An electric field modeling study with meta-analysis to understand the antidepressant effects of transcranial direct current stimulation (tDCS)

Objective: Transcranial direct current stimulation (tDCS) has mixed effects for major depressive disorder (MDD) symptoms, partially owing to large inter-experimental variability in tDCS protocols and their correlated induced electric fields (E-fields). We investigated whether the E-field strength of distinct tDCS parameters was associated with antidepressant effect. Methods: A meta-analysis was performed with placebo-controlled clinical trials of tDCS enrolling MDD patients. PubMed, EMBASE, and Web of Science were searched from inception to March 10, 2023. Effect sizes of tDCS protocols were correlated with E-field simulations (SimNIBS) of brain regions of interest (bilateral dorsolateral prefrontal cortex [DLPFC] and bilateral subgenual anterior cingulate cortex [sgACC]). Moderators of tDCS responses were also investigated. Results: A total of 20 studies were included (21 datasets, 1,008 patients), using 11 distinct tDCS protocols. Results revealed a moderate effect for MDD (g = 0.41, 95%CI 0.18-0.64), while cathode position and treatment strategy were found to be moderators of response. A negative association between effect size and tDCS-induced E-field magnitude was seen, with stronger E-fields in the right frontal and medial parts of the DLPFC (targeted by the cathode) leading to smaller effects. No association was found for the left DLPFC and the bilateral sgACC. An optimized tDCS protocol is proposed. Conclusions: Our results highlight the need for a standardized tDCS protocol in MDD clinical trials. Registration number: PROSPERO CRD42022296246.

Mechanism of anterior cingulate cortex in modulating pain and anxiety-like behavior in chronic non-specific low back pain model rats / 中华行为医学与脑科学杂志

Objective:To explore the potential mechanisms of anterior cingulate cortex (ACC) in modulating pain behavior and anxiety-like behavior of rats with chronic non-specific low back pain induced by nerve growth factor (NGF).Methods:Ninety-six male SPF grade SD rats aged 8 weeks were randomly divided into four groups according the random number table method: control group, model group, control+ D-2-amino-5-phosphonopentanoate (D-AP5) group (control+ D-AP5 group) and model+ D-AP5 group, with 24 rats in each group.Low back pain model of rat was established by injection of NGF into multifidus muscle (left side) of the low backs of rats(two times with a five-day interval). Five days after modeling, rats in model+ D-AP5 group and control+ D-AP5 group were injected with the N-methyl-D-aspartate (NMDA) receptor antagonist D-AP5(2 μg, 0.3 μL) at the right side of the ACC once a day for consecutive 3 days, and rats in control group and model group were injected with the same amount of 0.9% sodium chloride solution. Seven days after modeling, the pain threshold of rats was evaluated by mechanical stimulation test and hot and cold plate test.The anxiety-like behavior was tested by open field test.The density of glial fibrillary acidic protein (GFAP) positive cells and c-Fos(a kind of immediate early gene) positive cells of the spinal cord were observed by immunofluorescence. The expression of GFAP, c-Fos, phosphorylated-c-Jun N-terminal kinases (p-JNK), monocyte chemoattractant protein-1 (MCP-1), and chemokine (C-X-C motif) ligand 1 (CXCL-1) proteins in the L2 segment of the spinal cord were detected by Western blot. SPSS 23.0 software was used for statistical analysis. One-way ANOVA was used to analyze normal distribution measurement data for comparison among multiple groups, and Tukey test was used for further pairwise comparisons. The Kruakal-Wallis H test was used for non-normal distribution measurement data, and Mann-Whitney U test was used for further pairwise comparisons with Bonferroni-corrected P-values. Results:In the experiments measuring pressure pain threshold (PPT) and paw withdrawal threshold (PWT), there were statistically significant differences in the PPT and PWT of rats among the four groups ( F=53.498, 41.939, both P<0.001). Seven days after modeling, PPT ((418.5±46.9) g) and PWT ( (55.6±7.1) g) in the ipsilateral side of the rats in model+ D-AP5 group were higher than those in model group ((290.0±32.0) g, (30.5±7.5) g) (both P<0.001). In the open field test, there were statistically significant differences in percentage of the inner zone distance ( H=11.922, P<0.01) and the percentage of inner zone time ( H=21.614, P<0.001) of rats among the four groups. The percentage of inner zone time in model+ D-AP5 group was higher than that in model group (5.6(4.3, 7.9) %, 3.1(2.1, 3.8) %) ( P<0.01). The results of immunofluorescence showed that there were statistically significant differences in the density of GFAP positive cells and c-Fos positive cells at the ipsilateral side of the superficial laminae of rats among the four groups ( H=49.085, F=18.120, both P<0.001). The density of GFAP positive cells (34.3(21.1, 47.5) cells/mm 2) and c-Fos positive cells ((52.7±39.4) cells/mm 2) at the ipsilateral side of the superficial laminae in model+ D-AP5 group were less than those in model group (76.5(68.6, 94.9) cells/mm 2, (112.4±63.7) cells/mm 2) (both P<0.001). The Western blot results showed that there were statistically significant differences in the protein expression of GFAP, c-Fos, p-JNK, MCP-1 and CXCL-1 in the L2 segment of rats among the four groups ( F=49.413, 38.437, 41.867, 36.735, 130.951, all P<0.001). The protein expression of GFAP (1.7±0.5), c-Fos (1.1±0.1), p-JNK (1.7±0.3), MCP-1 (1.0±0.4) and CXCL-1 (0.8±0.1) in the L2 segment in model+ D-AP5 group were lower than those in model group ((4.3±0.7), (2.6±0.5), (2.8±0.4), (2.9±0.4), (3.5±0.4)) (all P<0.01). Conclusion:ACC modulates mechanical hyperalgesia and anxiety-like behavior in chronic non-specific low back pain rats, which might be associated with the involvement of spinal astrocytes, p-JNK signal pathway and chemokines such as MCP-1 and CXCL-1.

