Activity In Anterior Cingulate Cortex Research Articles

Empathy in schizophrenia: neural alterations during emotion recognition and affective sharing

IntroductionDeficits in emotion recognition and processing are characteristic for patients with schizophrenia [SCZ].MethodsWe targeted both emotion recognition and affective sharing, one in static and one in dynamic facial stimuli, during functional magnetic resonance imaging [fMRI] in 22 SCZ patients and 22 matched healthy controls [HC]. Current symptomatology and cognitive deficits were assessed as potential influencing factors.ResultsBehaviorally, patients only showed a prolonged response time in age-discrimination trials. For emotion-processing trials, patients showed a difference in neural response, without an observable behavioral correlate. During emotion and age recognition in static stimuli, a reduced activation of the bilateral anterior cingulate cortex [ACC] and the right anterior insula [AI] emerged. In the affective sharing task, patients showed a reduced activation in the left and right caudate nucleus, right AI and inferior frontal gyrus [IFG], right cerebellum, and left thalamus, key areas of empathy.DiscussionWe conclude that patients have deficits in complex visual information processing regardless of emotional content on a behavioral level and that these deficits coincide with aberrant neural activation patterns in emotion processing networks. The right AI as an integrator of these networks plays a key role in these aberrant neural activation patterns and, thus, is a promising candidate area for neurofeedback approaches.

Neural responses to facial emotions and subsequent clinical outcomes in difficult-to-treat depression.

Amygdala and dorsal anterior cingulate cortex responses to facial emotions have shown promise in predicting treatment response in medication-free major depressive disorder (MDD). Here, we examined their role in the pathophysiology of clinical outcomes in more chronic, difficult-to-treat forms of MDD. Forty-five people with current MDD who had not responded to ⩾2 serotonergic antidepressants (n = 42, meeting pre-defined fMRI minimum quality thresholds) were enrolled and followed up over four months of standard primary care. Prior to medication review, subliminal facial emotion fMRI was used to extract blood-oxygen level-dependent effects for sad v. happy faces from two pre-registered a priori defined regions: bilateral amygdala and dorsal/pregenual anterior cingulate cortex. Clinical outcome was the percentage change on the self-reported Quick Inventory of Depressive Symptomatology (16-item). We corroborated our pre-registered hypothesis (NCT04342299) that lower bilateral amygdala activation for sad v. happy faces predicted favorable clinical outcomes (rs[38] = 0.40, p = 0.01). In contrast, there was no effect for dorsal/pregenual anterior cingulate cortex activation (rs[38] = 0.18, p = 0.29), nor when using voxel-based whole-brain analyses (voxel-based Family-Wise Error-corrected p < 0.05). Predictive effects were mainly driven by the right amygdala whose response to happy faces was reduced in patients with higher anxiety levels. We confirmed the prediction that a lower amygdala response to negative v. positive facial expressions might be an adaptive neural signature, which predicts subsequent symptom improvement also in difficult-to-treat MDD. Anxiety reduced adaptive amygdala responses.

Involvement and regulation of the left anterior cingulate cortex in the ultrasonic communication deficits of autistic mice

