Rostral Anterior Cingulate Cortex–Ventrolateral Periaqueductal Gray Circuit Underlies Electroacupuncture to Alleviate Hyperalgesia but Not Anxiety-Like Behaviors in Mice With Spared Nerve Injury

Neuropathic pain is a common cause of chronic pain and is often accompanied by negative emotions, making it complex and difficult to treat. However, the neural circuit mechanisms underlying these symptoms remain unclear. Herein, we present a novel pathway associated with comorbid chronic pain and anxiety. Using chemogenetic methods, we found that activation of glutamatergic projections from the rostral anterior cingulate cortex (rACCGlu) to the ventrolateral periaqueductal gray (vlPAG) induced both hyperalgesia and anxiety-like behaviors in sham mice. Inhibition of the rACCGlu-vlPAG pathway reduced anxiety-like behaviors and hyperalgesia in the spared nerve injury (SNI) mice model; moreover, electroacupuncture (EA) effectively alleviated these symptoms. Investigation of the related mechanisms revealed that the chemogenetic activation of the rACCGlu-vlPAG circuit effectively blocked the analgesic effect of EA in the SNI mice model but did not affect the chronic pain-induced negative emotions. This study revealed a novel pathway, the rACCGlu-vlPAG pathway, that mediates neuropathic pain and pain-induced anxiety.

Suppressed activity of the rostral anterior cingulate cortex as a biomarker for depression remission

Background Suppression of the rostral anterior cingulate cortex (rACC) has shown promise as a prognostic biomarker for depression. We aimed to use machine learning to characterise its ability to predict depression remission. Methods Data were obtained from 81 15- to 25-year-olds with a major depressive disorder who had participated in the YoDA-C trial, in which they had been randomised to receive cognitive behavioural therapy plus either fluoxetine or placebo. Prior to commencing treatment patients performed a functional magnetic resonance imaging (fMRI) task to assess rACC suppression. Support vector machines were trained on the fMRI data using nested cross-validation, and were similarly trained on clinical data. We further tested our fMRI model on data from the YoDA-A trial, in which participants had completed the same fMRI paradigm. Results Thirty-six of 81 (44%) participants in the YoDA-C trial achieved remission. Our fMRI model was able to predict remission status (AUC = 0.777 [95% confidence interval (CI) 0.638–0.916], balanced accuracy = 67%, negative predictive value = 74%, p < 0.0001). Clinical models failed to predict remission status at better than chance levels. Testing the model on the alternative YoDA-A dataset confirmed its ability to predict remission (AUC = 0.776, balanced accuracy = 64%, negative predictive value = 70%, p < 0.0001). Conclusions We confirm that rACC activity acts as a prognostic biomarker for depression. The machine learning model can identify patients who are likely to have difficult-to-treat depression, which might direct the earlier provision of enhanced support and more intensive therapies.

Serotonergic gene-to-gene interaction is associated with mood and GABA concentrations but not with pain-related cerebral processing in fibromyalgia subjects and healthy controls

The neurotransmitter serotonin, involved in the regulation of pain and emotion, is critically regulated by the 5‐HT1A autoreceptor and the serotonin transporter (5-HTT). Polymorphisms of these genes affect mood and endogenous pain modulation, both demonstrated to be altered in fibromyalgia subjects (FMS). Here, we tested the effects of genetic variants of the 5‐HT1A receptor (CC/G-carriers) and 5-HTT (high/intermediate/low expression) on mood, pain sensitivity, cerebral processing of evoked pain (functional MRI) and concentrations of GABA and glutamate (MR spectroscopy) in rostral anterior cingulate cortex (rACC) and thalamus in FMS and healthy controls (HC). Interactions between serotonin-relevant genes were found in affective characteristics, with genetically inferred high serotonergic signalling (5-HT1A CC/5-HTThigh genotypes) being more favourable across groups. Additionally, 5‐HT1A CC homozygotes displayed higher pain thresholds than G-carriers in HC but not in FMS. Cerebral processing of evoked pressure pain differed between groups in thalamus with HC showing more deactivation than FMS, but was not influenced by serotonin-relevant genotypes. In thalamus, we observed a 5‐HT1A-by-5-HTT and group-by-5-HTT interaction in GABA concentrations, with the 5-HTT high expressing genotype differing between groups and 5‐HT1A genotypes. No significant effects were seen for glutamate or in rACC. To our knowledge, this is the first report of this serotonergic gene-to-gene interaction associated with mood, both among FMS (depression) and across groups (anxiety). Additionally, our findings provide evidence of an association between the serotonergic system and thalamic GABA concentrations, with individuals possessing genetically inferred high serotonergic signalling exhibiting the highest GABA concentrations, possibly enhancing GABAergic inhibitory effects via 5-HT.