An Anterior Cingulate Cortex-to-Midbrain Projection Controls Chronic Itch in Mice / 神经科学通报·英文版

Itch is an unpleasant sensation that provokes the desire to scratch. While acute itch serves as a protective system to warn the body of external irritating agents, chronic itch is a debilitating but poorly-treated clinical disease leading to repetitive scratching and skin lesions. However, the neural mechanisms underlying the pathophysiology of chronic itch remain mysterious. Here, we identified a cell type-dependent role of the anterior cingulate cortex (ACC) in controlling chronic itch-related excessive scratching behaviors in mice. Moreover, we delineated a neural circuit originating from excitatory neurons of the ACC to the ventral tegmental area (VTA) that was critically involved in chronic itch. Furthermore, we demonstrate that the ACC→VTA circuit also selectively modulated histaminergic acute itch. Finally, the ACC neurons were shown to predominantly innervate the non-dopaminergic neurons of the VTA. Taken together, our findings uncover a cortex-midbrain circuit for chronic itch-evoked scratching behaviors and shed novel insights on therapeutic intervention.

A narrative review on invasive brain stimulation for treatment-resistant depression

While most patients with depression respond to pharmacotherapy and psychotherapy, about one-third will present treatment resistance to these interventions. For patients with treatment-resistant depression (TRD), invasive neurostimulation therapies such as vagus nerve stimulation, deep brain stimulation, and epidural cortical stimulation may be considered. We performed a narrative review of the published literature to identify papers discussing clinical studies with invasive neurostimulation therapies for TRD. After a database search and title and abstract screening, relevant English-language articles were analyzed. Vagus nerve stimulation, approved by the U.S. Food and Drug Administration as a TRD treatment, may take several months to show therapeutic benefits, and the average response rate varies from 15.2-83%. Deep brain stimulation studies have shown encouraging results, including rapid response rates (> 30%), despite conflicting findings from randomized controlled trials. Several brain regions, such as the subcallosal-cingulate gyrus, nucleus accumbens, ventral capsule/ventral striatum, anterior limb of the internal capsule, medial-forebrain bundle, lateral habenula, inferior-thalamic peduncle, and the bed-nucleus of the stria terminalis have been identified as key targets for TRD management. Epidural cortical stimulation, an invasive intervention with few reported cases, showed positive results (40-60% response), although more extensive trials are needed to confirm its potential in patients with TRD.

To Blame or Not? Modulating Third-Party Punishment with the Framing Effect / 神经科学通报·英文版

People as third-party observers, without direct self-interest, may punish norm violators to maintain social norms. However, third-party judgment and the follow-up punishment might be susceptible to the way we frame (i.e., verbally describe) a norm violation. We conducted a behavioral and a neuroimaging experiment to investigate the above phenomenon, which we call the "third-party framing effect". In these experiments, participants observed an anonymous perpetrator deciding whether to keep her/his economic benefit while exposing a victim to a risk of physical pain (described as "harming others" in one condition and "not helping others" in the other condition), then they had a chance to punish that perpetrator at their own cost. Our results showed that the participants were more willing to execute third-party punishment under the harm frame compared to the help frame, manifesting a framing effect. Self-reported anger toward perpetrators mediated the relationship between empathy toward victims and the framing effect. Meanwhile, activation of the insula mediated the relationship between mid-cingulate cortex activation and the framing effect; the functional connectivity between these regions significantly predicted the size of the framing effect. These findings shed light on the psychological and neural mechanisms of the third-party framing effect.

Anterior Cingulate Cortex Mediates Hyperalgesia and Anxiety Induced by Chronic Pancreatitis in Rats / 神经科学通报·英文版

