She didn't just have the rug pulled out from under her, she had the rug, the home, the husband, the… her entire life gone, even the health insurance. She moved into the city to find work and I never heard from her again. I'm glad she's seeing a man this time. I think that will help."Dr. Victoria Siebert explains her history treating Emily, which spans back to when Emily met Martin. Dr. Siebert also explains Emily's relationship with the men in her life, a pitfall in which Dr. Banks soon finds himself.
Dr. Jonathan Banks: "Why is that?"
Dr. Victoria Siebert: "She never felt seen by her father. Then her husband ends up in jail and she is abandoned again. I'd be happy to see her have a different kind of experience."


text:
CAD tip # 9004:
% platform category
applies to: * ·
|See also:
|Tip 13152:
|Compatibility of Autodesk products with Windows 11.
|Tip 12555:
|Can I upgrade my CAD/PDM server to Windows Server 2019?
|Tip 11959:
|Supported file types (applications) with reference detection in Autodesk Desktop Connector.
|Tip 11816:
|How to convert 3D CAD model to the format glTF 2.0 (GLB)?
|Tip 10702:
|How to find which AutoCAD version was used to save a particular DWG drawing?
Selected tip: Classic hatch dialog in AutoCAD 2011,2012...
Elevation label with automatic text of Level and Elevation relative to UCS. « | » Missing images when plotting from Revit to HP Designjet T620.
Have we helped you? If you want to support the CAD Forum web service, consider buying one of our CAD applications, or our custom software development offerings, or donating via PayPal (see above). You may also add a link to your web - like this "fan" link:
DwgTextTranslator translates a series of drawings from one language to another using MS Access.
Download a fully functional trial version.
Please use these tips at your own risk.
Arkance Systems is not responsible for possible problems that may occur as a result of using any of these tips.


text:
Movie Buzz
Kathakali Telugu Movie Review & Rating – Story, Verdict
Kathakali Telugu Movie Review & Rating: Vishal Kathakali Tamil version released on January 14, 2016. And got rave reviews from everywhere. After so many postponements Kathakali Telugu Movie is going to hit the screens on March 18, 2016, and competing with some other small flicks. This romantic – action movie directed by Pandiraj. featuring Vishal, who has also produced the film. Allu Arjun's Iddharammailatho fame actress Catherine Tresa plays the female lead, supported by a host of actors like Madhusudhan Rao, Karunas, Mime Gopi and Lakshmi Ramakrishnan. While music is composed by Hip Hop Tamizha. Check out the Vishal's "Kathakali" Telugu Movie complete review, rating, story line, plus points, minus points & verdict from below.
You Might Also Like:
- Kathakali Tamil Movie Review and Rating
- Sardaar Gabbarsingh Latest Audio Teaser Free Download MP4, 3GP
Vishal Kathakali Telugu Movie Review & Rating:
Kathakali Movie Details, Cast & Crew (Credits):
Release Date: March 18, 2016.
Language: Telugu.
Star Cast: Vishal, Catherine Tresa, Nassar, Karunas, Soori, Madhusudhan Rao etc.
Director: Pandiraj
Producers: Vishal & Pandiraj.
Cinematography: Balasubramaniem.
Editor: Pradeep E. Ragav.
Music Director: Hiphop Tamizha.
Vishal Kathakali Telugu Movie Story: (In Brief)
The movie contained an honest person story that who caught in a web of problems when he accused killing a leader of a rowdy gang. At last, how he knew about himself that how he caught in a web and how come out from those issues is next story of the film.
Kathakali Movie Highlights:
- Vishal.
- Story & Screenplay.
- Cinematography.
- Run Time.
- Interval Block.
- Screen Play.
- Climax.
- Twists.
Kathakali Movie Drawbacks:
- Romance & Comedy Not Convincing.
- No importance for heroine role.
- Dragged in few scenes.
Kathakali is a nice action thriller with many twists & turns till the very end revolving around a murder mystery. This is such a movie which will glue you to the theater seats without any on-screen gimmicks. Pandiraj screenplay takes the movie into an international style.
Vishal's Kathakali Telugu Movie Rating:
- Critics Rating: 2.75/5
- Audience Rating: 3/5
That's it guys this is the perfect & genuine review and rating of Hero Vishal's Kathakali Movie. If you like this Kathakali Telugu Movie Genuine Review. Then please share it to your friends. But, Don't forget one thing i.e. please watch the movie in theatres. Kill Piracy and save industry.
As soon as possible we will update the Kathakali Telugu Movie First Day, 3 Days, 1st Week Collections Worldwide, India, AP & Telangana.