Electroacupuncture Alleviates Chronic Pain-Induced Anxiety Disorders by Regulating the rACC-Thalamus Circuitry

Anxiety is a common comorbidity associated with chronic pain, which results in chronic pain complexification and difficulty in treatment. Electroacupuncture (EA) is commonly used to treat chronic pain and anxiety. However, the underlying mechanisms of the EA effect are largely unknown. Here, we showed that a circuitry underlying chronic pain induces anxiety disorders, and EA can treat them by regulating such circuitry. Using chemogenetic methods, we found that chemogenetic activation of the rostral anterior cingulate cortex (rACC) glutamatergic output to the thalamus induced anxiety disorders in control rats. Then, chemogenetic inhibition of the rACC-thalamus circuitry reduced anxiety-like behavior produced by intraplantar injection of the complete Freund’s adjuvant (CFA). In this study, we examined the effects of EA on a rat model of CFA-mediated anxiety-like behaviors and the related mechanisms. We found that chemogenetic activation of the rACC-thalamus circuitry effectively blocked the effects of EA on chronic pain-induced anxiety-like behaviors in CFA rats. These results demonstrate an underlying rACC-thalamus glutamatergic circuitry that regulates CFA-mediated anxiety-like behaviors. This study also provides a potential mechanistic explanation for EA treatment of anxiety caused by chronic pain.

Depression Is Associated With Preserved Cortical Thickness Relative to Apathy in Frontotemporal Dementia

Objectives: To understand the differential neuroanatomical substrates underlying apathy and depression in Frontotemporal dementia (FTD). Methods: T1-MRIs and clinical data of patients with behavioral and aphasic variants of FTD were obtained from an open database. Cortical thickness was derived, its association with apathy severity and difference between the depressed and not depressed were examined with appropriate covariates. Results: Apathy severity was significantly associated with cortical thinning of the lateral parts of the right sided frontal, temporal and parietal lobes. The right sided orbitofrontal, parsorbitalis and rostral anterior cingulate cortex were thicker in depressed compared to patients not depressed. Conclusions: Greater thickness of right sided ventromedial and inferior frontal cortex in depression compared to patients without depression suggests a possible requisite of gray matter in this particular area for the manifestation of depression in FTD. This study demonstrates a method for deriving neuroanatomical patterns across non-harmonized neuroimaging data in a neurodegenerative disease.

Distinct Function of Estrogen Receptors in the Rodent Anterior Cingulate Cortex in Pain-related Aversion

