Modulation of itch and pain signals processing in ventrobasal thalamus by thalamic reticular nucleus.

Thalamic reticular nucleus (TRN) is known to be crucial for dynamically modulating sensory processing. Recently, the functional role of TRN in itch and pain sensation processing has drawn much attention. We found that ventrobasal thalamus (VB) neurons exhibited scratching behavior-related and nociceptive behavior-related neuronal activity changes, and most of VB neurons responsive to pruritic stimulus were also activated by nociceptive stimulus. Inhibition of VB could relieve itch-induced scratching behaviors and pathological pain without affecting basal nociceptive thresholds, and activation of VB could facilitate scratching behaviors. Tracing and electrophysiology recording results showed that VB mainly received inhibitory inputs from ventral TRN. Furthermore, optogenetic activation of TRN-VB projections suppressed scratching behaviors, and ablation of TRN enhanced scratching behaviors. In addition, activation of TRN-VB projections relieved the pathological pain without affecting basal nociceptive thresholds. Thus, our study indicates that TRN modulates itch and pain signals processing via TRN-VB inhibitory projections.

Alterations of regional spontaneous brain activities in anxiety disorders: A meta-analysis.

BACKGROUND: Recent resting-state functional magnetic resonance imaging studies have provided strong evidence of abnormal regional spontaneous brain activities among anxiety-disordered patients. However, the evidence has been divergent and inconclusive. Therefore, it is necessary to perform a meta-analysis identifying a common pattern of altered regional spontaneous brain activity for anxiety disorders. METHOD: Corresponding research of anxiety disorders, namely, whole-brain rs-fMRI studies that measured differences in regional homogeneity, amplitude of low-frequency fluctuations, or fractional amplitude of low-frequency fluctuations, were analyzed in this study. Overall, seven studies with 235 anxiety-disordered patients and 241 healthy controls were ultimately included in the meta-analysis. The meta-analysis was processed by seed-based d mapping. RESULTS: Compared with healthy controls, patients with anxiety disorders showed significantly decreased regional spontaneous brain activities in the right putamen, the right orbital inferior frontal gyrus, and the right temporal pole. No increases in regional spontaneous brain activities were detected in patients relative to the controls. LIMITATION: Limited number of available studies, only Asian samples, and insufficient information of sample characteristics. CONCLUSION: The present study suggests that anxiety disorders are associated with aberrant regional brain activity in areas connected with emotion processing, which extends our understanding of anxiety disorders' pathophysiology.

Protocol for recording the discharge of locus coeruleus neurons in free-moving mice during different sleep-wake stages.

Cortical electroencephalography (EEG) is generally used to detect the different sleep-wake states of animals. EEG combined with in vivo multichannel recording provides a powerful tool for decoding the neural network of sleep-wake regulation. Here, we detail a protocol using cortical EEG combined with in vivo multichannel recording to examine the activity of locus coeruleus (LC) neurons in free-moving mice at different sleep-wake stages. The procedures for electrode fabrication, the surgery to implant electrodes, and post-recording data analysis are also included. For complete details on the use and execution of this protocol, please refer to Liang et al. (2021).

Frequency-Specific Blood Oxygen Level Dependent Oscillations Associated With Pain Relief From Ankle Acupuncture in Patients With Chronic Low Back Pain.

Objective: Recent advances in brain imaging have deepened our knowledge of the neural activity in distinct brain areas associated with acupuncture analgesia. However, there has not been conclusive research into the frequency-specific resting-state functional changes associated with acupuncture analgesia in patients with chronic pain. Here, we aimed to characterize changes across multiple frequencies of resting-state cortical activity associated with ankle acupuncture stimulation (AAS) in patients with chronic low back pain (CLBP) and healthy controls. Methods: Twenty seven patients with CLBP and Twenty five age- and gender-matched healthy volunteers were enrolled in the study. Participants received tactile sham acupuncture (TSA) and AAS, respectively. The whole-brain amplitude of low-frequency fluctuation (ALFF) in the range 0.01-0.25 Hz was assessed for changes associated with each intervention. Further, a visual analog scale (VAS) was used to collect subjective measures of pain intensity in patients. Linear mixed-effect modeling (LME) was used to examine the mean ALFF values of AAS and TSA between patients and healthy controls. Results: The ALFF was modulated in the default mode network (an increase in the medial prefrontal cortex, and a decrease in the cerebellum/posterior ingulate/parahippocampus, P < 0.01, corrected) in both patients and controls. Decreased ALFF in the bilateral insular was frequency-dependent. Modulations in the cerebellum and right insular were significantly correlated with VAS pain score after AAS (P < 0.01). Conclusion: Hence, frequency-specific resting-state activity in the cerebellum and insular was correlated to AAS analgesia. Our frequency-specific analysis of ALFF may provide novel insights related to pain relief from acupuncture.