IntroductionAutism spectrum disorder (ASD) is a group of diseases often characterized by poor sociability and challenges in social communication. The anterior cingulate cortex (ACC) is a core brain region for social function. Whether it contributes to the defects of social communication in ASD and whether it could be physiologically modulated to improve social communication have been poorly investigated. This study is aimed at addressing these questions.MethodsFragile X mental retardation 1 (FMR1) mutant and valproic acid (VPA)-induced ASD mice were used. Male–female social interaction was adopted to elicit ultrasonic vocalization (USV). Immunohistochemistry was used to evaluate USV-activated neurons. Optogenetic and precise target transcranial magnetic stimulation (TMS) were utilized to modulate anterior cingulate cortex (ACC) neuronal activity.ResultsIn wild-type (WT) mice, USV elicited rapid expression of c-Fos in the excitatory neurons of the left but not the right ACC. Optogenetic inhibition of the left ACC neurons in WT mice effectively suppressed social-induced USV. In FMR1−/−- and VPA-induced ASD mice, significantly fewer c-Fos/CaMKII-positive neurons were observed in the left ACC following USV compared to the control. Optogenetic activation of the left ACC neurons in FMR1−/− or VPA-pretreated mice significantly increased social activity elicited by USV. Furthermore, precisely stimulating neuronal activity in the left ACC, but not the right ACC, by repeated TMS effectively rescued the USV emission in these ASD mice.DiscussionThe excitatory neurons in the left ACC are responsive to socially elicited USV. Their silence mediates the deficiency of social communication in FMR1−/− and VPA-induced ASD mice. Precisely modulating the left ACC neuronal activity by repeated TMS can promote the social communication in FMR1−/− and VPA-pretreated mice.

Reward positivity affects temporal interval production in a continuous timing task.

The neural circuits of reward processing and interval timing (including the perception and production of temporal intervals) are functionally intertwined, suggesting that it might be possible for momentary reward processing to influence subsequent timing behavior. Previous animal and human studies have mainly focused on the effect of reward on interval perception, whereas its impact on interval production is less clear. In this study, we examined whether feedback, as an example of performance-contingent reward, biases interval production. We recorded EEG from 20 participants while they engaged in a continuous drumming task with different realistic tempos (1728 trials per participant). Participants received color-coded feedback after each beat about whether they were correct (on time) or incorrect (early or late). Regression-based EEG analysis was used to unmix the rapid occurrence of a feedback response called the reward positivity (RewP), which is traditionally observed in more slow-paced tasks. Using linear mixed modeling, we found that RewP amplitude predicted timing behavior for the upcoming beat. This performance-biasing effect of the RewP was interpreted as reflecting the impact of fluctuations in reward-related anterior cingulate cortex activity on timing, and the necessity of continuous paradigms to make such observations was highlighted.

From learned value to sustained bias: how reward conditioning changes attentional priority.

Attentional bias to reward-associated stimuli can occur even when it interferes with goal-driven behavior. One theory posits that dopaminergic signaling in the striatum during reward conditioning leads to changes in visual cortical and parietal representations of the stimulus used, and this, in turn, sustains attentional bias even when reward is discontinued. However, only a few studies have examined neural activity during both rewarded and unrewarded task phases. In the current study, participants first completed a reward-conditioning phase, during which responses to certain stimuli were associated with monetary reward. These stimuli were then included as non-predictive cues in a spatial cueing task. Participants underwent functional brain imaging during both task phases. The results show that striatal activity during the learning phase predicted increased visual cortical and parietal activity and decreased ventro-medial prefrontal cortex activity in response to conditioned stimuli during the test. Striatal activity was also associated with anterior cingulate cortex activation when the reward-conditioned stimulus directed attention away from the target. Our findings suggest that striatal activity during reward conditioning predicts the degree to which reward history biases attention through learning-induced changes in visual and parietal activities.

359 Low-Intensity Focused Ultrasound to Human Dorsal Anterior Cingulate Cortex and Insula Attenuates Measures of Central Sensitization

