2019年疼痛防治和痛觉机制十大研究突破

1.N Engl J Med+Lancet— 人源化抗CGRP抗体或者CGRP阻断剂防治偏头痛取得较好疗效

英文摘:1：

BACKGROUND:

Antibodiestargeting calcitonin gene-related peptide (CGRP) or its receptor have shownefficacy in the prevention of migraine attacks. We investigated the efficacyand tolerability of fremanezumab, a fully humanised CGRP antibody, in patientswith migraine who had previously not responded to two to four classes ofmigraine preventive medications.

METHODS:

Therandomised, double-blind, placebo-controlled, parallel-group, phase 3b FOCUStrial was done at 104 sites (including hospitals, medical centres, researchinstitutes, and group practice clinics) across Belgium, the Czech Republic,Denmark, Finland, France, Germany, Italy, the Netherlands, Poland, Spain,Sweden, Switzerland, the UK, and the USA. We enrolled participants aged 18-70years with episodic or chronic migraine who had documented failure to two tofour classes of migraine preventive medications in the past 10 years. Failurewas defined as no clinically meaningful improvement after at least 3 months oftherapy at a stable dose, as per the treating physician's judgment;discontinuation because of adverse events that made treatment intolerable; ortreatment contraindicated or unsuitable for the preventive treatment ofmigraine for the patient. Participants were randomly assigned (1:1:1) byelectronic interactive response technology to subcutaneously administeredquarterly fremanezumab (month 1, 675 mg; months 2 and 3: placebo), monthlyfremanezumab (month 1: 225 mg in episodic migraine and 675 mg in chronicmigraine; months 2 and 3: 225 mg in both migraine subgroups), or matchedmonthly placebo for 12 weeks. The primary outcome was mean change from baselinein the monthly average number of migraine days during the 12-week treatmentperiod. This trial is registered with ClinicalTrials.gov, number NCT03308968,and is now completed.

FINDINGS:

BetweenNov 10, 2017, and July 6, 2018, 838 participants with episodic (329 [39%]) orchronic (509 [61%]) migraine were randomly assigned to placebo (n=279),quarterly fremanezumab (n=276), or monthly fremanezumab (n=283). Reductionsfrom baseline in monthly average migraine days over 12 weeks were greaterversus placebo (least-squares mean [LSM] change -0·6 [SE 0·3]) with quarterlyfremanezumab (LSM change -3·7 [0·3]; LSM difference vs placebo -3·1 [95% CI-3·8 to -2·4]; p<0·0001) and with monthly fremanezumab (LSM change -4·1[0·34]; LSM difference vs placebo -3·5 [-4·2 to -2·8]; p<0·0001). Adverseevents were similar for placebo and fremanezumab. Serious adverse events werereported in four (1%) of 277 participants with placebo, two (<1%) of 276with quarterly fremanezumab, and four (1%) of 285 with monthly fremanezumab.

INTERPRETATION:

Fremanezumabwas effective and well tolerated in patients with difficult-to-treat migrainewho had previously not responded to up to four classes of migraine preventivemedications.

英文摘要2：

BACKGROUND:

Rimegepant,a small molecule calcitonin gene-related peptide receptor antagonist, has shownefficacy in the acute treatment of migraine using a standard tabletformulation. The objective of this trial was to compare the efficacy, safety,and tolerability of a novel orally disintegrating tablet formulation ofrimegepant at 75 mg with placebo in the acute treatment of migraine.

METHODS:

Inthis double-blind, randomised, placebo-controlled, multicentre phase 3 trial,adults aged 18 years or older with history of migraine of at least 1 year wererecruited to 69 study centres in the USA. Participants were randomly assignedto receive rimegepant (75 mg orally disintegrating tablet) or placebo andinstructed to treat a single migraine attack of moderate or severe painintensity. The randomisation was stratified by the use of prophylacticmedication (yes or no), and was carried out using an interactive web responsesystem that was accessed by each clinical site. All participants,investigators, and the sponsor were masked to treatment group assignment. Thecoprimary endpoints were freedom from pain and freedom from the most bothersomesymptom at 2 h postdose. The efficacy analyses used the modifiedintention-to-treat population, which included all patients who were randomlyassigned, had a migraine attack with pain of moderate or severe intensity, tooka dose of rimegepant or placebo, and had at least one efficacy assessment afteradministration of the dose. The safety analyses included all randomly assignedparticipants who received at least one dose of study medication. This study isregistered with ClinicalTrials.gov, number NCT03461757, and is closed toaccrual.