Central sensitization is essential in maintaining chronic pain induced by chronic pancreatitis (CP), but cortical modulation of painful CP remains elusive. Here, we examined the role of the anterior cingulate cortex (ACC) in the pathogenesis of abdominal hyperalgesia in a rat model of CP induced by intraductal administration of trinitrobenzene sulfonic acid (TNBS). TNBS treatment resulted in long-term abdominal hyperalgesia and anxiety in rats. Morphological data indicated that painful CP induced a significant increase in FOS-expressing neurons in the nucleus tractus solitarii (NTS) and ACC, and some FOS-expressing neurons in the NTS projected to the ACC. In addition, a larger portion of ascending fibers from the NTS innervated pyramidal neurons, the neural subpopulation primarily expressing FOS under the condition of painful CP, rather than GABAergic neurons within the ACC. CP rats showed increased expression of vesicular glutamate transporter 1, and increased membrane trafficking and phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) subunit NR2B and the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit GluR1 within the ACC. Microinjection of NMDAR and AMPAR antagonists into the ACC to block excitatory synaptic transmission significantly attenuated abdominal hyperalgesia in CP rats, which was similar to the analgesic effect of endomorphins injected into the ACC. Specifically inhibiting the excitability of ACC pyramidal cells via chemogenetics reduced both hyperalgesia and comorbid anxiety, whereas activating these neurons via optogenetics failed to aggravate hyperalgesia and anxiety in CP rats. Taken together, these findings provide neurocircuit, biochemical, and behavioral evidence for involvement of the ACC in hyperalgesia and anxiety in CP rats, as well as novel insights into the cortical modulation of painful CP, and highlights the ACC as a potential target for neuromodulatory interventions in the treatment of painful CP.

Efficacy and possible mechanism study of low-intensity focused ultrasound therapy for neuropathic pain in mice / 中华超声影像学杂志

Objective:To study the efficacy of low-intensity focused ultrasound (LIFU) on neuropathic pain (NP) in mice, and its effect on the activation of astrocytes and the expression of pro-inflammatory cytokines were discussed.Methods:Thirty-six male C57BL/6J mice were randomly divided into three groups: sham operation (Sham) group and chroinc constriction injury (CCI) model group and treatment (CCI+ LIFU) group, 12 mice in each group.NP model was established by CCI on the sciatic nerve. The group of CCI+ LIFU received LIFU treatment for the anterior cingulate cortex (ACC) on the 7th day after surgery, the mechanical withdrawal threshold (MWT) on the affected side of mice was measured at preoperation 3, 6, 12, 18, 24, and 27 days after operation, respectively, H&E staining was used to observe pathological morphological changes in the ACC region, the expression levels of ACC region AQP4 and GFAP protein were detected by Western Blot and immunofluorescence, and the expression levels of ACC region pro-inflammatory cytokines IL-1β and TNF-α were detected by enzyme-linked immunosorption assay.Results:Compared with Sham group, MWT in the CCI group decreased from the 3rd day until the 27th day after surgery( P<0.05); Compared with the CCI group, the MWT in the CCI+ LIFU group increased on the 24th day after surgery, and was significantly higher than that of the CCI group on the 24th and 27th day after surgery ( P<0.05); LIFU stimulation did not produce significant pathological changes in the ACC region; Western Blot and immunofluorescence showed that AQP4 and GFAP protein expression in the ACC region were upregulated ( P<0.05) after peripheral nerve injury, while AQP4 and GFAP protein expression was downregulated after LIFU treatment ( P<0.05); Enzyme-linked immunosorbents showed that the expression of pro-inflammatory cytokines IL-1β and TNF-α in the region of ACC was upregulated ( P<0.05) after peripheral nerve injury, while the expression of IL-1β and TNF-α was downregulated after LIFU treatment ( P<0.05). Conclusions:LIFU can effectively relieve mechanical pain sensitivity symptoms in mice induced by CCI, possibly by inhibiting activation of astrocytes and neuro-inflammatory responses.

Modulation of transcutaneous auricular vagus nerve stimulation on default mode network in patients with primary insomnia / 中国针灸

OBJECTIVE@#To explore the modulation of transcutaneous auricular vagus nerve stimulation (taVNS) on default mode network (DMN) in patients with primary insomnia (PI).@*METHODS@#A total of 22 PI patients (one patient dropped off and two patients were excluded) were included and treated with taVNS. The bilateral auricular points of Xin (CO15) and Shen (CO10) were selected and treated with disperse-dense wave at frequency of 4 Hz/20 Hz, the intensity was based on the patient's tolerance. taVNS was given once in the morning and once in the evening for 30 minutes each time. The treatment lasted for at least 5 days a week for 4 weeks. At the same time, 16 healthy subjects matched with gender and age were recruited. The Pittsburgh sleep quality index (PSQI) score was evaluated before and after treatment in PI patients. The resting-state functional magnetic resonance imaging (rs-fMRI) data of PI patients before and after treatment and healthy subjects at baseline period were collected to observe the effect of taVNS on the functional connection (FC) between posterior cingulate cortex (PCC) and whole brain.@*RESULTS@#After treatment, the total score of PSQI in PI patients was lower than that before treatment (P<0.01). Compared with healthy subjects, the FC of the left PCC was increased either with the left orbital superior frontal gyrus or with left middle frontal gyrus (P<0.001), and the FC between right PCC and left middle frontal gyrus was increased in PI patients before treatment (P<0.001). Compared before treatment, the FC between left PCC and left middle frontal gyrus was decreased (P<0.05), and the FC of the right PCC was decreased either with the right medial prefrontal cortex or with the left middle frontal gyrus in PI patients after treatment (P<0.001, P<0.01).@*CONCLUSION@#taVNS can modulate the FC between anterior and posterior DMN, and between DMN and cognitive control network of PI patients, which may be one of the brain effect mechanisms of taVNS in the treatment of PI patients.