Latest Updates:
Check Out the Latest Updates by clicking the below links and Update Yourself.
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Game Description
Block Cars is a 3D multiplayer car shooter. You can participate in races or go into the colorful arena and shoot other gamers. There are numerous game
modes in the video game such as - vehicle, hero mode, arena and even FPS mode where you can enjoy shooting without a car. Earn in-game cash and purchase various kinds of chests to unlock futuristic cars and trucks, incredible tanks, powerful guns, strolling robots, gorgeous skins, and more! Start playing Blocky Cars and enjoy incredible gameplay!
Release Date: 27 November 2021 , Platform: Web browser (Desktop and Mobile),
2362 played times
Category: Adventure
Which games are similar to Blocky Cars?: Blocky Zombie And Vehicles, Blocky Sky Jumping, Slither Blocky Snake 3D, Supercars Drift Racing Cars, Drifting SuperCars Racing 3D , Extreme Offroad Cars 3: Cargo, Blocky Siege, Blocky wars vehicle multy, Car Drifting Pro Racing Cars, Mad Cars 3D, Rocket Cars Highway Race,


text:
Propofol is a general anesthetic option for deep brain stimulation (DBS) of the subthalamic nucleus (STN) of patients with Parkinson's disease (PD). However, its effects on STN activity and neuropsychological outcomes are controversial. The optimal propofol anesthesia for asleep DBS is unknown. This study investigated the safety and effectiveness of an optimized propofol anesthesia regimen in asleep DBS.
This retrospective study enrolled 68 PD patients undergoing bilateral STN-DBS surgery. All patients received local scalp anesthesia, with (asleep group, n = 35) or without (awake group, n = 33) propofol-remifentanil general anesthesia by target-controlled infusion under electroencephalogram monitoring. The primary outcome was subthalamic neuronal spiking characterization during microelectrode recording. The secondary outcomes were clinical outcomes including motor, cognition, mind, sleep, and quality of life at 6 months.
Significantly increased delta and theta power were obtained under propofol anesthesia (awake vs. asleep group, mean ± standard deviation; delta: 31.97 ± 9.87 vs. 39.77 ± 10.56, p < 0.01; theta: 21.09 ± 5.55 vs. 24.82 ± 6.63, p = 0.01). After excluding the influence of confounding factors of age and preoperative motor scores, there was a statistically significant influence on the delta, theta, and alpha power of STN neuronal activity under different anesthesia regimens (delta: β = 2.64, p < 0.01; theta: β = 2.11, p < 0.01; alpha: β = 1.42, p = 0.01). There were no differences in modified burst index, firing rate, tract numbers of microelectrode recording, and other clinical outcomes between the two groups.
Optimized propofol anesthesia enhanced the delta, theta, and alpha power in STN compared with the awake technique and likely contributed to target recognition under propofol anesthesia. These results demonstrate that propofol is suitable, but needs to be optimized, for asleep STN-DBS.
Trial Registration
Chinese Clinical Trial Registry Identification number: ChiCTR2100045942. Registered 29 April 2021–Retrospectively registered
|Why carry out this study?
|Propofol is a general anesthetic option for deep brain stimulation (DBS) of the subthalamic nucleus (STN) of patients with Parkinson's disease (PD). However, its effects on STN activity and neuropsychological outcomes are controversial.
|This study investigated the safety and effectiveness of an optimized propofol anesthesia regimen in asleep DBS.
|What was learned from the study?
|Optimized propofol anesthesia enhanced the delta, theta, and alpha power in STN compared with the awake technique, and there were no differences in clinical outcomes between the two groups.
|These results demonstrate that propofol is suitable, but needs to be optimized, for asleep STN-DBS.
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Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective treatment for advanced Parkinson's disease (PD) [1]. The application of intraoperative microelectrode recording (MER) is conducive to target definition but traditionally requires an awake and cooperative patient [2]. Some patients with PD must undergo STN-DBS surgery under an asleep condition due to severe anxiety, rigidity, and dystonia in the off-drug phase. Several DBS centers always conduct surgery under general anesthesia. Different general anesthetic methods are used in different DBS centers, such as inhalation anesthesia, sedation with dexmedetomidine, or propofol-based intravenous anesthesia [3,4,5,6,7], but none of these has proven to be superior [8]. The optimal anesthetic regimen should provide sufficient comfort and safety, but should not affect the intraoperative electrophysiological signal and clinical efficacy [8,9,10,11].