INTRODUCTION: Central sensitization is the abnormal amplified response to pain and is associated with chronic pain. Increased insula and dorsal anterior cingulate cortex (dACC) activity is associated with central sensitization. Low-intensity focused ultrasound (LIFU) is a novel form of non-invasive neuromodulation that can precisely target the anterior insula (AI), posterior insula (PI) and dACC. METHODS: N = 18 healthy participants underwent conditioned pain modulation (CPM) and temporal summation of pain (TSP) tasks before and after 10 minutes of LIFU or sham stimulations. For CPM, the conditioning stimulus (CS) was a cold pressor test to the left hand and the test stimulus (TS) was a brief transient heat stimulus to the dorsum of the right hand. For TSP, 10 transient heat stimuli (&gt;0.33 Hz) were administered to the dorsum of the right hand. The primary outcome measure for both tasks was perceived pain ratings (0-9). Electrodermal response and electrocardiogram was collected to evaluate the effect of LIFU on autonomic reactivity. RESULTS: LIFU to PI increased CPM 0.5 ± 0.181 compared to sham (p = 0.024). LIFU to PI also significantly reduced perceived pain during the TSP task compared to sham (p &lt; 0.001). We also found a significant difference between dACC and sham conditions during TSP by -0.55 ± 0.05 (p &lt; 0.001). LIFU to the AI increases frequency domain measures of heart-rate variability. CONCLUSIONS: LIFU to the insula and dACC affects pain processing in measures of central sensitization. This demonstrates the neuromodulation abilities of LIFU and is a promising tool to develop noninvasive clinical therapies for chronic pain conditions.

Claustrum projections to the anterior cingulate modulate nociceptive and pain-associated behavior

The anterior cingulate cortex (ACC) is critical for the perception and unpleasantness of pain.1,2,3,4,5,6 It receives nociceptive information from regions such as the thalamus and amygdala and projects to several cortical and subcortical regions of the pain neuromatrix.7,8 ACC hyperexcitability is one of many functional changes associated with chronic pain, and experimental activation of ACC pyramidal cells produces hypersensitivity to innocuous stimuli (i.e., allodynia).9,10,11,12,13,14 A less-well-studied projection to the ACC arises from a small forebrain region, the claustrum.15,16,17,18,19,20 Stimulation of excitatory claustrum projection neurons preferentially activates GABAergic interneurons, generating feed-forward inhibition onto excitatory cortical networks.21,22,23,24 Previous work has shown that claustrocingulate projections display altered activity in prolonged pain25,26,27; however, it remains unclear whether and how the claustrum participates in nociceptive processing and high-order pain behaviors. Inhibition of ACC activity reverses mechanical allodynia in animal models of persistent and neuropathic pain,1,9,28 suggesting claustrum inputs may function to attenuate pain processing. In this study, we sought to define claustrum function in acute and chronic pain. We found enhanced claustrum activity after a painful stimulus that was attenuated in chronic inflammatory pain. Selective inhibition of claustrocingulate projection neurons enhanced acute nociception but blocked pain learning. Inversely, chemogenetic activation of claustrocingulate neurons had no effect on basal nociception but rescued inflammation-induced mechanical allodynia. Together, these results suggest that claustrocingulate neurons are a critical component of the pain neuromatrix, and dysregulation of this connection may contribute to chronic pain.

Similar imaging changes and their relations to genetic profiles in bipolar disorder across different clinical stages

Bipolar disorder (BD) across different clinical stages may present shared and distinct changes in brain activity. We aimed to reveal the neuroimaging homogeneity and heterogeneity of BD and its relationship with clinical variables and genetic variations. In present study, we conducted fractional amplitude of low-frequency fluctuations (fALFF), functional connectivity (FC) and genetic neuroimaging association analyses with 32 depressed, 26 manic, 35 euthymic BD patients and 87 healthy controls (HCs). Significant differences were found in the bilateral pre/subgenual anterior cingulate cortex (ACC) across the four groups, and all bipolar patients exhibited decreased fALFF values in the ACC when compared to HCs. Furthermore, positive associations were significantly observed between fALFF values in the pre/subgenual ACC and participants' cognitive functioning. No significant changes were found in ACC-based FC. We identified fALFF-alteration-related genes in BD, with enrichment in biological progress including synaptic and ion transmission. Taken together, abnormal activity in ACC is a characteristic change associated with BD, regardless of specific mood stages, serving as a potential neuroimaging feature in BD patients. Our genetic neuroimaging association analysis highlights possible heterogeneity in biological processes that could be responsible for different clinical stages in BD.