FINDINGS:

BetweenFeb 27 and Aug 28, 2018, 1811 participants were recruited and assessed foreligibility. 1466 participants were randomly assigned to the rimegepant (n=732)or placebo (n=734) groups, of whom 1375 received treatment with rimegepant(n=682) or placebo (n=693), and 1351 were evaluated for efficacy (rimegepantn=669, placebo n=682). At 2 h postdose, rimegepant orally disintegrating tabletwas superior to placebo for freedom from pain (21% vs 11%, p<0·0001; riskdifference 10, 95% CI 6-14) and freedom from the most bothersome symptom (35%vs 27%, p=0·0009; risk difference 8, 95% CI 3-13). The most common adverseevents were nausea (rimegepant n=11 [2%]; placebo n=3 [<1%]) and urinarytract infection (rimegepant n=10 [1%]; placebo n=4 [1%]). One participant ineach treatment group had a transaminase concentration of more than 3 × theupper limit of normal; neither was related to study medication, and noelevations in bilirubin greater than 2 × the upper limit of normal werereported. Treated participants reported no serious adverse events.

INTERPRETATION:

Inthe acute treatment of migraine, a single 75 mg dose of rimegepant in an orallydisintegrating tablet formulation was more effective than placebo. Tolerabilitywas similar to placebo, with no safety concerns.

英文摘要3：

BACKGROUND:

Calcitoningene-related peptide receptor has been implicated in the pathogenesis ofmigraine. Rimegepant is an orally administered, small-molecule, calcitoningene-related peptide receptor antagonist that may be effective in acutemigraine treatment.

METHODS:

In amulticenter, double-blind, phase 3 trial, we randomly assigned adults with atleast a 1-year history of migraine and two to eight migraine attacks ofmoderate or severe intensity per month to receive rimegepant orally at a doseof 75 mg or matching placebo for the treatment of a single migraine attack. Theprimary end points were freedom from pain and freedom from the most bothersomesymptom (other than pain) identified by the patient, both of which wereassessed 2 hours after the dose of rimegepant or placebo was administered.

RESULTS:

Atotal of 1186 patients were randomly assigned to receive rimegepant (594 patients)or placebo (592 patients); of these, 537 patients in the rimegepant group and535 patients in the placebo group could be evaluated for efficacy. The overallmean age of the patients evaluated for efficacy was 40.6 years, and 88.7% werewomen. In a modified intention-to-treat analysis, the percentage of patientswho were pain-free 2 hours after receiving the dose was 19.6% in the rimegepantgroup and 12.0% in the placebo group (absolute difference, 7.6 percentagepoints; 95% confidence interval [CI], 3.3 to 11.9; P<0.001). The percentageof patients who were free from their most bothersome symptom 2 hours after thedose was 37.6% in the rimegepant group and 25.2% in the placebo group (absolutedifference, 12.4 percentage points; 95% CI, 6.9 to 17.9; P<0.001). The mostcommon adverse events were nausea and urinary tract infection.

CONCLUSIONS:

Treatmentof a migraine attack with the oral calcitonin gene-related peptide receptorantagonist rimegepant resulted in a higher percentage of patients who were freeof pain and free from their most bothersome symptom than placebo. (Funded byBiohaven Pharmaceuticals; ClinicalTrials.gov number, NCT03237845.).

参考文献：

1.Ferrari et al (2019). Fremanezumab versus placebo for migraine prevention inpatients with documented failure to up to four migraine preventive medicationclasses (FOCUS): a randomised, double-blind, placebo-controlled, phase 3btrial. Lancet. 2019 Sep 21;394(10203):1030-1040.

2.Croop et al (2019). Efficacy, safety, and tolerability of rimegepant orally disintegratingtablet for the acute treatment of migraine: a randomised, phase 3,double-blind, placebo-controlled trial. Lancet. 2019 Aug 31;394(10200):737-745.

3.Lipton et al (2019). Rimegepant, an Oral Calcitonin Gene-Related PeptideReceptor Antagonist, for Migraine. N Engl J Med. 2019 Jul 11;381(2):142-149.

