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The default mode network (DMN) is atypically active in patients with ADHD, likely contributing to the inattention patterns observed in patients with the disorder. Nonetheless, magnetic resonance spectroscopy (MRS) studies have rarely targeted the posterior cingulate cortex, a key DMN region, and little is known about the biochemical setting within this network in patients with ADHD. We aimed to assess the differences in metabolite profiles of the posterior cingulate cortex-a key region of the DMN-between patients with ADHD and controls. Five brain metabolites-glutamate, inositol, N-acetyl aspartate, choline, and creatine-were measured through MRS in the posterior cingulate cortex of patients and controls in a 3.0 T scanner. Between-group comparison of neurometabolite concentrations in PCC was performed using multivariate analysis of covariance. A total of 88 patients and 44 controls were included in the analysis. Patients with ADHD showed lower levels of glutamate in the posterior cingulate cortex compared to controls (p = 0.003). Lower concentrations of glutamate in the posterior cingulate cortex suggest that a glutamatergic imbalance within the posterior cingulate cortex might play a role in the pathogenesis of ADHD. Further understanding of the causes and consequences of such glutamate decrease might help explain how some glutamate-related drug effects impact on ADHD symptomatology.

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Studies have suggested that endoplasmic reticulum stress (ERS) is involved in neurological dysfunction and that electroacupuncture (EA) attenuates neuropathic pain (NP) via undefined pathways. However, the role of ERS in the anterior cingulate cortex (ACC) in NP and the effect of EA on ERS in the ACC have not yet been investigated. In this study, an NP model was established by chronic constriction injury (CCI) of the left sciatic nerve in rats, and mechanical and cold tests were used to evaluate behavioral hyperalgesia. The protein expression and distribution were evaluated using western blotting and immunofluorescence. The results showed that glucose-regulated protein 78 (BIP) and inositol-requiring enzyme 1α (IRE-1α) were co-localized in neurons in the ACC. After CCI, BIP, IRE-1α, and phosphorylation of IRE-1α were upregulated in the ACC. Intra-ACC administration of 4-PBA and Kira-6 attenuated pain hypersensitivity and downregulated phosphorylation of IRE-1α, while intraperitoneal injection of 4-PBA attenuated hyperalgesia and inhibited the activation of P38 and JNK in ACC. In contrast, ERS activation by intraperitoneal injection of tunicamycin induced behavioral hyperalgesia in naive rats. Furthermore, EA attenuated pain hypersensitivity and inhibited the CCI-induced overexpression of BIP and pIRE-1α. Taken together, these results demonstrate that EA attenuates NP by suppressing BIP- and IRE-1α-mediated ERS in the ACC. Our study presents novel evidence that ERS in the ACC is implicated in the development of NP and provides insights into the molecular mechanisms involved in the analgesic effect of EA.

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In the retrosplenial cortex (RSC), the role of cholinergic modulation via α7 nicotinic receptors and their involvement in memory is unknown. In recent years, the RSC has been shown to deteriorate in the early stages of Alzheimer's disease (AD). Likewise, the cholinergic system has been postulated as one of those responsible for cognitive impairment in patients with AD. Great interest has arisen in the study of α7 nicotinic receptors as more specific targets for the treatment of this disease. For this reason, we aim to study the role of α7 receptors of the RSC in memory processing. We infused a selective α7 receptor antagonist into the anterior part of the RSC (aRSC) to assess its role in different phases of aversive memory processing using an inhibitory avoidance task. We found that α7 nicotinic receptors are involved in memory acquisition and expression, but not in its consolidation. These results identify aRSC α7 nicotinic receptors as key players in aversive memory processing and highlight their significant potential as therapeutic targets for Alzheimer's disease.

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Fibromyalgia, a condition characterized by chronic pain, is frequently accompanied by emotional disturbances. Here we aimed to study brain activation and functional connectivity (FC) during processing of emotional stimuli in fibromyalgia. Thirty female patients with fibromyalgia and 31 female healthy controls (HC) were included. Psychometric tests were administered to measure alexithymia, affective state, and severity of depressive and anxiety symptoms. Next, participants performed an emotion processing and regulation task during functional magnetic resonance imaging (fMRI). We performed a 2 × 2 ANCOVA to analyze main effects and interactions of the stimuli valence (positive or negative) and group (fibromyalgia or HC) on brain activation. Generalized psychophysiological interaction analysis was used to assess task-dependent FC of brain regions previously associated with emotion processing and fibromyalgia (i.e., hippocampus, amygdala, anterior insula, and pregenual anterior cingulate cortex [pACC]). The left superior lateral occipital cortex showed more activation in fibromyalgia during emotion processing than in HC, irrespective of valence. Moreover, we found an interaction effect (valence x group) in the FC between the left pACC and the precentral and postcentral cortex, and central operculum, and premotor cortex. These results suggest abnormal brain activation and connectivity underlying emotion processing in fibromyalgia, which could help explain the high prevalence of psychopathological symptoms in this condition.

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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.