Background Brain-derived estrogen is implicated in pain-related aversion; however, which estrogen receptors mediate this effect remains unclear. This study hypothesized that the different estrogen receptors in the rostral anterior cingulate cortex play distinct roles in pain-related aversion. Methods Formalin-induced conditioned place avoidance and place escape/avoidance paradigms were used to evaluate pain-related aversion in rodents. Immunohistochemistry and Western blotting were used to detect estrogen receptor expression. Patch-clamp recordings were used to examine N-methyl-d-aspartate–mediated excitatory postsynaptic currents in rostral anterior cingulate cortex slices. Results The administration of the estrogen receptor-β antagonist 4-(2-phenyl-5,7-bis [trifluoromethyl] pyrazolo [1,5-a] pyrimidin-3-yl) phenol (PHTPP) or the G protein–coupled estrogen receptor-1 antagonist (3aS*,4R*,9bR*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta [c] quinolone (G15) but not the estrogen receptor-α antagonist 1,3-bis (4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1H-pyrazole dihydrochloride (MPP) into the rostral anterior cingulate cortex blocked pain-related aversion in rats (avoidance score, mean ± SD: 1,3-bis [4-hydroxyphenyl]-4-methyl-5-(4-[2-piperidinylethoxy] phenol)-1H-pyrazole dihydrochloride (MPP): 47.0 ± 18.9%, 4-(2-phenyl-5,7-bis [trifluoromethyl] pyrazolo [1,5-a] pyrimidin-3-yl) phenol (PHTPP): −7.4 ± 20.6%, and [3aS*,4R*,9bR*]-4-[6-bromo-1,3-benzodioxol-5-yl]-3a,4,5,9b-3H-cyclopenta [c] quinolone (G15): −4.6 ± 17.0% vs. vehicle: 46.5 ± 12.2%; n = 7 to 9; P &lt; 0.0001). Consistently, estrogen receptor-β knockdown but not estrogen receptor-α knockdown by short-hairpin RNA also inhibited pain-related aversion in mice (avoidance score, mean ± SD: estrogen receptor-α–short-hairpin RNA: 26.0 ± 7.1% and estrogen receptor-β–short-hairpin RNA: 6.3 ± 13.4% vs. control short-hairpin RNA: 29.1 ± 9.1%; n = 7 to 10; P &lt; 0.0001). Furthermore, the direct administration of the estrogen receptor-β agonist 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN) or the G protein–coupled estrogen receptor-1 agonist (±)-1-([3aR*,4S*,9bS*]-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl)-ethanone (G1) into the rostral anterior cingulate cortex resulted in conditioned place avoidance (avoidance score, mean ± SD: 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN): 35.3 ± 9.5% and (±)-1-([3aR*,4S*,9bS*]-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl)-ethanone (G1): 43.5 ± 22.8% vs. vehicle: 0.3 ± 14.9%; n = 8; P &lt; 0.0001) but did not affect mechanical or thermal sensitivity. The activation of the estrogen receptor-β/protein kinase A or G protein–coupled estrogen receptor-1/protein kinase B pathway elicited the long-term potentiation of N-methyl-d-aspartate–mediated excitatory postsynaptic currents. Conclusions These findings indicate that estrogen receptor-β and G protein–coupled estrogen receptor-1 but not estrogen receptor-α in the rostral anterior cingulate cortex contribute to pain-related aversion by modulating N-methyl-d-aspartate receptor–mediated excitatory synaptic transmission. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

0081 Habitual Sleep Duration is Negatively Correlated with Emotional Reactivity within the Rostral Anterior Cingulate Cortex in Individuals with PTSD

Introduction Sleep difficulties, such as insomnia, are highly prevalent in individuals with Post-Traumatic Stress Disorder (PTSD). However, sleep deprivation can also increase emotional reactivity to positive (as well as negative) stimuli. While the effects of sleep loss on emotional perception healthy individuals has been documented, it remains unclear how lack of sleep in individuals with PTSD may affect their emotional reactivity to positive stimuli. We hypothesized that lower habitual sleep duration would be associated with greater functional brain activation changes in response to subliminally presented happy faces in brain areas of the reward network, such as the rostral anterior cingulate cortex (rACC). Methods Thirty-nine individuals with DSM-5 confirmed PTSD were administered the Pittsburgh Sleep Quality Index (PSQI) as a measure of their average nightly sleep duration over the past month. Participants then underwent fMRI imagining while viewing subliminal presentations of faces displaying happiness, using a backward masked facial affect paradigm to minimize conscious awareness of the expressed emotion. Brain activation to masked happy expressions was regressed against sleep duration in SPM12. Results There was a negative correlation between habitual sleep duration and activation within the rACC in response to the masked happy faces (x=14,y=40,z=0; k=102, pFWE-corr= 0.008). Conclusion Individuals with PTSD who average less sleep at night showed greater emotional reactivity, as indexed by greater functional brain activation changes within an area of the reward network, than individuals who obtained more sleep per night. Future research involving actual sleep duration manipulation will be necessary to determine whether this finding reflects the well-known antidepressant effect of sleep deprivation or a form of greater emotional expression error monitoring among traumatized patients when lacking sleep. Regardless, these findings suggest that insufficient sleep could affect unconsciously perceived emotion in faces and potentially affect social and emotional responses among individuals with PTSD. Support US Army Medical Research and Materiel Command: W81XWH-14-1-0570