Propofol is a widely used intravenous anesthetic agent with the advantages of rapid metabolism, safety, controllable anesthetic state, and neuroprotective effects [8, 12,13,14]. However, its effects on STN activity and neuropsychological outcomes on asleep DBS for PD remain controversial. Some studies have reported STN activity interference with propofol anesthesia, such as the absence of typical widening of the background noise baseline [15] and a decrease in the root mean square [16] and the relative beta power [17]. In contrast, others have reported successful propofol use by combining anesthesia depth monitoring [18, 19], target-controlled infusion (TCI) techniques [18], and a dosage reduction [18, 20] during MER under propofol. These studies suggest that the contradictory results could be due to the various concentration, dose, mode, and timing of propofol administration [17, 21, 22]. Therefore, it is necessary to optimize propofol anesthesia for asleep DBS surgery.
There are limited data on the effectiveness of propofol anesthesia in postoperative improvement of non-motor symptoms including cognition, mental status, sleep, and quality of life in PD. Two studies have reported adverse effects on postoperative neuropsychological outcomes and memory function after DBS under propofol anesthesia [15, 23]. As significant cognitive decline has also been observed under volatile anesthesia [24], we hypothesized that the possible reason for the adverse effects is related to target location and postoperative stimulation parameters, rather than propofol. Therefore, establishing the effectiveness of propofol anesthesia in asleep DBS requires further analysis.
In this study, we used an electroencephalogram monitoring-guided propofol-remifentanil TCI with a multimodal analgesic regimen for asleep STN-DBS procedures. We quantitatively and qualitatively analyzed the neuronal signatures, including power distribution, oscillatory activity, total numbers of MER trajectory, and length of STN. The neuronal activity of STN and clinical outcomes in asleep PD patients were compared with those in age- and disease-matched awake patients. The goal of the study was to verify the safety and effectiveness of an optimized propofol general anesthesia regimen. In particular, we hypothesized that propofol anesthesia should be further optimized and widely used in asleep DBS because it has no deleterious effects on electrophysiological signals and clinical outcomes.
Patient Population
We performed a retrospective offline analysis of MER data of 159 consecutive PD patients undergoing bilateral STN-DBS surgery in the First Affiliated Hospital of Sun Yat-sen University from July 2008 to August 2019. This manuscript adheres to the applicable Consolidated Standards of Reporting Trials (CONSORT) guidelines. The study was approved by the relevant local ICE for clinical research and animal trials of the First Affiliated Hospital of Sun Yat-sen University (reference numbers IIT2016192). Because this study retrospectively analyzed routine clinical data, written informed consent from the patients was not required. The retrospective study was grouped according to the type of anesthesia used. The method of anesthesia was determined by the patients according to their own wishes. All anesthesia in this study was performed by the same anesthesiologist. Because some conditions seriously affect the results or analyses, we exclude data for the following cases: (1) patients who had undergone brain surgery before surgery, (2) patients who took special drugs (antidepressants, benzodiazepines, or antiparkinsonian medications) that would affect the MER data before surgery, (3) the regimen of anesthesia was changed during the MER (for example, the awake patients changed their will for various reasons and then received general anesthesia, or asleep patients received other sedative drugs such as sevoflurane), (4) MER data were lost or incomplete, and (5) the quality of the MER data was poor. Therefore, we finally analyzed MER data of 68 PD patients. Figure 1 shows the flowchart. Of the remaining 68 patients, 33 patients were included in the awake group and 35 patients were included in the asleep group, depending on the method of anesthesia they received.
Imaging and Stereotactic Procedures
All antiparkinsonian medications were withdrawn at 12 h before the surgery. The head of each patient was scanned using a 3T magnetic resonance imaging (MRI) machine to identify the STN. On the day of the surgery, the patient was positioned in a stereotactic frame (Leksell G type) under local anesthesia to perform computed tomography (CT) scanning, and the MRI and CT images were then merged. The VectorVision neuronavigational system was used to calculate the three-dimensional coordinates of the STN and plan out 10 electrode tracks.