Optogenetic stimulation of neurons in the anterior cingulate cortex induces changes in intravesical bladder pressure and the micturition reflex

Lower urinary tract (LUT) function is controlled by the central nervous system, including higher-order cognitive brain regions. The anterior cingulate cortex (ACC) is one of these regions, but the role of its activity in LUT function remains poorly understood. In the present study, we conducted optogenetic experiments to manipulate neural activity in mouse ACC while monitoring bladder pressure to elucidate how the activity of ACC regulates LUT function. Selective optogenetic stimulation of excitatory neurons in ACC induced a sharp increase in bladder pressure, whereas activation of inhibitory neurons in ACC prolonged the interval between bladder contractions. Pharmacological manipulation of ACC also altered bladder contractions, consistent with those observed in optogenetic experiments. Optogenetic mapping of the cortical area responsible for eliciting the increase in bladder pressure revealed that stimulation to ACC showed more potent effects than the neighboring motor cortical areas. These results suggest that ACC plays a crucial role in initiating the bladder pressure change and the micturition reflex. Thus, the balance between excitation and inhibition in ACC may regulate the reflex bidirectionally.

Anterior cingulate cross-hemispheric inhibition via the claustrum resolves painful sensory conflict

The anterior cingulate cortex (ACC) responds to noxious and innocuous sensory inputs, and integrates them to coordinate appropriate behavioral reactions. However, the role of the projections of ACC neurons to subcortical areas and their influence on sensory processing are not fully investigated. Here, we identified that ACC neurons projecting to the contralateral claustrum (ACC→contraCLA) preferentially respond to contralateral mechanical sensory stimulation. These sensory responses were enhanced during attending behavior. Optogenetic activation of ACC→contraCLA neurons silenced pyramidal neurons in the contralateral ACC by recruiting local circuit fast-spiking interneuron activation via an excitatory relay in the CLA. This circuit activation suppressed withdrawal behavior to mechanical stimuli ipsilateral to the ACC→contraCLA neurons. Chemogenetic silencing showed that the cross-hemispheric circuit has an important role in the suppression of contralateral nociceptive behavior during sensory-driven attending behavior. Our findings identify a cross-hemispheric cortical-subcortical-cortical arc allowing the brain to give attentional priority to competing innocuous and noxious inputs.

Dysfunctional feedback processing in male methamphetamine abusers: Evidence from neurophysiological and computational approaches

Methamphetamine use disorder (MUD) as a major public health risk is associated with dysfunctional neural feedback processing. Although dysfunctional feedback processing in people who are substance dependent has been explored in several behavioral, computational, and electrocortical studies, this mechanism in MUDs requires to be well understood. Furthermore, the current understanding of latent components of their behavior such as learning speed and exploration-exploitation dilemma is still limited. In addition, the association between the latent cognitive components and the related neural mechanisms also needs to be explored. Therefore, in this study, the underlying neurocognitive mechanisms of feedback processing of such impairment, and age/gender-matched healthy controls are evaluated within a probabilistic learning task with rewards and punishments. Mathematical modeling results based on the Q-learning paradigm suggested that MUDs show less sensitivity in distinguishing optimal options. Additionally, it may be worth noting that MUDs exhibited a slight decrease in their ability to learn from negative feedback compared to healthy controls. Also through the lens of underlying neural mechanisms, MUDs showed lower theta power at the medial-frontal areas while responding to negative feedback. However, other EEG measures of reinforcement learning including feedback-related negativity, parietal-P300, and activity flow from the medial frontal to lateral prefrontal regions, remained intact in MUDs. On the other hand, the elimination of the linkage between value sensitivity and medial-frontal theta activity in MUDs was observed. The observed dysfunction could be due to the adverse effects of methamphetamine on the cortico-striatal dopamine circuit, which is reflected in the anterior cingulate cortex activity as the most likely region responsible for efficient behavior adjustment. These findings could help us to pave the way toward tailored therapeutic approaches.