2. N Engl J Med—人源CGRP单克隆抗体Galcanezumab可预防丛集性头痛

英文摘要：

BACKGROUND:

Episodic cluster headache is a disabling neurologic disorderthat is characterized by daily headache attacks that occur over periods ofweeks or months. Galcanezumab, a humanized monoclonal antibody to calcitoningene-related peptide, may be a preventive treatment for cluster headache.

METHODS:

We enrolled patients who had at least one attack every otherday, at least four total attacks, and no more than eight attacks per day duringa baseline assessment, as well as a history of cluster headache periods lastingat least 6 weeks, and randomly assigned them to receive galcanezumab (at a doseof 300 mg) or placebo, administered subcutaneously at baseline and at 1 month.The primary end point was the mean change from baseline in the weekly frequencyof cluster headache attacks across weeks 1 through 3 after receipt of the firstdose. The key secondary end point was the percentage of patients who had areduction from baseline of at least 50% in the weekly frequency of clusterheadache attacks at week 3. Safety was also assessed.

RESULTS:

Recruitment was halted before the trial reached the plannedsample size of 162 because too few volunteers met the eligibility criteria. Of106 enrolled patients, 49 were randomly assigned to receive galcanezumab and 57to receive placebo. The mean (±SD) number of cluster headache attacks per weekin the baseline period was 17.8±10.1 in the galcanezumab group and 17.3±10.1 inthe placebo group. The mean reduction in the weekly frequency of clusterheadache attacks across weeks 1 through 3 was 8.7 attacks in the galcanezumabgroup, as compared with 5.2 in the placebo group (difference, 3.5 attacks perweek; 95% confidence interval, 0.2 to 6.7; P = 0.04). The percentage ofpatients who had a reduction of at least 50% in headache frequency at week 3was 71% in the galcanezumab group and 53% in the placebo group. There were nosubstantial between-group differences in the incidence of adverse events,except that 8% of the patients in the galcanezumab group had injection-sitepain.

CONCLUSIONS:

Galcanezumab administered subcutaneously at a dose of 300 mgonce monthly reduced the weekly frequency of attacks of episodic clusterheadache across weeks 1 through 3 after the initial injection, as compared withplacebo. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT02397473.).

参考文献：

Goadsby et al (2019). Trial of Galcanezumab in Preventionof Episodic Cluster Headache. N Engl J Med. 2019 Jul 11;381(2):132-141.

3. Lancet Neurol—脊髓刺激可治疗慢性背痛和腿痛：诱导复合动作电位控制的闭合环路脊髓刺激可缓解慢性背痛和腿痛

英文摘要：

BACKGROUND:

Spinalcord stimulation has been an established treatment for chronic back and legpain for more than 50 years; however, outcomes are variable and unpredictable,and objective evidence of the mechanism of action is needed. A novel spinalcord stimulation system provides the first in vivo, real-time, continuousobjective measure of spinal cord activation in response to therapy via recordedevoked compound action potentials (ECAPs) in patients during daily use. TheseECAPs are also used to optimise programming and deliver closed-loop spinal cordstimulation by adjusting the stimulation current to maintain activation withinpatients' therapeutic window. We aimed to examine pain relief and the extent ofspinal cord activation with ECAP-controlled closed-loop versus fixed-output,open-loop spinal cord stimulation for the treatment of chronic back and legpain.

METHODS:

Thismulticentre, double-blind, parallel-arm, randomised controlled trial was doneat 13 specialist clinics, academic centres, and hospitals in the USA. Patientswith chronic, intractable pain of the back and legs (Visual Analog Scale [VAS]pain score ≥60 mm;Oswestry Disability Index [ODI] score 41-80) who were refractory toconservative therapy, on stable pain medications, had no previous experiencewith spinal cord stimulation, and were appropriate candidates for a spinal cordstimulation trial were screened. Eligible patients were randomly assigned (1:1)to receive ECAP-controlled closed-loop spinal cord stimulation (investigationalgroup) or fixed-output, open-loop spinal cord stimulation (control group). Therandomisation sequence was computer generated with permuted blocks of size 4and 6 and stratified by site. Patients, investigators, and site staff weremasked to the treatment assignment. The primary outcome was the proportion ofpatients with a reduction of 50% or more in overall back and leg pain with noincrease in pain medications. Non-inferiority (δ=10%) followed by superioritywere tested in the intention-to-treat population at 3 months (primary analysis)and 12 months (additional prespecified analysis) after the permanent implant.This study is registered with ClinicalTrials.gov, NCT02924129, and is ongoing.