Anesthetic Technique
All patients received local scalp anesthesia with ropivacaine 0.5%. In the awake group, 33 patients were conscious during MER and received electrode implantation without sedatives. In the asleep group, 35 patients underwent endotracheal intubation under total intravenous general anesthesia. Dexmedetomidine was infused (0.3 μg/kg) before induction. For induction, propofol was administered by TCI (Alaris Medical Systems, Inc., San Diego, CA, USA) based on the Marsh model with a target plasma concentration of 2 μg/ml. Sufentanil (0.2 μg/kg) and cisatracurium (0.2 mg/kg) were given intravenously. After endotracheal intubation, anesthesia was maintained with propofol TCI (1–2 μg/ml), remifentanil TCI (4–6 ng/ml), and cisatracurium (1.5 μg/kg/min). For TCI remifentanil, a target plasma concentration based on the Minto model was maintained by a TCI pump (Orchestra® Base Primea, Fresenius Vial, Brezins, France). At least 10 min before MER, the target propofol and remifentanil concentrations were reduced to 1–2 μg/ml and 2–3 ng/ml, respectively. During MER, the anesthetic depth was titrated to maintain it at the C level on Narcotrend monitoring (MonitorTechnik, Bad Bramstedt, Germany).
Surgical Procedures and Intraoperative MER
All DBS surgical operations were performed by the same surgeon. After scalp incision and perforation, a single-channel microelectrode with a diameter of 25 μm was conducted by a manual microdrive device (microTargeting®, FHC Inc., Bowdoin, ME, USA). MER started 15 mm above the theoretical STN target at increments of 0.5 mm for 10 s at each depth until the typical neuronal discharges of the STN were no longer observed. The entrance and exit of STN were mainly based on visual and auditory evaluation. Typically, the background activity, noise, and peak frequency of spontaneous neurons apparently increased when the microelectrode entered STN and decreased when it was out of STN [25]. A surgical monitoring system (Leadpoint®, Medtronic, Englewood, CO, USA) was used to record and store MER data. All data were filtered using a 500-Hz high-pass filter and a 5-kHz low-pass filter with a sampling rate of 24 kHz. The path length of the microelectrode through the entire STN was recorded as the length of the STN. The criteria for selecting the optimal trajectory were based on Benazzouz et al. [25]. Both groups of patients were tested for passive movement of the contralateral extremities.
Permanent quadripolar DBS electrodes (DBS model 3389 electrode, Medtronic, Inc., Minneapolis, MN, USA) were implanted along the optimal trajectory after X-ray examination. The stereotactic frame was removed, and infraclavicular placement of the internal pulse generators (Medtronic, Minneapolis, MN) was performed under general anesthesia. The pulse generator was turned on 1 month after the operation.
Extraction of Spiking Activity in the STN and Parameter Calculations
Data Screening
MER signals recorded along the DBS electrode tracks were collected for off-line analysis. In this study, the microelectrode was inserted into the STN in increments of 0.5 mm, and the mean length of the electrophysiological signal of the unilateral STN was 6 mm. To reduce errors caused by differences in data-depth ranges, the boundary fragments were removed and the middle 4 mm section was selected for further analysis. Therefore, analyses were conducted on the middle 8 fragments for each STN. Collectively, a total of 1088 groups of MER data were contained [68 subjects × 8 depths × 2(bilateral)].
Based on extraction of all spikes from raw MER signals, according to the eight different depth datasets of each side of the STN of each patient, the firing frequency of the bilateral STN of each patient was calculated. Specifically, 0–100 Hz was selected as the main frequency band for signal analysis. This main frequency band was further subdivided into five frequency bands: delta, theta, alpha, beta, and gamma. The relationships among the mean spike power in different frequency bands under different anesthetic methods and different sides of the STN were then determined.
Action Potential (Spike) Extraction
The action-potential spike reflects the firing characteristics of the STN. According to the spikes extracted from the raw MER signals, the modified burst index (MBI) and firing rate (FR) of the spikes were calculated to reflect the characteristics of STN firing in order to analyze the effects of different anesthetic methods on the firing characteristics of the STN. To extract the envelope of MER data, the Hilbert transform is used, which is the convolution result of the original signal x(t) and the signal 1/πt [26]:
To estimate the envelope of spikes, the modulus of the analytic signal is calculated as \(\left| {\tilde{x}\left( t \right)} \right| = \sqrt {x\left( t \right)^{2} + \hat{x}\left( t \right)^{2} }\).
The autocorrelogram is calculated based on the detected spike sequence as [27]:
where \(\rho \left( t \right)\) is the spike sequence, \(T\) indicates the data length, \(r = \frac{n}{T}\) is the firing rate of the spike, and \(n\) is the number of spikes in the time \(T\).
The raw MER signals contained both background noise and spikes. To extract spikes, background noise was filtered out. The background noise in the STN MER was mainly composed of microelectrode-recording equipment noise, biological background noise, and action potentials generated by neurons surrounding the target neurons during the acquisition process. Most of these noises were Gaussian noises, and their standard deviation can be calculated as the median of the absolute values of the raw signals divided by 0.6745: [28]
where s(t) represents the raw MER signal. The threshold (Th) of the spikes in the signals is four times the standard deviation of Gaussian noise, i.e., Th = 4σ [21].