Electroacupuncture Alleviates Hyperalgesia and Anxiety-Like Behaviors in Pain Memory Model Rats Through Activation of GABAergic Neurons and GABA Receptor in the Rostral Anterior Cingulate Cortex.

Recent studies have confirmed that pain memory is often accompanied by negative emotions. Electroacupuncture (EA) can block the retrieval of painful memories, thereby alleviating the associated negative behaviors. However, the underlying mechanism is poorly understood. This study revealed that the effect of EA on pain memory-induced negative behaviors is related to the mediation of GABAergic neuron activity and GABA receptor expression in the rostral anterior cingulate cortex (rACC). Previous studies have shown that the rACC is a crucial area for regulating nociceptive behaviors and negative emotions in pain memory models. The GABAergic neurons and receptors in the rACC are largely involved in pain sensation and related effects. However, the relationships among pain memory, GABAergic neurons and receptors in the rACC have not been investigated. In this study, we established a pain memory model via secondary plantar cross-injection of carrageenan and EA treatment. Using chemogenetic methods and behavioral assessments of pain and negative emotion, we found that early excitation of GABAergic neurons in the rACC blocked the recall of pain memories and reduced anxiety-like behaviors in pain memory model rats. Furthermore, pharmacological methods revealed that excitation of GABAA and GABAB receptors in the rACC blocks hyperpathia associated with pain memory and pain-induced anxiety-like behaviors, while inhibition of GABAA and GABAB receptors reverses these effects. These results suggest that EA may alleviate pain and associated anxiety-like behaviors related to pain memories through the activation of GABAergic neurons and excitation of GABAA and GABAB receptors in the rACC.

Differential role of fusiform gyrus coupling in depressive and anxiety symptoms during emotion perception.

Anxiety and depression co-occur; the neural substrates of shared and unique components of these symptoms are not understood. Given emotional alterations in internalizing disorders, we hypothesized that function of regions associated with emotion processing/regulation, including the anterior cingulate cortex (ACC), amygdala and fusiform gyrus (FG), would differentiate these symptoms. Forty-three adults with depression completed an emotional functional magnetic resonance imaging task and the Hamilton Depression and Anxiety Scales. We transformed these scales to examine two orthogonal components, one representing internalizing symptom severity and the other the type of internalizing symptoms (anxiety vs depression). We extracted blood oxygen level dependent signal from FG subregions, ACC, and amygdala and performed generalized psychophysiological interaction analyses to assess relationships between symptoms and brain function. Type of internalizing symptoms was associated with FG3-FG1 coupling (F = 8.14, P = 0.007). More coupling was associated with a higher concentration of depression, demonstrating that intra-fusiform coupling is differentially associated with internalizing symptom type (anxiety vs depression). We found an interaction between task condition and internalizing symptoms and dorsal (F = 4.51, P = 0.014) and rostral ACC activity (F = 4.27, P = 0.012). Post hoc comparisons revealed that less activity was associated with greater symptom severity during emotional regulation. Functional coupling differences during emotional processing are associated with depressive relative to anxiety symptoms and internalizing symptom severity. These findings could inform future treatments for depression.

Chemogenetics Modulation of Electroacupuncture Analgesia in Mice Spared Nerve Injury-Induced Neuropathic Pain through TRPV1 Signaling Pathway.