FINDINGS:

BetweenFeb 21, 2017, and Feb 20, 2018, 134 patients were enrolled and randomlyassigned (67 to each treatment group). The intention-to-treat analysiscomprised 125 patients at 3 months (62 in the closed-loop group and 63 in theopen-loop group) and 118 patients at 12 months (59 in the closed-loop group and59 in the open-loop group). The primary outcome was achieved in a greaterproportion of patients in the closed-loop group than in the open-loop group at3 months (51 [82·3%] of 62 patients vs 38 [60·3%] of 63 patients; difference21·9%, 95% CI 6·6-37·3; p=0·0052) and at 12 months (49 [83·1%] of 59 patientsvs 36 [61·0%] of 59 patients; difference 22·0%, 6·3-37·7; p=0·0060). We observedno differences in safety profiles between the two groups. The most frequentlyreported study-related adverse events in both groups were lead migration (nine[7%] patients), implantable pulse generator pocket pain (five [4%]), and musclespasm or cramp (three [2%]).

INTERPRETATION:

ECAP-controlledclosed-loop stimulation provided significantly greater and more clinicallymeaningful pain relief up to 12 months than open-loop spinal cord stimulation.Greater spinal cord activation seen in the closed-loop group suggests amechanistic explanation for the superior results, which aligns with theputative mechanism of action for spinal cord stimulation and warrants furtherinvestigation.

参考文献：

Mekhail et al (2019). Long-term safety and efficacy ofclosed-loop spinal cord stimulation to treat chronic back and leg pain (Evoke):a double-blind, randomised, controlled trial. Lancet Neurol. 2019 Dec 20. pii:S1474-4422(19)30414-4.

4. Lancet Neurol —蝶腭神经节刺激可缓解慢性丛集性头痛

英文摘要：

BACKGROUND:

Chronic cluster headache is the most disabling form ofcluster headache. The mainstay of treatment is attack prevention, but theavailable management options have little efficacy and are associated withsubstantial side-effects. In this study, we aimed to assess the safety andefficacy of sphenopalatine ganglion stimulation for treatment of chroniccluster headache.

METHODS:

We did a randomised, sham-controlled, parallel group,double-blind, safety and efficacy study at 21 headache centres in the USA. Werecruited patients aged 22 years or older with chronic cluster headache, whoreported a minimum of four cluster headache attacks per week that wereunsuccessfully controlled by preventive treatments. Participants were randomlyassigned (1:1) via an online adaptive randomisation procedure to eitherstimulation of the sphenopalatine ganglion or a sham control that delivered acutaneous electrical stimulation. Patients and the clinical evaluator andsurgeon were masked to group assignment. The primary efficacy endpoint, whichwas analysed with weighted generalised estimated equation logistic regressionmodels, was the difference between groups in the proportion ofstimulation-treated ipsilateral cluster attacks for which relief from pain wasachieved 15 min after the start of stimulation without the use of acute drugsbefore that timepoint. Efficacy analyses were done in all patients who wereimplanted with a device and provided data for at least one treated attackduring the 4-week experimental phase. Safety was assessed in all patientsundergoing an implantation procedure up to the end of the open-label phase ofthe study, which followed the experimental phase. This trial is registered withClinicalTrials.gov, number NCT02168764.

FINDINGS:

Between July 9, 2014, and Feb 14, 2017, 93 patients were enrolledand randomly assigned, 45 to the sphenopalatine ganglion stimulation group and48 to the control group. 36 patients in the sphenopalatine ganglion stimulationgroup and 40 in the control group had at least one attack during theexperimental phase and were included in efficacy analyses. The proportion ofattacks for which pain relief was experienced at 15 min was 62·46% (95% CI49·15-74·12) in the sphenopalatine ganglion stimulation group versus 38·87%(28·60-50·25) in the control group (odds ratio 2·62 [95% CI 1·28-5·34];p=0·008). Nine serious adverse events were reported by the end of theopen-label phase. Three of these serious adverse events were related to theimplantation procedure (aspiration during intubation, nausea and vomiting, andvenous injury or compromise). A fourth serious adverse event was an infectionthat was attributed to both the stimulation device and the implantationprocedure. The other five serious adverse events were unrelated. There were nounanticipated serious adverse events.