Cerebral Responses to Stationary Emotional Stimuli Measured by fMRI in Women with Persistent Postural-Perceptual Dizziness

Abstract Introduction Persistent postural-perceptual dizziness (PPPD) is a functional vestibular disorder characterized by chronic dizziness, unsteadiness, and hypersensitivity to motion. Preexisting anxiety disorders and neurotic personality traits confer vulnerability to PPPD. High anxiety during acute vertigo or dizziness incites it. A functional magnetic resonance imaging (fMRI) study of chronic subjective dizziness found unexpectedly hypoactive responses to vestibular stimulation in cortical regions that integrate threat assessment and spatial perception. Objective This fMRI study used non-moving, but emotionally charged visual stimuli to investigate the brain's activity of PPPD patients and control subjects. Methods The participants included 16 women with PPPD and 16 age-matched women who recovered completely from acute episodes of vertigo or dizziness capable of triggering PPPD. Brain responses to positive, neutral, and negative figures from the International Affective Picture System were measured with fMRI and compared between the groups. Dizziness handicap, anxiety, and depression were assessed with validated questionnaires. Results Between group analyses: Participants with PPPD showed reduced activity in anterior cingulate cortex and increased activity in left angular gyrus in response to negative versus positive stimuli, which was not observed in recovered individuals. Within group analyses: Participants with PPPD had increased activity in visuospatial areas (parahippocampal gyrus, intraparietal sulcus) in negative versus positive and negative versus neutral contrasts, whereas recovered individuals had increased activity in anxiety regions (amygdala, orbitofrontal cortex). Conclusion Patients with PPPD may be more attuned to spatial elements than to the content of emotionally charged visual stimuli.

Chemokine CCL21 in anterior cingulate cortex is involved in chronic neuropathic pain in a rat model / 中国组织工程研究

BACKGROUND: The pathogenesis of chronic pathological pain is yet unknown. Some studies have shown that after spinal cord injury, CCL21 can activate microglia in the central nervous system and is expressed only in damaged neurons, promoting the formation of chronic pathological pain. OBJECTIVE: To investigate whether the anterior cingulate cortex is involved in the formation of chronic pathological pain after inferior orbital nerve ligation in rats, and whether blocking chemokine CCL21 in the anterior cingulate cortex can reduce the chronic neuropathic pain. METHODS: A total of 80 male Sprague-Dawley rats were randomly divided into 4 groups with 20 rats in each group. In the sham group, only the infraorbital nerve of the rats was exposed; in the model group, the left infraorbital nerve was ligated; in the anti-CCL21 group, CCL21 neutralizing antibodies was administered to the anterior cingulate cortex of the rats on the 7th day after surgery; and in the PBS control group, PBS solution was given into the anterior cingulate cortex of rats on the 7th day after surgery. Rats in the sham and model groups were subjected to behavioral tests on the 3rd, 5th, 7th, and 14th days after surgery, and those in the anti-CCL21 and PBS control groups were subjected to the behavioral test at 6 hours after administration. All rats were sacrificed under anesthesia after behavioral tests. The cortical tissues were taken from the anterior cingulate, and the protein content of CCL21 was determined by western blot and immunofluorescence. RESULTS AND CONCLUSION: The pain threshold of the rats in the model group was lower than that in the sham group, and the expression of CCL21 in the anterior cingulate cortex was significantly higher in the model group than the sham group. After the administration of CCL21 neutralizing antibody, the expression of CCL21 was reduced to some extents, and the rat pain threshold was increased accordingly. These findings reveal that the anterior cingulate cortex of rats may be involved in the production of chronic pathological pain, and the administration of CCL21 neutralizing antibody can relief the pain.

Mechanism of Chuanxiong Rhizoma intervention on central sensitization of Panx1-Src-NMDAR-2B signaling pathway in neuropathic pain model rats / 中国中药杂志

Excitatory toxicity(ET) is an important factor of neuropathic pain(NPP) induced by central sensitization(CS), and the association of pannexin-1(Panx1)-Src-N-methyl-D-aspartate receptor subunit 2 B(NMDAR-2 B) is an important new pathway for ET to initiate CS. The present study confirmed whether the central analgesic effect of Chuanxiong Rhizoma extract(CRE) was achieved through the synchronous regulation of the brain and spinal pathways of Panx1-Src-NMDAR-2 B. In this study, dynamic and simulta-neo-us microdialysis of the brain and spinal cord in vivo combined with behavioristics, high performance liquid chromatography(HPLC)-fluorescence detection, microdialysis analysis(ISCUS~(flex)), ultrasensitive multifactorial electrochemiluminescence immunoassay, ELISA, and Western blot was employed to investigate the protein expression of NMDAR-2 B, Src, and Panx1, extracellular excitatory amino acids, cytokines, energy metabolites, and substance P in spinal dorsal horn(SDH) and anterior cingulate cortex(ACC) after CRE intervention with the rat model of spared sciatic nerve injury(SNI) as the experimental tool. Compared with the sham group, the SNI group exhibited diminished mechanical withdrawal threshold(MWT)(P<0.01), increased cold spray scores(P<0.01), glutamate(Glu), D-serine(D-Ser), and glycine(Gly) in extracellular fluids of ACC, and Glu, D-Ser, interleukin-1β(IL-1β), and lactic acid(Lac) in extracellular fluids of SDH(P<0.05), dwindled tumor necrosis factor(TNF-α)(P<0.05), and elevated protein levels of NMDAR-2 B, Src, and Panx1 in ACC(P<0.05). Compared with the SNI model rats, high-and medium-dose CRE(CRE-H/M) could potentiate the analgesic activity as revealed by the MWT test(P<0.05) and CRE-M enabled the decrease in cold spray scores(P<0.05). CRE-H/M could inhibit the levels of Glu, D-Ser and Gly in the extracellular fluids of ACC(P<0.05), and the levels of Glu in the extracellular fluids of SDH(P<0.05) in SNI rats. CRE-M significantly increased the levels of glucose(Gluc), Lac, interferon-gamma(IFN-γ), keratinocyte chemoattractant/human growth-regulated oncogenes(KC/GRO), and IL-4 in extracellular fluids of SDH in SNI rats(P<0.05). CRE-H/M/L could also inhibit the levels of NMDAR-2 B, Src and Panx1 in ACC and SDH in SNI rats(P<0.05). The central analgesic effect of CRE is presumedly related to the inhibited release of excitatory amino acid transmitters(Glu, D-Ser and Gly) in ACC and SDH of SNI rats, decreased protein expression of NMDAR-2 B, Src and Panx1 in the two regions, and the regulation of the Panx1-Src-NMDAR-2 B pathway in the spinal cord and brain. The above findings partially clarified the scientific basis of clinical analgesic effect of Chuanxiong Rhizoma.