Figure 2 shows the process of spike extraction from one typical signal with a length of 1 s. Figure 2A shows the raw MER signal, and Fig. 2B shows the MER signal with detected spikes. The threshold of this signal was calculated, and data with an amplitude higher than the threshold were considered as spikes. The times corresponding to the selected spikes were assigned a pulse value of 1 and the rest positions were assigned an amplitude of 0 to construct a new spike signal sequence (spike train), as shown in Fig. 2C.
The MBI is defined as the ratio of the number of inter-spike intervals (ISI) less than 10 ms to the number of ISIs greater than 10 ms [21] which reflects the characteristics of the timing of STN. The equation for this calculation is as follows:
where Nl represents the number of ISIs shorter than 10 ms, and Ng represents the number of ISIs greater than 10 ms.
FR is defined as the number of spikes in 1 s [21]. The equation for this calculation is as follows:
where tspk represents the time sequence in which the spikes appear in the STN MER signals, and T represents the duration of the signals in seconds.
The means of the overall MBIs and FRs in the asleep and awake groups were calculated according to the multiple sets of MER signals from the bilateral STNs of the included patients. The equation is as follows:
where xi represents the MBI or the FR value of the ith patient and n represents the total number of patients.
The standard deviations of the overall MBIs and FRs in the awake and asleep group were calculated according to the MBI and FR data from the bilateral STN in each patient, which were used to measure the degree of data dispersion.
Clinical Outcomes
Motor and non-motor evaluations were performed by professionally trained neurologists before surgery and 6 months following surgery. Motor symptoms were evaluated using the third part of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS III). The improvement rate of motor symptoms is the percentage of the difference of scores before and after surgery divided by the score before surgery. Non-motor assessments included assessments of cognition, sleep, quality of life, and mental status. The 39-item Parkinson's Disease Questionnaire (PDQ39) and Non-Motor Symptom Scale (NMSS) were used to assess each patient's quality of life. The Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) were used for mental assessments. The Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and Parkinson's Disease Sleep Scale (PDSS) were used to evaluate sleep quality and the severity of sleep disorders. We used the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) to assess the level of cognitive function in each patient.
In all cases, the common postoperative adverse events were recorded, and these were as follows: (1) complications related to surgery or anesthesia, such as incision-related infection, pneumonia, deep vein thrombosis, air embolism, pulmonary edema, hemiplegia, and death; (2) complications related to hardware, such as intracranial hematoma, implant infection, and electrode displacement/damage; (3) complications related to stimulation, such as difficulty opening eyes, dysarthria, and dysphagia; (4) other complications, such as neuropsychiatric symptoms, drowsiness, restlessness, delirium, and indifference.
Statistical Analysis
SPSS version 26.0 software (IBM Corp., Armonk, NY, USA) was used for all statistical analyses. Continuous variables with normal distribution were expressed as mean ± standard deviation (SD). Categorical variables were expressed as number (percentage).
The mean spike power in the five frequency bands of each sample group was compared using an independent-samples t test. Two-way analysis of variance (ANOVA) was used to determine whether the average frequencies of different levels of spikes of the two factors (different anesthetic methods and different sides of STN) were significantly different between the two groups, as well as whether there was an interaction between the average spike frequency of the two factors. To account for variance of age and MDS-UPDRS III between the two groups, we conducted a linear regression analysis to regress out the effects of age and preoperative MDS-UPDRS III on the power of STN neuronal activity. Similarly, two-way ANOVA was used to determine whether there was no interaction between the MBIs and FRs of different anesthetic methods and different sides of the STN.
Differences in the postoperative improvements in ESS, PDQ-39, and MOCA, MDS-UPDRS III, PSQI, PDSS, NMSS, HAMD, HAMA, and MMSE scores between the awake and asleep group were tested using an independent-samples t test. Categorical variables were compared using Pearson's chi-square test. Significance was recognized when p < 0.05.
Baseline Characteristics
Baseline characteristics of the 68 analyzed PD patients are listed in Table 1. The mean age was 56.35 ± 9.09 years. Forty-three (63.2%) of the patients were male. The mean PD duration was 9.43 ± 2.98 years. The levodopa equivalent daily dose was calculated according to drug correspondence proposed by Tomlinson et al. [29]. The baseline values of the two groups were comparable (all p values were greater than 0.05).