Neuropathic pain, which is initiated by a malfunction of the somatosensory cortex system, elicits inflammation and simultaneously activates glial cells that initiate neuroinflammation. Electroacupuncture (EA) has been shown to have therapeutic effects for neuropathic pain, although with uncertain mechanisms. We suggest that EA can reliably cure neuropathic disease through anti-inflammation and transient receptor potential V1 (TRPV1) signaling pathways from the peripheral to the central nervous system. To explore this, we used EA to treat the mice spared nerve injury (SNI) model and explore the underlying molecular mechanisms through novel chemogenetics techniques. Both mechanical and thermal pain were found in SNI mice at four weeks (mechanical: 3.23 ± 0.29 g; thermal: 4.9 ± 0.14 s). Mechanical hyperalgesia was partially attenuated by 2 Hz EA (mechanical: 4.05 ± 0.19 g), and thermal hyperalgesia was fully reduced (thermal: 6.22 ± 0.26 s) but not with sham EA (mechanical: 3.13 ± 0.23 g; thermal: 4.58 ± 0.37 s), suggesting EA's specificity. In addition, animals with Trpv1 deletion showed partial mechanical hyperalgesia and no significant induction of thermal hyperalgesia in neuropathic pain mice (mechanical: 4.43 ± 0.26 g; thermal: 6.24 ± 0.09 s). Moreover, we found increased levels of inflammatory factors such as interleukin-1 beta (IL1-β), IL-3, IL-6, IL-12, IL-17, tumor necrosis factor alpha, and interferon gamma after SNI modeling, which decreased in the EA and Trpv1-/- groups rather than the sham group. Western blot and immunofluorescence analysis showed similar tendencies in the dorsal root ganglion, spinal cord dorsal horn, somatosensory cortex (SSC), and anterior cingulate cortex (ACC). In addition, a novel chemogenetics method was used to precisely inhibit SSC to ACC activity, which showed an analgesic effect through the TRPV1 pathway. In summary, our findings indicate a novel mechanism underlying neuropathic pain as a beneficial target for neuropathic pain.

Altered task-related decoupling of the rostral anterior cingulate cortex in depression

Dysfunctional activity of the rostral anterior cingulate cortex (rACC) – an extensively connected hub region of the default mode network – has been broadly linked to cognitive and affective impairments in depression. However, the nature of aberrant task-related rACC suppression in depression is incompletely understood. In this study, we sought to characterize functional connectivity of rACC activity suppression (‘deactivation’) – an essential feature of rACC function – during external task engagement in depression. Specifically, we aimed to explore neural patterns of functional decoupling and coupling with the rACC during its task-driven suppression. We enrolled 81 15- to 25-year-old young people with moderate-to-severe major depressive disorder (MDD) before they commenced a 12-week clinical trial that assessed the effectiveness of cognitive behavioral therapy plus either fluoxetine or placebo. Ninety-four matched healthy controls were also recruited. Participants completed a functional magnetic resonance imaging face matching task known to elicit rACC suppression. To identify brain regions associated with the rACC during its task-driven suppression, we employed a seed-based functional connectivity analysis. We found MDD participants, compared to controls, showed significantly reduced ‘decoupling’ of the rACC with extended task-specific regions during task performance. Specifically, less decoupling was observed in the occipital and fusiform gyrus, dorsal ACC, medial prefrontal cortex, cuneus, amygdala, thalamus, and hippocampus. Notably, impaired decoupling was apparent in participants who did not remit to treatment, but not treatment remitters. Further, we found MDD participants showed significant increased coupling with the anterior insula cortex during task engagement. Our findings indicate that aberrant task-related rACC suppression is associated with disruptions in adaptive neural communication and dynamic switching between internal and external cognitive modes that may underpin maladaptive cognitions and biased emotional processing in depression.

Hypo- and hyper-activation in frontotemporal lobe during humor processing in patients with first episode schizophrenia