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Incoercible or intractable pain is defined as pain that is refractory to pharmacological treatment to such an extent that opioid and analgesic adverse effects outweigh the therapeutic effects. The anterior cingulate cortex (ACC) is involved in the perception of pain, especially emotional pain, so it is logical that cingulotomy has an effective therapeutic effect. Therefore, we evaluated the effectiveness of cingulotomy for the treatment of incoercible pain. An observational, longitudinal, retrospective, and analytical study was carried out on a series of cases in which bilateral cingulotomy was performed for incoercible pain, and follow-up was performed 6 months after neurosurgery in the outpatient clinic at the Neurotraumatology Clinic. A positive correlation was observed between pain intensity and medication use, indicating that an increase in pain was associated with a greater requirement for analgesics. The result was a significant reduction in pain, as measured by the visual analog scale of pain, and decreased drug use after cingulotomy. We concluded that cingulotomy reduces incoercible pain and the need for medication.

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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. CONCLUSION: Our results highlight the need for a standardized tDCS protocol in MDD clinical trials.

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Maladaptive neuronal plasticity is a main mechanism for the development and maintenance of pathological pain. Affective, motivational and cognitive deficits that are comorbid with pain involve cellular and synaptic modifications in the anterior cingulate cortex (ACC), a major brain mediator of pain perception. Here we use a model of neuropathic pain (NP) in male mice and ex-vivo electrophysiology to investigate whether layer 5 caudal ACC (cACC) neurons projecting to the dorsomedial striatum (DMS), a critical region for motivational regulation of behavior, are involved in aberrant neuronal plasticity. We found that while the intrinsic excitability of cortico-striatal cACC neurons (cACC-CS) was preserved in NP animals, excitatory postsynaptic potentials (EPSP) induced after stimulation of distal inputs were enlarged. The highest synaptic responses were evident both after single stimuli and in each of the EPSP that compose responses to trains of stimuli, and were accompanied by increased synaptically-driven action potentials. EPSP temporal summation was intact in ACC-CS neurons from NP mice, suggesting that the plastic changes were not due to alterations in dendritic integration but rather through synaptic mechanisms. These results demonstrate for the first time that NP affects cACC neurons that project to the DMS and reinforce the notion that maladaptive plasticity of the cortico-striatal pathway may be a key factor in sustaining pathological pain.

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BACKGROUND: There have been significant challenges in understanding functional brain connectivity associated with adolescent depression, including the need for a more comprehensive approach to defining risk, the lack of representation of participants from low- and middle-income countries, and the need for network-based approaches to model connectivity. The current study aimed to address these challenges by examining resting-state functional connectivity of frontolimbic circuitry associated with the risk and presence of depression in adolescents in Brazil. METHODS: Adolescents in Brazil ages 14 to 16 years were classified into low-risk, high-risk, and depressed groups using a clinical assessment and composite risk score that integrates 11 sociodemographic risk variables. After excluding participants with excessive head movement, resting-state functional magnetic resonance imaging data of 126 adolescents were analyzed. We compared group differences in frontolimbic network connectivity using region of interest-to-region of interest, graph theory, and seed-based connectivity analyses. Associations between self-reported depressive symptoms and brain connectivity were also explored. RESULTS: Adolescents with depression showed greater dorsal anterior cingulate cortex (ACC) connectivity with the orbitofrontal cortex compared with the 2 risk groups and greater dorsal ACC global efficiency than the low-risk group. Adolescents with depression also showed reduced local efficiency and a lower clustering coefficient of the subgenual ACC compared with the 2 risk groups. The high-risk group also showed a lower subgenual ACC clustering coefficient relative to the low-risk group. CONCLUSIONS: These findings highlight altered connectivity and topology of the ACC within frontolimbic circuitry as potential neural correlates and risk factors of developing depression in adolescents in Brazil. This study broadens our understanding of the neural connectivity associated with adolescent depression in a global context.

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The retrosplenial cortex (RSC) has been widely related to spatial and contextual memory. However, we recently demonstrated that the anterior part of the RSC (aRSC) is required for object recognition (OR) memory consolidation. In this study, we aimed to analyze the requirement of dopaminergic inputs into the aRSC for OR memory consolidation in male rats. We observed amnesia at 24-h long-term memory when we infused SCH23390, a D1/D5 dopamine receptors antagonist, into aRSC immediately after OR training session. However, the same infusion had no effect on OR short-term memory. Then, we analyzed whether the ventral tegmental area (VTA) is necessary for OR consolidation. VTA inactivation by intra-VTA administration of muscimol, a GABAA agonist, immediately after an OR training session induced amnesia when animals were tested at 24 h. Moreover, we observed that this VTA inactivation-induced amnesia was reversed by the simultaneous intra-aRSC delivery of SKF38393, a D1/D5 receptor agonist. Altogether, our results suggest that VTA dopaminergic inputs to aRSC play an important modulatory role in OR memory consolidation.

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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.