INTERPRETATION:

Sphenopalatine ganglion stimulation seems efficacious and iswell tolerated, and potentially offers an alternative approach to the treatmentof chronic cluster headache.

参考文献：

Goadsby et al (2019). Safety and efficacy of sphenopalatine ganglion stimulation for chronic cluster headache: adouble-blind, randomised controlled trial. Lancet Neurol. 2019Dec;18(12):1081-1090.

5. Nat Nanotechno—纳米药物治疗慢性疼痛初现曙光：靶向于内体neurokinin 1受体的纳米颗粒可以预防慢性疼痛

英文摘要：

Nanoparticle-mediateddrug delivery is especially useful for targets within endosomes because of theendosomal transport mechanisms of many nanomedicines within cells. Here, wereport the design of a pH-responsive, soft polymeric nanoparticle for thetargeting of acidified endosomes to precisely inhibit endosomal signallingevents leading to chronic pain. In chronic pain, the substance P (SP) neurokinin 1 receptor (NK₁R)redistributes from the plasma membrane to acidified endosomes, where it signalsto maintain pain. Therefore, the NK₁Rin endosomes provides an important target for painrelief. The pH-responsive nanoparticles enter cells by clathrin- anddynamin-dependent endocytosis and accumulate in NK₁R-containingendosomes. Following intrathecal injection into rodents, the nanoparticles,containing the FDA-approved NK₁R antagonist aprepitant, inhibitSP-induced activation of spinal neurons and thus prevent paintransmission. Treatment with the nanoparticles leads to complete and persistentrelief from nociceptive, inflammatory and neuropathic nociception and offers amuch-needed non-opioid treatment option for chronic pain.

参考文献：

Ramírez-Garcíaet al (2019). A pH-responsive nanoparticle targets the neurokinin 1 receptor inendosomes to prevent chronic pain. Nat Nanotechnol. 2019 Dec;14(12):1150-1159.

6. Science—科学家发现新型皮肤痛觉感受器：特异化上皮施旺细胞能够感受伤害性和机械性刺激

英文摘要：

Anessential prerequisite for the survival of an organism is the ability to detectand respond to aversive stimuli. Current belief is that noxious stimulidirectly activate nociceptive sensory nerve endings in the skin. We discovereda specialized cutaneous glial cell type with extensive processes forming amesh-like network in the subepidermal border of the skin that conveys noxiousthermal and mechanical sensitivity. We demonstrate a direct excitatoryfunctional connection to sensory neurons and provide evidence of a previouslyunknown organ that has an essential physiological role in sensing noxiousstimuli. Thus, these glial cells, which are intimately associated withunmyelinated nociceptive nerves, are inherently mechanosensitive and transmitnociceptive information to the nerve.

参考文献：

Abdoet al (2019). Specialized cutaneous Schwann cells initiate pain sensation. Science.2019 Aug 16;365(6454):695-699.

7. Science— 白细胞IRE1α-XBP1信号通路激活调控前列腺素合成和痛觉

英文摘要：

Inositol-requiringenzyme 1[α] (IRE1[α])-X-box binding protein spliced (XBP1) signaling maintainsendoplasmic reticulum (ER) homeostasis while controlling immunometabolicprocesses. Yet, the physiological consequences of IRE1α-XBP1 activation inleukocytes remain unexplored. We found that induction ofprostaglandin-endoperoxide synthase 2 (Ptgs2/Cox-2) and prostaglandin Esynthase (Ptges/mPGES-1) was compromised in IRE1α-deficient myeloidcells undergoing ER stress or stimulated through pattern recognition receptors.Inducible biosynthesis of prostaglandins, including the pro-algesic mediatorprostaglandin E2 (PGE₂), was decreased in myeloid cells that lackIRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivatedthe human PTGS2 and PTGES genes to enable optimal PGE₂production. Mice that lack IRE1α-XBP1 in leukocytes, or that were treated withIRE1α inhibitors, demonstrated reduced painbehaviors in PGE₂-dependent models of pain.Thus, IRE1α-XBP1 is a mediator of prostaglandin biosynthesis and a potentialtarget to control pain.