Spectral Analysis
During MER, well-recognized STN signals recorded during propofol anesthesia were similar to those detected under the awake condition (Fig. 3). In the awake group, there was no difference in the mean spike power in the delta, theta, alpha, beta, and gamma between the left and right STN (Fig. 4A). In the asleep group, there was also no difference in the mean spike power between the left and right STN (Fig. 4B). For left STN, the mean spike power was significantly different between the two groups in the theta band (awake vs. asleep group, mean ± SD; theta: 20.99 ± 5.45 vs. 25.25 ± 8.97, p = 0.02, see Table S1 and Table S2 in the supplementary material for details), while there were no differences in the delta, alpha, beta, and gamma frequency bands (Fig. 4C). For right STN, the mean spike power was significantly different between the two groups in the delta band (awake vs. asleep group, mean ± SD; delta: 31.11 ± 12.57 vs. 40.61 ± 13.85, p < 0.01; Fig. 4D, see Table S1 and Table S2 in the supplementary material for details). For bilateral STN, the mean spike power between the two groups was significantly different in the delta and theta bands (awake vs. asleep group, mean ± SD; delta: 31.97 ± 9.87 vs. 39.77 ± 10.56, p < 0.01; theta: 21.09 ± 5.55 vs. 24.82 ± 6.63, p = 0.01; Fig. 5, see Tables S1 and S2 in the supplementary material for details). The results analyzed using two-way ANOVA and independent-samples t tests were consistent (see Table S2 in the supplementary material for details). There was no interaction between the average spike power across different anesthetic methods and different sides of the STN. Linear regression analysis showed that there was a statistically significant influence on the delta, theta, and alpha power of STN neuronal activity under different anesthesia regimens (delta: β = 2.64, p < 0.01; theta: β = 2.11, p < 0.01; alpha: β = 1.42, p = 0.01, see Table 2).
Comparisons of MBIs and FRs
There was no significant difference between the MBIs and FRs of the STN on different sides or on the same side of the brain within each patient (all p > 0.05; see Table S3 in the supplementary material for details). There was no interaction between the MBIs and FRs of different anesthetic methods and different sides of the STN (see Table S4 in the supplementary material for details).
Comparisons of MER Trajectories and Length of STN
The operation results of the two groups were compared (see Table S5 in the supplementary material for details). The mean total number (bilateral STN) of MER trajectories was 3.12 ± 1.54. There was no statistical difference between the two groups in terms of the total number of MER trajectories, the ratio when the total number of MER trajectories was equal to 2, and the length of the left STN (p > 0.05, for all). Although the length of the right STN in the asleep group was statistically longer than that in the awake group (p = 0.02), there was limited clinical relevance.
Comparisons of Clinical Outcomes at the 6-Month Follow-up
Table 3 compares the improvement in motor symptoms and non-motor symptoms between the two groups. There was no significant difference between the two groups (all p > 0.05). In the adverse events category, no patient suffered permanent deficits, bleeding, or death. In the awake group, a 6-month follow-up result of adverse events showed that one case had an incision-induced infection. One patient developed mental abnormality as a result of self-administered overdoses of antiparkinsonian medications. In the asleep group, there were no occurrences of intraoperative awareness, perioperative neurocognitive disorders, or mental disorders. Five cases had incision-related infections and seven cases developed transient hiccups. One patient had drug-induced hallucinations, with a previous history of this before surgery. One patient with respiratory comorbid conditions experienced dyspnea after tracheal extubation failure and required re-intubation.
In this study, the anesthetic approach of Narcotrend-optimized anesthesia-depth control and TCI-guided propofol and remifentanil dosage achieved good STN signals and clinical efficacy. This regimen allowed effective MER under propofol without affecting the bursting or firing rates, and increased the power of delta and theta in the MERs for the asleep group. We found no significant changes in the debated non-motor effects between two groups, in particular cognitive and psychobehavioral.