The predicting effect of disrupted functional connectivity of anterior cingulate cortex on the efficacy of nonsteroidal anti-inflammatory drugs in migraineurs without aura / 中华行为医学与脑科学杂志

Objective:To investigate the predicting effect of the disrupted functional connectivity of the anterior cingulate cortex (ACC) on the efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with migraineurs without aura (MwoA).Methods:From January 2019 to January 2021, seventy patients with migraine and thirty-three healthy people in the same period were selected.The functional connectivity analysis based on the ACC was used in MwoA patients with NSAIDS-effective ( n=35), MwoA patients with NSAIDS-ineffective ( n=35), and healthy controls (HCs) ( n=33). The abnormal resting-state functional connectivity patterns among the three groups were analyzed to reveal potential correlations with clinical characteristics in migraine. Then the receiver operating characteristic (ROC) curve was used to analyze the predictive ability of the abnormal ACC functional connectivity on the efficacy of NSAIDs in patients with MwoA. Results:(1)Compared with the MwoA patients with NSAIDs-ineffective, the MwoA patients with NSAIDs-effective showed higher functional connectivity between bilateral ACC and left middle cingulate cortex (MCC) (MNI: x, y, z=0, -24, 48, cluster=14, t=3.380) and postcentral gyrus (PoCG)( MNI: x, y, z=-21, -45, 69, cluster=12, t=3.016) (all P<0.005, Bonferroni correction). Compared with the HCs, patients with MwoA showed increased functional connectivity between left ACC and ipsilateral inferior parietal lobule, middle frontal gyrus (MFG) and angular gyrus (AG), and between right ACC and right precuneus, bilateral MFG and left AG (all P<0.005, Bonferroni correction). (2)There was a positive correlation between the functional connectivity of right ACC to right precuneus and MIDAS scores ( r=0.375, P=0.035) in MwoA patients with NSAIDs-effective. In MwoA patients with NSAIDs-ineffective, there were also significant correlations between the functional connectivity of left ACC to ipsilateral AG and MFG and headache onset duration ( r=0.357, P=0.045) and disease duration ( r=-0.367, P=0.039). (3)ROC curve analysis showed that the area under the curve (AUC) for the functional connectivity between the right ACC and left MCC and between the left ACC and left PoCG to predict the efficacy of NSAIDs were 0.728 and 0.736, respectively. Conclusions:Resting-state functional connectivity of the ACC is involved in the evaluation and prediction for analgesic efficacy of NSAIDs in migraine patients, which provides neuroimaging evidence for further investigations on the neurophysiological mechanism of migraine and assistance in clinical individualized precise treatment.

Role of the Anterior Cingulate Cortex in Translational Pain Research / 神经科学通报·英文版

As the most common symptomatic reason to seek medical consultation, pain is a complex experience that has been classified into different categories and stages. In pain processing, noxious stimuli may activate the anterior cingulate cortex (ACC). But the function of ACC in the different pain conditions is not well discussed. In this review, we elaborate the commonalities and differences from accumulated evidence by a variety of pain assays for physiological pain and pathological pain including inflammatory pain, neuropathic pain, and cancer pain in the ACC, and discuss the cellular receptors and signaling molecules from animal studies. We further summarize the ACC as a new central neuromodulation target for invasive and non-invasive stimulation techniques in clinical pain management. The comprehensive understanding of pain processing in the ACC may lead to bridging the gap in translational research between basic and clinical studies and to develop new therapies.