The NAergic locus coeruleus-ventrolateral preoptic area neural circuit mediates rapid arousal from sleep.

The locus coeruleus (LC), which is located in the brain stem, plays an important role in promoting arousal. However, the neural circuitry underlying this function remains unclear. Using cortical electroencephalography combined with optrode recording, we found that LC noradrenergic (LCNA) neurons exhibit high activity during wakefulness, while suppressing the activity of these neurons causes a reduction in wakefulness. Viral tracing showed that LCNA neurons directly project to the ventrolateral preoptic area (VLPO) and that optogenetic activation of the noradrenergic (NAergic) LC-VLPO (NAergicLC-VLPO) neural circuit promotes arousal. Optrode recordings in the VLPO revealed two functionally distinct neuronal populations that were stimulated in response to the optogenetic activation of LCNA neurons. Consistently, we identified two types of VLPO neurons that exhibited different responses to NAergic projections from the LC mediated by discrete adrenergic receptors. Together, our results demonstrate that the NAergicLC-VLPO neural circuit is a critical pathway for controlling wakefulness and that a synergistic effect is produced by inhibition of sleep-active neurons in the VLPO through α2 receptors and activation of wake-active neurons in the VLPO through α1 and ß receptors.

Resting-state abnormalities in functional connectivity of the default mode network in autism spectrum disorder: a meta-analysis.

Increasing evidence has shown that the resting state brain connectivity of default mode network (DMN) which are important for social cognition are disrupted in autism spectrum disorder (ASD). However, previous neuroimaging studies did not present consistent results. Therefore, we performed a meta-analysis of resting-state functional connectivity (rsFC) studies of DMN in the individuals with ASD and healthy controls (HCs) to provide a new perspective for investigating the pathophysiology of ASD. We carried out a search using the terms: ("ASD" OR "Autism") AND ("resting state" OR "rest") AND ("DMN" OR "default mode network") in PubMed, Web of Science and Embase to identify the researches published before January 2020. Ten resting state datasets including 203 patients and 208 HCs were included. Anisotropic Effect Size version of Signed Differential Mapping (AES-SDM) method was applied to identify group differences. In comparison with the HCs, the patients with ASD showed increased connectivity in cerebellum, right middle temporal gyrus, superior occipital gyrus, right supramarginal gyrus, supplementary motor area and putamen. Decreased connectivity was discovered in some nodes of DMN, such as medial prefrontal cortex, precuneus and angular gyrus. These results may help us to further clarify the neurobiological mechanisms in patients with ASD.

[Effect of electroacupuncture on morphine-conditioned place preference and activation of glutamatergic neurons in the ventromedial prefrontal cortex in rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Zusanli"(ST36) and "Sanyinjiao"(SP6) on conditioned place preference (CPP) and activation of glutamatergic neurons in the ventromedial prefrontal cortex (VMPFC) of morphine-addiction rats, so as to explore its mechanisms underlying detoxification. METHODS: Thirty male SD rats were randomly and equally divided into control, model and EA groups. The rats with acquisition of morphine-induced CPP received intraperitoneal injection of morphine (10 mg/kg) in the morphine-paired chamber, once daily for 3 consecutive days, and those of the control group received intraperitoneal injection of the same dose of normal saline in saline-paired chamber. Thirty minutes before CPP acquisition training, EA (2 Hz/100 Hz, 0.5 to 1.0 mA) was applied to ST36 and SP6 for 20 min every day. The double-labeled neurons of Fos/vesicular glutamate transporter 2 (VGLUT2) in the VMPFC were detected by using fluorescent immunohistochemistry. The discharges of the VMPFC neurons were recorded by using a multi-channel microarray electrophysiological system, followed by performing a z-score standardized processing. The ratio of firing rate frequency of rats in the morphine-paired chamber/saline-paired chamber was calculated, and further statistical analysis was conducted on the data based on the standardized z-scores. The neuronal firing characteristic of glutamatergic neuron is low frequency and wide wave. RESULTS: Compared with the control group, the score of morphine-induced CPP and numbers of Fos, VGLUT2-positive and Fos-VGLUT2 double-labeled positive cells were significantly increased in the model group (P<0.01，P<0.05). After EA and in comparison with the model group, the morphine CPP score and numbers of Fos, VGLUT2-positive and Fos-VGLUT2 double-labeled cells were significantly reduced in the EA group (P<0.01，P<0.05). The ratio of firing rate of the VMPFC neurons in the preference chamber and the percentage of inhibitory neurons as well as the z-score were considerably lower in the EA group than in the model group (P<0.001). CONCLUSION: EA can suppress morphine-induced seeking behavior in rats, which may be related to its inhibitory effect on glutamatergic neurons in the VMPFC.