Previous studies have shown that the use of remifentanil or propofol inhibits MER signals, which seems to be different from our results [16, 30, 31]. However, it is worth noting that Mciver et al. [30] used a bolus administration (propofol 0.3 mg/kg or remifentanil 0.05 mg/kg) and Benady et al. [31] used continuous constant rate administration (propofol 50 μg/kg/min or remifentanil 0.1 μg/kg/min) without an objective level of consciousness assessment or local scalp anesthesia. In this study, we used an electroencephalogram monitoring-guided propofol-remifentanil TCI (1–2 μg/ml and 2–3 ng/ml, respectively) with the local scalp anesthesia regimen. Typically, continuous infusion of 0.1–0.5 ug/kg/min remifentanil is approximately 3–7 ng/ml when using a TCI [32]. Therefore, our doses tended to be lower. At the same time, it is important to note that our study did not explore the effect of a single drug on MER. These controversial results suggest the importance of choice, dosage, and the timing of anesthetic agents for the recording of STN neuron firing [15,16,17, 21, 33]. Our combined use of propofol and remifentanil has the advantage that these drugs exhibit synergistic effects, which reduces their required doses and any associated adverse drug reactions. Also, a multimodal analgesic regimen, including local scalp anesthesia, and a small dose of dexmedetomidine and flurbiprofen can reduce the amount of analgesics. For PD patients, lower-than-average propofol doses are sufficient [9, 34]. Previous research showed that the propofol requirement for induction and remifentanil requirement for tracheal intubation and skin incision were significantly reduced compared to the requirements for non-PD patients [35, 36]. This phenomenon may be due to increased sensitivity to anesthetics in PD patients due to degenerative brain lesions, resulting in abnormal pharmacodynamic characteristics of the anesthetics. Therefore, the conventional pharmacodynamic concept and drug infusion methods of administering IV drugs (bolus dose and continuous infusion) might lead to a relative overdose of propofol and opioid analgesics during MER. This could further affect the recording of STN neuron firing and lead to compromise of cardiovascular function, delayed emergence, and postoperative delirium due to over-sedation. Compared to traditional drug infusion methods, TCI may be more suitable for patients with PD especially during MER, with the advantage of achieving micro-injection and more precisely controlled target drug concentration in the plasma or at the effect site. On the other hand, monitoring the depth of anesthesia may be sufficiently reliable to maintain proper light-state anesthesia during MER under a low dose of narcotics. This has significance in minimizing the interference of electrophysiological signals, preventing intraoperative consciousness and intracranial hypertension caused by physical movement and asphyxia. It will help to avoid hemodynamic events caused by deep anesthesia and postoperative cognitive dysfunction.
A similar study demonstrated the feasibility of using propofol and remifentanil combined with BIS monitoring for modulating anesthesia during STN-DBS surgery, with propofol TCI and continuous infusion of remifentanil [15]. However, this study did not perform quantitative analysis of intraoperative electrophysiology and did not follow up on the outcomes of postoperative non-motor symptoms (such as cognitive/mental function). MER can be achieved during asleep DBS as long as the drug and the depth of anesthesia are appropriate, but it is also important for anesthesiologists to protect the cognitive/mental aspects of elderly PD patients [18]. Therefore, emphasis should be placed on the choice of anesthetic drugs used. Compared with sevoflurane, propofol anesthesia can reduce the incidence of postoperative delirium in elderly patients, and it has the advantage of protecting the fragile brains of the elderly. Additionally, propofol anesthesia can reduce the incidence of delayed neurocognitive recovery in elderly patients after tumor surgeries [12]. In a vulnerable mouse transgenic model, the incidence of cognitive impairment and neuroinflammatory sequelae after using propofol were lower than after using inhaled anesthetic drugs [37]. It has been reported that propofol can alleviate 1-methyl-4-phenylpyridinium-induced oxidative stress by increasing the content of reactive oxygen and ATP levels, as well as by improving mitochondrial membrane potential. This prevents the neurotoxicity of 1-methyl-4-benzene pyridinium that leads to PD [14]. In general, propofol is more suitable for anesthesia in elderly patients.
Propofol induces variable anesthetic effects when it is used at different doses and acts on different receptors. However, it is still unclear which molecular targets have the greatest clinical effects and which cause unnecessary side effects. Different concentrations of propofol have different effects on the central nervous system and electroencephalogram. At sedative concentrations, propofol significantly decreased the activity of neurons in the cortical neural network, weakened alpha power, and enhanced frontal beta power. At higher hypnotic concentrations, the activity of neurons in the subcortical structures was also affected, while the slow-wave activity in the delta band became more prominent and the frontal beta power decreased [38]. It seems that the effect of propofol on the basal ganglia discharge is closely related to the dose. For patients with dystonia, the average firing rates of internal globus pallidus were lower under propofol anesthesia [39]. Similarly, it appears to be dose-related, as one of the patients receiving a low dose of propofol (60 mg IV) had firing patterns that were not different from those in other non-sedated patients. Our data show that propofol anesthesia does not inhibit the MER signal, but it does enhance the power of low-frequency signals. This finding, which was not observed in the awake group, may be used as an electrophysiological marker for STN signals during MER under propofol anesthesia and helps to target localization. It supports the view that propofol anesthesia needs to optimize the depth of anesthesia and increase the controllability of anesthesia from the perspective of concentration, dose, and time of administration. No studies have determined whether increased low-frequency power during anesthesia directly affects clinical prognostic outcomes. However, the current hypothesis of the mechanism of STN-DBS, "information damage" and "synaptic filtering" [40], indicates that the lack of low-frequency information increases the limitation of DBS, and propofol enhancement of low-frequency information during anesthesia may play a short-term role by compensating for this defect.