Posterior cingulate gyri metabolic alterations in HIV-positive patients with and without memory deficits / Alterações metabólicas no giro do cíngulo posterior em pacientes HIV-positivos com e sem déficit de memória

Abstract Objective: We aimed to evaluate whether human immunodeficiency virus (HIV)-positive patients with and without clinically significant memory deficits and healthy control participants differ on in vivo hydrogen-1 magnetic resonance spectroscopy (H-MRS) in the posterior cingulate gyri. Materials and Methods: In total, 21 HIV-positive patients with memory deficit (HIV+wMD) were compared with 15 HIV-positive patients without memory deficit (HIV+wOMD) and 22 sex-, age-, and education-matched control participants. Memory impairments were classified based on the participants' performance on the Rey Auditory Verbal Learning Test. Short echo time (30 ms), single-voxel H-MRS was performed using a 1.5-T magnetic resonance scanner. Results: The HIV+wMD and HIV+wOMD groups had higher choline/creatine ratio in the posterior cingulate gyri than the control group. There were no significant metabolite ratio differences between the HIV+wMD and HIV+wOMD groups. Conclusion: HIV-positive patients with and without memory deficits had significantly higher choline/creatine ratios than controls in the posterior cingulate gyri, which may reflect cerebral inflammation, altered cell membrane metabolism, microgliosis, and/or astrocytosis.

Resumo Objetivo: Nós avaliamos se os pacientes HIV-positivos com e sem déficits de memória clinicamente significativos e controles saudáveis diferem na espectroscopia de prótons do giro do cíngulo posterior, por ressonância magnética (RM) cerebral. Materiais e Métodos: Vinte e um pacientes HIV-positivos com déficit de memória foram comparados com 15 pacientes HIV-positivos sem déficit de memória e 22 controles, pareados por sexo, idade e escolaridade. As deficiências de memória foram classificadas por meio do desempenho no Teste de Aprendizagem Auditivo-Verbal de Rey. A espectroscopia de prótons foi realizada com tempo de eco curto (30 ms), por voxel único, no giro do cíngulo posterior, utilizando aparelho de RM de 1,5 T. Resultados: Os pacientes HIV-positivos com e sem déficit de memória apresentaram aumento da relação colina/creatina no giro do cíngulo posterior, comparados aos controles. Não houve diferenças significativas nas relações metabólicas no grupo HIV-positivo com déficit de memória, em relação ao grupo de pacientes HIV-positivo sem déficit. Conclusão: Pacientes HIV-positivos com e sem déficits de memória apresentaram relações colina/creatina significativamente aumentadas em relação aos controles, no giro do cíngulo posterior, o que pode refletir inflamação cerebral, alteração do metabolismo da membrana celular, microgliose e/ou astrocitose.

Comparison of the effect between electroacupuncture and NSAIDs on pain memory based on cAMP/PKA/CREB pathway in anterior cingulate gyrus / 中国针灸

OBJECTIVE@#To observe the direct intervention effects of electroacupuncture (EA) and non-steroid anti-inflammatory drugs (NSAIDs) on pain memory, and to explore their effects on cAMP/PKA/cAMP pathway in anterior cingulate gyrus (ACC).@*METHODS@#Fifty clean healthy male SD rats were randomly divided into a control group, a model group, an indomethacin group, an EA group and a sham EA group, 10 rats in each group. Except the control group, the pain memory model was established in the remaining four groups by twice injection of carrageenan at foot; 0.1 mL of 2%λ-carrageenan was subcutaneously injected at the left foot of rats; 14 days later, when the pain threshold of rats of each group returned to the basic level, the second injection was performed with the same procedure. The rats in the EA group were treated with EA at bilateral "Zusanli" (ST 36) for 30 min; the rats in the indomethacin group was treated with indomethacin intragastric administration with the dose of 3 mg/kg; the rats in the sham EA group was treated with EA without electricity at the point 0.3 mm forward "Zusanli" (ST 36) with the depth of 2 mm for 30 min; the rats in the control group was not given any invention. All the above interventions were performed 5 h, 1 d, 2 d and 3 d after the second injection of 2% λ-carrageenan. The left-side paw withdrawal thresholds (PWT) were observed before the first injection, 4 h, 3 d, 5 d after the first injection, before the second injection and 4 h, 1 d, 2 d, 3 d after the second injection. Three days after the second injection, the number of positive cells of cAMP, p-PKA, p-CREB and the number of positive cells of protein co-expression in the right ACC brain area were detected by immunofluorescence, and the relative protein expression of p-PKA and p-CREB were detected by Western blot.@*RESULTS@#Compared with the control group, the PWTs in the model group decreased significantly 4 h, 3 d and 5 d after the first injection and 1 d, 2 d and 3 d after the second injection (<0.05); compared with the control group, the positive expression of cAMP, p-PKA and p-CREB in the right ACC brain area in the model group increased significantly (<0.05), and the number of positive cells of the co-expression of cAMP/p-PKA and p-PKA/p-CREB also increased significantly (<0.05). Compared with the model group, indomethacin group and sham EA group, the PWTs in the EA group were increased significantly 1 d, 2 d and 3 d after the second injection (<0.05); compared with the model group, indomethacin group and sham EA group, the positive expression of p-PKA and p-CREB in the right ACC brain area in the EA group decreased significantly (<0.05), and the number of positive cells of co-expression of cAMP/p-PKA and p-PKA/p-CREB was decreased significantly (<0.05). Compared with the model group and sham EA group, the positive expression of cAMP in the right ACC brain area was decreased in the EA group (<0.05).@*CONCLUSION@#EA have a direct intervention effect on pain memory, which have significant advantage over NSAIDs in the treatment of chronic pain. The advantage effect of EA on pain memory may be related to the inhibition of cAMP/PKA/CREB pathway in ACC area.