Approach Behavior Induced by 10.6-µm Laser Stimulation at Acupoint ST36 in a Rat Model of Incisional Pain.

Objective: Laser stimulation (LS) at both the injury site and specific acupoints may induce analgesic effects. The purpose of this study is to investigate the effects of LS at injury site or acupoint on analgesic-associated approach behavior and determine whether opioid receptors in the anterior cingulate cortex (ACC) were involved. Methods: The left hindpaw incision was established in rats. LS (10.6 µm) was performed at the ipsilateral (left) acupoint ST36 (Zusanli) or locally to the incision site. Characteristic guarding pain behavior was measured to assess incision-induced pain. A two-chamber conditioned place preference (CPP) paradigm was used to measure approach behavior induced by pain relief. To inhibit opioid receptors, naloxone was microinjected into the ACC before LS. Results: A delayed analgesic effect (24 h after treatment) was induced in both the LS groups (ST36 and incision site) as compared with the sham control or model groups (p < 0.05). An immediate (30 min after the end of the LS) decrease in guarding pain (p < 0.001) and CPP for the LS chamber (p < 0.001) were observed only in the ST36 LS group. The administration of naloxone in ACC inhibited the LS-induced analgesic effect and CPP (p < 0.05). Conclusions: Our results highlight the novel approach behavior of pain relief induced by 10.6-µm LS at ST36 in a rat model of incisional pain, and implicate ACC opioid receptor signaling in these actions.

Laser photobiomodulation for cartilage defect in animal models of knee osteoarthritis: a systematic review and meta-analysis.

To review and assess the efficacy of laser photobiomodulation for cartilage defect in animal models of knee osteoarthritis (KOA). Medline, Web of Science, and EMBASE were searched. Studies were considered if the global quality score of cartilage were parallelly reported between laser and untreated control groups. The methodological quality of each study was assessed using a modified 10-item checklist. The effect size was estimated by standardized mean difference (SMD) and pooled based on the random-effects model. Stratified analysis and regression analysis were conducted to partition potential heterogeneity. An adjusted significant level of 0.01 was acceptable. Five hundred eight initial search recordings were identified, of which 14 studies (including 274 animals) were included for quantitative analysis. The global quality scores mostly weighted by the structural integrity and chondrocyte distribution were measured by different four scales including Histologic Histochemical Grading System (HHGS), Osteoarthritis Research Society International (OARSI), Pineda, and Huang. There were considerable variances on laser parameters and irradiation time among those included studies. Overall, a moderate level of methodological qualities was determined. The synthesis results indicated that the SMD effect size was significantly larger in HHGS (z = 2.61, P = 0.01) and Huang (z = 4.90, P < 0.01) groups. Stratified by irradiance, SMD of low (< 1 W/cm2) but not high (≥ 1 W/cm2) level estimated significant difference (z = 5.62, P < 0.01). Meta-regression identified a significant association for SMDs and irradiation time (P < 0.01). Yet, Egger's test detected small study effect (P < 0.01). No individual study with significant variance was found in homogeneity tests. The results demonstrated the positive effect of laser photobiomodulation for cartilage defect in animal models of KOA under proper irradiance and adequate irradiation time.

The low-frequency BOLD signal oscillation response in the insular associated to immediate analgesia of ankle acupuncture in patients with chronic low back pain.

PURPOSE: The present study evaluated the modulation effect of a painless acupuncture technique, ankle acupuncture (AA), on resting-state functional change in patients with chronic low back pain (CLBP). PATIENTS AND METHODS: Fourteen participants diagnosed with CLBP received AA and underwent one brain functional image scan after tactile stimulation and another one following the insertion of the needle. The needling sensations and clinical pain intensities were evaluated after the end of each functional image scan. The significance levels of Visual Analog Scales/Scores (VASs) before and after acupuncture were determined using paired t-test. The brain areas showing differences in the amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) between the two scans were identified. We also explored the relationship between mean ALFF values in brain areas identified and VAS scores based on Pearson correlation coefficient. RESULTS: A complete-case analysis was performed on 12 participants. Neither different needling sensations nor any local sensations during the two scans was found. The clinical findings indicated that the scores of VAS scores were significantly lower after AA intervention (P<0.001). Compared with those after tactile stimulation, ALFF decreased in the left insular and increased in the left precuneus and right precentral gyrus, and fALFF decreased in the left insular, during retaining of AA (corrected). Moreover, there was a positive correlation found between mean ALFF change in the left insular and that of VAS values (P<0.05). CONCLUSION: The present study demonstrated the low-frequency BOLD signal oscillation response in the left insular in brain activity was associated with an immediate analgesia of AA in patients with CLBP, which provides new insights into intrinsic connections between low-frequency brain signals and analgesic effects of acupuncture.