This study had some limitations. The anesthesia method was determined by patient's choice so patients were not randomly assigned to the awake group and asleep group. Nevertheless, the comparable baseline for both groups and the rigorous surgery, anesthesia, and follow-up procedures performed by the same team strengthen the results. In this study, spike sorting was not performed when comparing the FRs, MBIs, and total power of the two groups. Although some related studies were also based on data without spike sorting, our results are not sufficient to reach any conclusions at the level of single units. Multi-center large sample-size prospective studies are required to distinguish the subtle differences in electrophysiological characteristics and long-term clinical outcomes between the two groups that we reported here.
We conclude that the anesthetic regimen reported here, during STN-DBS, is safe and effective for patients with advanced PD. Propofol anesthesia in asleep DBS needs to optimize the depth of anesthesia and increase the controllability of anesthesia from the aspects of concentration, dose, and time of administration. The increased delta, theta, and alpha power observed during MER reflects characteristic signature in the STN under optimized propofol anesthesia, which may be helpful for target identification.
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The authors wish to thank the patients for the use of their data in this study.
No funding or sponsorship was received for this study or publication of this article. The Rapid Service Fee was funded by the authors.
Statistical Analysis and Other Assistance
Constructive and critical comments in the preparation of this article were provided by Shi-Ming Shi at the Department of Pediatric Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Statistical analysis in the preparation of this article was provided by Xiao-Ling Huang at the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors Contributions
Conception and design: Jin-Long Liu, Nan Jiang, Yu-Ting Ling. Acquisition of data: Jin-Long Liu, Nan Jiang, Yu-Ting Ling, Chao Yang, Li-Nan Zhang, Qian-Qian Guo, Xing-Yi Jin, Ling Chen, Zhi-Guo Zhang. Analysis and interpretation of data: Jin-Long Liu, Yu-Ting Ling, Wen-Biao Xian, Yi Liu, Xing-Yi Jin, Bin Wu, Chang-Ming Zhang, Ling Chen, Zhi-Guo Zhang. Drafting the article: Nan Jiang, Yu-Ting Ling, Xing-Yi Jin, Bin Wu, Chang-Ming Zhang, Zhi-Guo Zhang. Critically revising the article: Nan Jiang, Yu-Ting Ling, Wen-Biao Xian, Xing-Yi Jin, Bin Wu, Chang-Ming Zhang, Zhi-Guo Zhang. Reviewed submitted version of manuscript: Jin-Long Liu, Nan Jiang, Yu-Ting Ling, Bin Wu, Chang-Ming Zhang, Zhi-Guo Zhang. Approved the final version of the manuscript on behalf of all authors: Nan Jiang, Jin-Long Liu. Statistical analysis: Yu-Ting Ling, Xing-Yi Jin. Study supervision: Jin-Long Liu, Nan Jiang, Ling Chen, Zhi-Guo Zhang.
Nan Jiang, Yu-Ting Ling, Chao Yang, Yi Liu, Wen-Biao Xian, Li-Nan Zhang, Qian-Qian Guo, Xing-Yi Jin, Bin Wu, Chang-Ming Zhang, Ling Chen, Zhi-Guo Zhang, and Jin-Long Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was approved by the relevant local ICE for clinical research and animal trials of the First Affiliated Hospital of Sun Yat-sen University (reference numbers IIT2016192). Informed consent was not required because this is a retrospective study. The study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments.
Data Availability
All data generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
About this article
Cite this article
Jiang, N., Ling, YT., Yang, C. et al. Optimized Propofol Anesthesia Increases Power of Subthalamic Neuronal Activity in Patients with Parkinson's Disease Undergoing Deep Brain Stimulation. Neurol Ther 10, 785–802 (2021). https://doi.org/10.1007/s40120-021-00259-y
Issue Date:
DOI: https://doi.org/10.1007/s40120-021-00259-y
- Deep brain stimulation
- General anesthesia
- Microelectrode recording
- Parkinson's disease
- Propofol
- Subthalamic nucleus


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