Alterações do córtex cingulado anterior como um preditor de resposta à terapia cognitivo-comportamental / Alterations of anterior cingulate cortex as predictors of response to cognitive-behavioral therapy

RESUMO Objetivo A terapia cognitivo-comportamental (TCC) tem eficácia bem-documentada na literatura científica para transtornos relacionados aos sintomas da ansiedade. No entanto, há uma parcela de pacientes que não responde ao tratamento psicoterápico. Por isso, os estudos sobre as alterações no córtex cingulado anterior (CCA) como preditoras neurais do tratamento têm contribuído para encontrar respostas sobre as diferenças nas respostas ao tratamento. O objetivo do presente estudo é descrever, por meio de revisão sistemática, os estudos encontrados até o ano de 2018 sobre o papel do CCA na predição de resposta à terapia. Métodos Foram realizadas buscas nas bases PsycInfo, Web of Science e PubMed com termos referentes ao tema "córtex cingulado anterior", "terapia cognitivo-comportamental" e "predição de respostas", incluindo estudos com neuroimagem estrutural e funcional. Resultados As buscas apresentaram 14 artigos sobre "transtorno de estresse pós-traumático (TEPT)", "transtorno obsessivo-compulsivo (TOC)" e "transtorno de ansiedade social (TAS)". Os estudos com neuroimagem estrutural apresentaram resultados promissores. A maior espessura do CCA foi preditora de melhor resposta ao tratamento para TEPT e TOC. Os resultados de neuroimagem funcional foram promissores para maior ativação como preditora de melhor resposta para TAS. Por outro lado, os resultados para TEPT apontaram que a menor ativação pode ser preditora de melhores respostas. Conclusão As alterações nos estudos de neuroimagem sugerem que o CCA tenha um papel de predição de resposta ao tratamento com TCC. Estudos posteriores com amostras maiores podem contribuir para a ampliação da eficácia nos tratamentos de tais transtornos.

ABSTRACT Objective The efficacy of cognitive-behavioral therapy (CBT) on the treatment of anxiety-related disorders has been well documented. However, a number of patients do not respond to psychotherapeutic treatment. Therefore, changes in the anterior cingulate cortex (ACC) as a neural predictor of treatment response have contributed to understanding the differences in treatment outcome. The aim of this study is to describe, through a systematic review, studies published until 2018 that investigate the role of the anterior cingulate cortex on the prediction of response to therapy. Methods Searches have been conducted in the PsycInfo, Web of Science and PubMed databases for articles related to the terms "anterior cingulate cortex", "cognitive-behavioral therapy" and "prediction of response", including studies with structural and functional neuroimaging. Results We selected 14 articles on "post-traumatic stress disorder (PTSD)", "obsessive-compulsive disorder (OCD)" and "social anxiety disorder (SAD)". Overall, Structural neuroimaging studies functional neuroimaging results were promising. A greater thickness on the ACC was associated with a better response to treatment for PTSD and OCD. Greater activation of the ACC was positively associated with a greater response to treatment for patients with SAD. On the other hand, for those with PTSD, lower activation may be a better predictor of improvement. Conclusion The structural and functional alterations observed in neuroimage studies suggest that the ACC has a role in predicting treatment response to CBT. Future studies with larger samples may contribute to the improvement of treatment efficacy in such disorders.

Smaller left anterior cingulate cortex in non-bipolar relatives of patients with bipolar disorder

Objective: Bipolar disorder (BD) is highly heritable. The present study aimed at identifying brain morphometric features that could represent markers of BD vulnerability in non-bipolar relatives of bipolar patients. Methods: In the present study, structural magnetic resonance imaging brain scans were acquired from a total of 93 subjects, including 31 patients with BD, 31 non-bipolar relatives of BD patients, and 31 healthy controls. Volumetric measurements of the anterior cingulate cortex (ACC), lateral ventricles, amygdala, and hippocampus were completed using the automated software FreeSurfer. Results: Analysis of covariance (with age, gender, and intracranial volume as covariates) indicated smaller left ACC volumes in unaffected relatives as compared to healthy controls and BD patients (p = 0.004 and p = 0.037, respectively). No additional statistically significant differences were detected for other brain structures. Conclusion: Our findings suggest smaller left ACC volume as a viable biomarker candidate for BD.