[Brain regions responding to acupuncture stimulation of Zusanli (ST36) in healthy subjects analyzed on the basis of spontaneous brain activity].

OBJECTIVE: To determine the attributes of responses of the higher nerve center to acupuncture stimulation of Zusanli (ST36) on the basis of spontaneous brain activity, so as to explore the synchronization level of different brain rejoins after acupuncture. METHODS: All studies using fMRI to investigate the effect of acupuncture stimulation of ST36 and/or other acupoints on the human brain (at least 10 healthy subjects or patients in one group) published in journals from January of 1995 to January of 2018 were searched from databases of CNKI and PubMed by using keywords of acupuncture, electroacupuncture, and resting-state functional magnetic resonance images (rs-fMRI) or regional homogeneity (ReHo). Brain functional image data of acupuncture stimulation of ST36 and/or other acupoints were collected and analyzed with anisotropic effect size-signed differential mapping (AES-SDM) software (Meta-analysis), and those of acupuncture of simple ST36 analyzed as a subgroup. RESULTS: A total of 229 papers in Chinese and 109 in English were collected. According to our inclusive and exclusive standards, 11 papers containing 235 subjects were brought into analysis at last. Meta-analysis of brain image data of acupuncture at ST36 and/or other acupoints (comparison between pre- and post-acupuncture) revealed that the same brain regions (generality) which showed a significant increase in ReHo, are the right and left anterior cingulated gyrus, right caudate, left superior frontal gyrus, right middle frontal gyrus, and the right paracentral lobe, and those which showed a marked decrease of ReHo are the left mid-inferior occipital gyrus, left and right precentral and postcentral gyrus. The brain regions responding to acupuncture at ST36 only (specificity) are the right inferior parietal lobe, left middle inferior gyrus, right posterior lobe of cerebellum, and the left angular gyrus which displayed an increase of ReHo, and the right middle superior frontal gyrus which showed a decrease in ReHo. CONCLUSION: After acupuncturing at ST36, the relative generality and specificity of the central response in healthy subjects reflected as the location of the affected brain regions and the difference in the synchronization level of the corresponding spontaneous brain activities.

The Immediate Analgesic Effect of Acupuncture for Pain: A Systematic Review and Meta-Analysis.

Although acupuncture is gaining popularity for the treatment of nonspecific pain, the immediate analgesic effect of acupuncture has never been reviewed. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) on disease-related pain to critically evaluate the immediate effect of acupuncture for pain relief. The PubMed and Cochrane Central Register of Controlled Trials databases as well as three Chinese databases including the China National Knowledge Infrastructure (CNKI), Wanfang, and VIP platforms were searched through November 2016. The outcome was the extent of pain relief from baseline within 30 min of the first acupuncture treatment. We evaluated all RCTs comparing acupuncture with other interventions for disease-related pain. Real acupuncture showed statistically significantly greater pain relief effect compared to sham acupuncture (SMD, -0.56; 95% confidence interval [CI], -1.00 to -0.12; 9 RCTs) and analgesic injection (SMD, -1.33; 95% CI, -1.94 to -0.72; 3 RCTs). No serious adverse events were documented. Acupuncture was associated with a greater immediate pain relief effect compared to sham acupuncture and analgesic injections. Further RCTs with stricter design and methodologies are warranted to evaluate the immediate pain relief effect of acupuncture for more disease-related pain.

Immediate relief of herniated lumbar disc-related sciatica by ankle acupuncture: A study protocol for a randomized controlled clinical trial.

BACKGROUND: Around 90% of sciatica cases are due to a herniated intervertebral disc in the lumbar region. Ankle acupuncture (AA) has been reported to be effective in the treatment of acute nonspecific low back pain. This study aims to evaluate the efficacy of a single session of ankle acupuncture for disc-related sciatica. METHOD: This will be a double-blinded, randomized controlled clinical trial. Patients diagnosed with disc-related sciatica will be randomly divided into 3 parallel groups. The treatment group (n = 30) will receive ankle acupuncture. The 2 control groups will either undergo traditional needle manipulation (n = 30) or sham acupuncture (n = 30) at the same point as the treatment group. The primary outcome will be pain intensity on a visual analog scale (VAS). The secondary outcomes will be paresthesia intensity on a VAS and the Abbreviated Acceptability Rating Profile (AAPR). The success of blinding will be evaluated, and the needle-induced sensation and adverse events will be recorded. All outcomes will be evaluated before, during, and after the treatment. DISCUSSION: This study will determine the immediate effect and specificity of ankle acupuncture for the treatment of disc-related sciatica. We anticipate that ankle acupuncture might be more effective than traditional needle manipulation or sham acupuncture. TRIAL REGISTRATION: ChiCTR-IPR-15007127 (http://www.chictr.org.cn/showprojen.aspx?proj=11989).