BackgroundPatients with schizophrenia present difficulties in humor recognition and appreciation, but the neural mechanism of these deficits remains unclear. This study aimed to elucidate neural substrates underlying humor processing in patients with first episode schizophrenia (FES). MethodsThis study recruited 40 patients with FES (illness duration ≤ 4 years) and 31 healthy controls matching for age, gender and education level. Participants completed a fMRI verbal humor processing paradigm comprising 96 stories, half for funny punch-line condition and the other half for unfunny condition. Participants were required to judge whether the story was funny or not. Signal detection theory (SDT) analysis was used to calculate d' and β values which represented sensitivity and inner criteria for humor signals respectively. The funny-unfunny contrast was analyzed to identify the brain regions related with humor processing. d' and β values were put into the imaging regression analysis. ResultsPatients with FES showed significantly lower hit rate and sensitivity of humor signals (d'). At the neural level, patients with FES hypo-activated in ventral medial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC) while hyper-activated in middle temporal gyrus (MTG) and superior temporal gyrus (STG) compared to controls. In addition, activity in vmPFC and ACC was positively associated with d’ and β values, while activity in STG was positively associated with β values in the clinical group. ConclusionsPatients with FES exhibited decreased sensitivity to humor signals. Hypo-activation in frontal regions and hyper-activation in temporal regions were associated with the humor processing deficits.

Acute hypoxia alters visuospatial attention orienting: an electrical neuroimaging study

Our study investigated the effects of hypoxia on visuospatial attention processing during preparation for a single/double-choice motor response. ERPs were recorded in two sessions in which participants breathed either ambient-air or oxygen-impoverished air. During each session, participants performed four cue-target attention orienting and/or alerting tasks. Replicating the classic findings of valid visuospatial attentional orienting modulation, ERPs to pre-target cues elicited both an Anterior directing attention negativity (ADAN)/CNV and a posterior Late directing attention positivity (LDAP)/TP, which in ambient air were larger for attention orienting than for alerting. Hypoxia increased the amplitude of both these potentials in the spatial orienting conditions for the upper visual hemifield, while, for the lower hemifield, it increased ADAN/CNV, but decreased LDAP/TP for the same attention conditions. To these ERP changes corresponded compensatory enhanced activation of right anterior cingulate cortex, left superior parietal lobule and frontal gyrus, as well as detrimental effects of hypoxia on behavioral overt performance. Together, these findings reveal for the first time, to our knowledge, that (1) these reversed alterations of the activation patterns during the time between cue and target occur at a larger extent in hypoxia than in air, and (2) acute normobaric hypoxia alters visuospatial attention orienting shifting in space.

Neurological Underpinnings of Psychological Factors Distinguishing Obsessive-Compulsive Disorder From Misophonia

Several studies have suggested that misophonia should be categorized as an obsessive-compulsive disorder (OCD) due to similar neural manifestations, such as impairments in limbic structures, and psychological features, such as perfectionism and disgust sensitivity. However, the two disorders may differ in the domains of disgust sensitivity. In OCD, the domain of pathogen disgust has been studied extensively as per the contamination subtype. In misophonia, pathogen disgust has not been reported. We hypothesized that moral disgust may better characterize individuals with misophonia, as studies indicate that people with misophonia view their triggers as morally unacceptable. Furthermore, neuroimaging has shown anterior cingulate cortex (ACC) activation particularly during exposure to misophonic triggers, which is an area associated with moral assessment of stimuli. Another psychological factor that may point to the two disorders being discrete is intolerance of uncertainty (IU), an aversion to undetermined events. IU has been well documented in OCD: It has been found to be positively associated with striatal volume and dysfunction in the ACC—both of which are common findings in OCD. We expected people with misophonia not to exhibit IU since they experience distress in response to specific triggers and, unlike individuals with OCD, do not experience preemptive anxiety. Multivariate logistic regression analysis run on survey-gathered data revealed IU as a significant predictor of OCD symptoms and moral disgust as a significant predictor of misophonia. Consistent with our hypotheses, our findings suggest that IU and moral disgust and the associated neural underpinnings differentiate misophonia from OCD. [ Psychiatr Ann . 2023;53(12):570–580.]