Increased CXCL13 and CXCR5 in Anterior Cingulate Cortex Contributes to Neuropathic Pain-Related Conditioned Place Aversion / 神经科学通报·英文版

Pain consists of sensory-discriminative and emotional-affective components. The anterior cingulate cortex (ACC) is a critical brain area in mediating the affective pain. However, the molecular mechanisms involved remain largely unknown. Our recent study indicated that C-X-C motif chemokine 13 (CXCL13) and its sole receptor CXCR5 are involved in sensory sensitization in the spinal cord after spinal nerve ligation (SNL). Whether CXCL13/CXCR5 signaling in the ACC contributes to the pathogenesis of pain-related aversion remains unknown. Here, we showed that SNL increased the CXCL13 level and CXCR5 expression in the ACC after SNL. Knockdown of CXCR5 by microinjection of Cxcr5 shRNA into the ACC did not affect SNL-induced mechanical allodynia but effectively alleviated neuropathic pain-related place avoidance behavior. Furthermore, electrophysiological recording from layer II-III neurons in the ACC showed that SNL increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), decreased the EPSC paired-pulse ratio, and increased the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor/N-methyl-D-aspartate receptor ratio, indicating enhanced glutamatergic synaptic transmission. Finally, superfusion of CXCL13 onto ACC slices increased the frequency and amplitude of spontaneous EPSCs. Pre-injection of Cxcr5 shRNA into the ACC reduced the increase in glutamatergic synaptic transmission induced by SNL. Collectively, these results suggest that CXCL13/CXCR5 signaling in the ACC is involved in neuropathic pain-related aversion via synaptic potentiation.

Distinct Neural Correlates of Executive Function by Amyloid Positivity and Associations with Clinical Progression in Mild Cognitive Impairment

PURPOSE: This study aimed to identify the neural basis of executive function (EF) in amnestic mild cognitive impairment (aMCI) according to beta-amyloid (Aβ) positivity. Furthermore, we explored if the identified brain areas could serve as predictors for clinical progression. MATERIALS AND METHODS: We included individuals with aMCI using data from [¹⁸F]-florbetapir-positron emission tomography (PET), fluorodeoxyglucose-PET, and EF scores, as well as follow-up clinical severity scores at 1 and 5 years from baseline from the Alzheimer's Disease Neuroimaging Initiative database. The correlations between EF score and regional cerebral glucose metabolism (rCMglc) were analyzed separately for aMCI with low Aβ burden (aMCI Aβ−, n=230) and aMCI with high Aβ burden (aMCI Aβ+, n=268). Multiple linear regression analysis was conducted to investigate the associations between rCMglc and clinical progression. RESULTS: Longitudinal courses differed between aMCI Aβ− and aMCI Aβ+ groups. On average, aMCI Aβ− subjects maintained their level of clinical severity, whereas aMCI Aβ+ subjects showed progression. EF impairment in aMCI Aβ− was related to the anterior cingulate cortex (ACC), whereas that in aMCI Aβ+ was related to Alzheimer's Disease-vulnerable brain regions. ACC and the posterior cingulate cortex were associated with clinical progression in aMCI Aβ− and aMCI Aβ+, respectively. CONCLUSION: Our findings suggest that although MCI subjects showed similar behavioral phenotypes at the time of diagnosis, EF and further progression were associated with different brain regions according to Aβ burden. Clarification of the etiologies and nature of EF impairment in aMCI are critical for disease prognosis and management.

Correlation between blood oxygen level dependent fMRI signal and GABA content in anterior cingulate cortex after acupuncture of Hegu (LI4) / 针刺研究

OBJECTIVE: To explore the correlation between blood oxygen level dependent functional magnetic resonance imaging (BOLD-fMRI) signal and neurotransmitter γ-aminobutyric acid (GABA) concentration in the prefrontal cortex area after acupuncture or Von Frey filament stimulation (epidermal stimulation) at the right Hegu (LI4). METHODS: A total of 76 healthy volunteers (23 men and 53 women, 24.5±1.4 years in age) were recruited in the pre-sent study. Each volunteer received two sessions of fMRI magnetic resonance scanning (MRS) examinations, with an interval of one week between two sessions. The MRI scan sequences included pre-task MRS, resting state BOLD and task MRS, BOLD. A region of Interest (ROI) of 35 mm×30 mm×25 mm was located at the bilateral medial prefrontal cortex areas. In the two sessions of examinations, the right LI4 point was stimulated by manual acupuncture or Von Frey filament-pressing. The tasks were designed as the block design. Each block contained 3 intermittent acupoint stimulations, lasting 30 s in each stimulation and with two minutes' pause between two stimulations. The MRS data were processed by using Linear Combination (LC) Model software (for assessing GABA content), and the BOLD data of fMRI was analyzed by using SPM12 software (comparison within each group), REST1.8 (comparison between two groups), separately. RESULTS: Extensive deactivations were induced by both stimulations, mainly involving the midline regions as the medial prefrontal lobe, and limbic lobe. The deactivation effect of manual acupuncture stimulation was more extensive and intensive than that of Von Frey filament stimulation, especially in the medial prefrontal lobe. Data from 66 volunteers (after exclusion of 10 participants due to bigger standard deviation of GABA/Glx) showed no marked correlation between the GABA concentration and BOLD activation in the anterior cingulate cortex area in both groups(manual acupuncture stimulation group: r=－0.07, －0.08, 0.04; P=0.57, 0.88, 0.74; Von Frey filament epidermal stimulation group: r=－0.10, －0.09, －0.01; P=0.43, 0.46, 0.96). CONCLUSION: Acupuncture of LI4 elicits a stronger and broader negative activation effect in the limbic-paralimbic-neocortical network including the medial prefrontal cortex in comparison with Von Frey filament stimulation, but no apparent correlation was found between the GABA concentration and BOLD activation in the anterior cingulate cortex after manual acupuncture and Von Frey stimulation.