参考文献：

Chopraet al (2019). IRE1α-XBP1 signaling in leukocytes controls prostaglandinbiosynthesis and pain.

Science.2019 Jul 19;365(6450).

8. Nature—疼痛应对有神经环路控制：研究发现一条小鼠调控疼痛应对行为的神经通路

英文摘要：

Animalsand humans display two types of response to noxious stimuli. The first includesreflexive defensive responses that prevent or limit injury; a well-knownexample of these responses is the quick withdrawal of one's hand upon touchinga hot object. When the first-line response fails to prevent tissue damage (forexample, a finger is burnt), the resulting paininvokes a second-line coping response-such as licking the injured area tosoothe suffering. However, the underlying neural circuits that drive these twostrings of behaviour remain poorly understood. Here we show in mice that spinalneurons marked by coexpression of TAC1^Cre and LBX1^Flpodrive coping responses associated with pain.Ablation of these spinal neurons led to the loss of both persistent licking andconditioned aversion evoked by stimuli (including skin pinching and burninjury) that-in humans-produce sustained pain,without affecting any of the reflexive defensive reactions that we tested. Thisselective indifference to sustained pain resemblesthe phenotype seen in humans with lesions of medial thalamic nuclei^1-3.Consistently, spinal TAC1-lineage neurons are connected to medial thalamicnuclei by direct projections and via indirect routes through the superiorlateral parabrachial nuclei. Furthermore, the anatomical and functionalsegregation observed at the spinal level also applies to primary sensoryneurons. For example, in response to noxious mechanical stimuli, MRGPRD- andTRPV1-positive nociceptors are required to elicit reflexive and copingresponses, respectively. Our study therefore reveals a fundamental subdivisionwithin the cutaneous somatosensory system, and challenges the validity of usingreflexive defensive responses to measure sustained pain.

参考文献：

Huang et al (2019). Identifying the pathways required forcoping behaviours associated with sustained pain. Nature. 2019Jan;565(7737):86-90.

9.Science—万事万物相生相克：科学家发现一个孤儿型抗阿片肽系统受体

英文摘要：

Opioidstarget the μ-opioid receptor (MOR) to produce unrivaled pain management, buttheir addictive properties can lead to severe abuse. We developed awhole-animal behavioral platform for unbiased discovery of genes influencingopioid responsiveness. Using forward genetics in Caenorhabditis elegans,we identified a conserved orphan receptor, GPR139, with anti-opioid activity.GPR139 is coexpressed with MOR in opioid-sensitive brain circuits, binds toMOR, and inhibits signaling to heterotrimeric guanine nucleotide-bindingproteins (G proteins). Deletion of GPR139 in mice enhanced opioid-inducedinhibition of neuronal firing to modulate morphine-induced analgesia, reward,and withdrawal. Thus, GPR139 could be a useful target for increasing opioidsafety. These results also demonstrate the potential of C. elegans as ascalable platform for genetic discovery of G protein-coupled receptor signalingprinciples.

参考文献：

Wanget al (2019). Genetic behavioral screen identifies an orphan anti-opioidsystem. Science. 2019 Sep 20;365(6459):1267-1273.

10. Science—痛苦引起负面情绪与杏仁核有关：研究发现杏仁核神经元编码痛觉引起的负面情绪

英文摘要：

Pain is an unpleasant experience. How the brain'saffective neural circuits attribute this aversive quality to nociceptiveinformation remains unknown. By means of time-lapse in vivo calcium imaging andneural activity manipulation in freely behaving mice encountering noxiousstimuli, we identified a distinct neural ensemble in the basolateral amygdalathat encodes the negative affective valence of pain.Silencing this nociceptive ensemble alleviated painaffective-motivational behaviors without altering the detection of noxiousstimuli, withdrawal reflexes, anxiety, or reward. Following peripheral nerveinjury, innocuous stimuli activated this nociceptive ensemble to drivedysfunctional perceptual changes associated with neuropathic pain, including painaversion to light touch (allodynia). These results identify the amygdalarrepresentations of noxious stimuli that are functionally required for thenegative affective qualities of acute and chronic painperception.