TET2 deficiency promotes anxiety and depression-like behaviors by activating NLRP3/IL-1β pathway in microglia of allergic rhinitis mice

BackgroundAnxiety and depression-like behaviors in allergic rhinitis (AR) are attracting attention, while the precise mechanism has not been clearly elucidated. Recent evidence shows that neuroinflammation in anterior cingulate cortex (ACC) may be the core of these neuropsychiatric symptoms in AR. Here, we investigated the molecular link between the anxiety and depression-like behaviors and neuroinflammation in ACC.MethodsMice were sensitized and challenged with ovalbumin (OVA) to induce AR. Nasal inflammation levels were assessed by H&E staining and PAS staining. Anxiety and depression-like behaviors were evaluated by behavioral experiments including open field test, forced swimming test, and sucrose preference test. Neuronal impairment was characterized via Nissl staining and 18FDG-PET. The role of ten-eleven translocation 2 (TET2) in AR-related anxiety and depression was assessed by Tet2−/− mice. In addition, the murine BV2 microglial cell line was utilized to explore the molecular mechanisms by which TET2 mediates neuroinflammation. The levels of TET2, NLRP3 and their downstream molecules were detected by immunohistochemistry, Western blot, Dot blot and ELISA. The effects of metformin on depression-like behaviors in AR mice were also evaluated.ResultsAR mice showed significant anxiety and depression-like behaviors, which associated with the activation of ACC. Loss of TET2 activated the NLRP3/IL-1β pathway of microglia in AR mice, further accelerating the anxiety and depression-like behaviors. In addition, knockdown of TET2 activated the NLRP3/IL-1β pathway in BV2 cells. Metformin improved the neuropsychiatric symptoms of AR mice by reducing the activation of NLRP3/IL-1β pathway after upregulating TET2.ConclusionTET2 deficiency activates the NLRP3/IL-1β pathway of microglia in the ACC, promoting the pathological process of anxiety and depression-like behavior in AR. Metformin could be effective in treating neuroinflammation by regulating microglia via TET2 up-regulation, indicating that metformin is a potential way to treat anxiety and depression-like behaviors in AR.

EEG-Based Cortical Alterations in Individuals With Chronic Knee Pain Secondary to Osteoarthritis: A Cross-sectional Investigation

Chronic painful knee osteoarthritis (OA) is a disabling physical health condition. Alterations in brain responses to arthritic changes in the knee may explain persistent pain. This study investigated source localized, resting-state electroencephalography activity and functional connectivity in people with knee OA, compared to healthy controls. Adults aged 44 to 85 years with knee OA (n = 37) and healthy control (n = 39) were recruited. Resting-state electroencephalography was collected for 10 minutes and decomposed into infraslow frequency (ISF) to gamma frequency bands. Standard low-resolution electromagnetic brain tomography statistical nonparametric maps were conducted, current densities of regions of interest were compared between groups and correlation analyses were performed between electroencephalography (EEG) measures and clinical pain and functional outcomes in the knee OA group. Standard low-resolution electromagnetic brain tomography nonparametric maps revealed higher (P = .006) gamma band activity over the right insula (RIns) in the knee OA group. A significant (P < .0001) reduction in ISF band activity at the pregenual anterior cingulate cortex, whereas higher theta, alpha, beta, and gamma band activity at the dorsal anterior cingulate cortex, pregenual anterior cingulate cortex, the somatosensory cortex, and RIns in the knee OA group were identified. ISF activity of the dorsal anterior cingulate cortex was positively correlated with pain measures and psychological distress scores. Theta and alpha activity of RIns were negatively correlated with pain interference. In conclusion, aberrations in infraslow and faster frequency EEG oscillations at sensory discriminative, motivational-affective, and descending inhibitory cortical regions were demonstrated in people with chronic painful knee OA. Moreover, EEG oscillations were correlated with pain and functional outcome measures. PerspectiveThis study confirms alterations in the rsEEG oscillations and its relationship with pain experience in people with knee OA. The study provides potential cortical targets and the EEG frequency bands for neuromodulatory interventions for managing chronic pain experience in knee OA.