参考文献：

Corder et al (2019). An amygdalar neural ensemble thatencodes the unpleasantness of pain. Science. 2019 Jan 18;363(6424):276-281.

2019年十大研究进展名录

1. 年终盘点：2019年帕金森病十大基础研究进展

2. 年终盘点：2019年帕金森病十大临床研究进展

3. 年终盘点：2019年阿尔茨海默病十大基础研究进展

4. 年终盘点：2019年阿尔茨海默病十大临床研究进展

5. 年终盘点：2019年神经科学领域十大基础研究进展

6. 年终盘点：2019年抑郁症领域十大基础研究进展（一半来自中国）

7. 年终盘点：2019年脑血管病领域十大基础研究进展

8. 年终盘点：2019年神经炎症领域十大基础研究进展

9. 年终盘点：2019年神经活动记录十大基础研究进展

10. 年终盘点：2019年ALS/FTD十大基础研究进展

11. 年终盘点：2019年医学和生物学领域深度学习和神经网络十大基础研究进展

12. 年终盘点：2019年神经内科十大临床研究突破

2018年十大研究进展名录

1.盘点2018年阿尔茨海默病十大研究突破

2.盘点2018年帕金森病十大研究突破

3. 盘点2018年神经科学二十大研究突破

4. 盘点2018年渐冻症（ALS）十大研究进展

5. 盘点2018年全球脑卒中十大研究进展

6. 盘点2018年神经影像十大研究进展

7. 盘点2018年神经炎症领域的十大研究突破

8. 盘点2018年神经变性痴呆十大研究突破

9. 2018年神经科学“学习和记忆”领域十大研究进展

10. 2018年抑郁症领域的十大研究突破

11. 2018年痛觉和疼痛领域的十大研究突破

12. 2018年的神经干细胞研究十大研究进展

13. 2018年的神经干细胞研究十大研究进展

14. 2018年的十大睡眠研究突破

15. 2018年“衰老和长生不老”领域的十大研究突破

16. 2018年自闭症领域的十大研究突破

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20个神经科学领域的突破可能获得诺贝尔奖

1. 意识研究：意识的本质、组成、运行机制及其物质载体；不同意识层次的操控和干预，意识障碍性疾病的治疗。

2. 学习和记忆的机制及其调控：记忆的形成和消退机制，记忆的人为移植和记忆的人为消除等；

3. 痴呆研究：阿尔茨海默病的机制和治疗研究，血管性痴呆、额颞叶痴呆、路易体痴呆的机制研究和治疗。

4. 睡眠和睡眠障碍的机制和干预研究。

5. 情绪研究：喜、怒、哀、恐等基本情绪的机制和相关疾病的治疗。

6. 计算和逻辑推理的神经科学基础研究。

7. 语言的神经科学基础研究。

8. 视觉图像形成和运用的神经科学基础研究。

9. 创造力、想象力和艺术文学创造的神经基础研究。

10. 痛觉的神经科学基础及其干预研究

11. 性行为研究：性行为的神经科学基础研究和性行为的调控和干预。

12. 脑和脊髓损伤的机制及其干预研究，包括脑卒中、脊髓损伤机制研究，神经干细胞移植研究，新型神经修复技术，神经康复技术。

13. 精神类疾病的机制和干预研究：自闭症、精分、抑郁症、智能障碍、药物成瘾等；

14. 运动神经元病等神经变性病机制研究及其干预。

15. 衰老的机制和永生研究，包括大脑衰老的机制和寿命延长研究。

16. 神经系统遗传病的机制研究及基因治疗。

17. 神经操纵和调控技术：光遗传技术、药物遗传技术、基因编辑技术、经颅磁刺激、深部脑刺激和电刺激等。

18. 脑组织兼容性电子微芯片及脑机互动装置研究，包括脑机接口、神经刺激芯片、记忆存储芯片，意识存储芯片，人脑非语言互动装置等。

19. 半人半机器人的设计、完善和修复技术：包括任何机械肢体的人类移植，大脑移植入机器体内等。

20. 新型大脑成像和神经元活动记录技术：高分辨率成像技术、大型电极微阵列技术等。