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Listening to samba percussion often elicits feelings of pleasure and the desire to move with the beat-an experience sometimes referred to as "feeling the groove"- as well as social connectedness. Here we investigated the effects of performance timing in a Brazilian samba percussion ensemble on listeners' experienced pleasantness and the desire to move/dance in a behavioral experiment, as well as on neural processing as assessed via functional magnetic resonance imaging (fMRI). Participants listened to different excerpts of samba percussion produced by multiple instruments that either were "in sync", with no additional asynchrony between instrumental parts other than what is usual in naturalistic recordings, or were presented "out of sync" by delaying the snare drums (by 28, 55, or 83 ms). Results of the behavioral experiment showed increasing pleasantness and desire to move/dance with increasing synchrony between instruments. Analysis of hemodynamic responses revealed stronger bilateral brain activity in the supplementary motor area, the left premotor area, and the left middle frontal gyrus with increasing synchrony between instruments. Listening to "in sync" percussion thus strengthens audio-motor interactions by recruiting motor-related brain areas involved in rhythm processing and beat perception to a higher degree. Such motor related activity may form the basis for "feeling the groove" and the associated desire to move to music. Furthermore, in an exploratory analysis we found that participants who reported stronger emotional responses to samba percussion in everyday life showed higher activity in the subgenual cingulate cortex, an area involved in prosocial emotions, social group identification and social bonding.

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Von Economo neurons (VENs) have been mentioned in the medical literature since the second half of the 19th century; however, it was not until the second decade of the 20th century that their cytomorphology was described in detail. To date, VENs have been found in limbic sectors of the frontal, temporal and insular lobes. In humans, their density seems to decrease in the caudo-rostral and ventro-dorsal direction; that is, from the anterior regions of the cingulate and insular cortices towards the frontal pole and the superior frontal gyrus. Several studies have provided similar descriptions of the shape of the VEN soma, but the size of the soma varies from one cortical region to another. There is consensus among different authors about the selective vulnerability of VENs in certain pathologies, in which a deterioration of the capacities involved in social behaviour is observed. In this review, we propose that the restriction of VENs towards the sectors linked to limbic information processing in Homo sapiens gives them a possible functional role in relation to the structures in which they are located. However, given the divergence in characteristics such as location, density, size and biochemical profile among VENs of different cortical sectors, the activities in which they participate could allow them to partake in a wide spectrum of neurological functions, including autonomic responses and executive functions.

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Cohabitation with a partner undergoing chronic restraint stress (CRE) induces anxiogenic-like behaviors through emotional contagion. We hypothesized that the anterior cingulate cortex (ACC) and the amygdala would be involved in the modulation of this emotional process. This study investigated the role of the ACC and amygdala in empathy-like behavior (e.g., anxiety-like responses) induced by living with a mouse subjected to CRE. Male Swiss mice were housed in pairs for 14 days and then allocated into two groups: cagemate stress (one animal of the pair was subjected to 14 days of restraint stress) and cagemate control (no animal experienced stress). Twenty-four hours after the last stress session, cagemates had their brains removed for recording FosB labeling in the ACC and amygdala (Exp.1). In experiments 2 and 3, 24 h after the last stress session, the cagemates received 0.1 µL of saline or cobalt chloride (CoCl2 1 mM) into the ACC or amygdala, and then exposed to the elevated plus-maze (EPM) for recording anxiety. Results showed a decrease of FosB labeling in the ACC without changing immunofluorescence in the amygdala of stress cagemate mice. Cohabitation with mice subjected to CRE provoked anxiogenic-like behaviors. Local inactivation of ACC (but not the amygdala) reversed the anxiogenic-like effects induced by cohabitation with a partner undergoing CRE. These results suggest the involvement of ACC, but not the amygdala, in anxiety induced by emotional contagion.

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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.

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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.

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The incidence of chronic pain is high in the general population and it is closely related to anxiety disorders, which promote negative effects on the quality of life. The cannabinoid system has essential participation in the pain sensitivity circuit. In this perspective, cannabidiol (CBD) is considered a promising strategy for treating neuropathic pain. Our study aimed to evaluate the effects of sub-chronic systemic treatment with CBD (0.3, 3, 10, or 30 mg/kg, i.p.) in male in rats submitted to chronic constriction injury of the sciatic nerve (CCI) or not (SHAM) and assessed in nociceptive tests (von Frey, acetone, and hot plate, three days CBD's treatment) and in the open field test (OFT, two days CBD's treatment). We performed a screening immunoreactivity of CB1 and TRPV1 receptors in cortical and limbic regions tissues, which were collected after 1.5 h of behavioral tests on the 24th experimental day. This study presents a dose-response curve to understand better the effects of low doses (3 mg/kg) on CBD's antiallodynic and anxiolytic effects. Also, low doses of CBD were able to (1) reverse mechanical and thermal allodynia (cold) and hyperalgesia, (2) reverse anxious behaviors (reduction of the % of grooming and freezing time, and increase of the % of center time in the OFT) induced by chronic pain. The peripheral neuropathy promoted the increase in the expression of CB1 and TRPV1 receptors in the anterior cingulate cortex (ACC), anterior insular cortex (AIC), basolateral amygdala (BLA), dorsal hippocampus (DH), and ventral hippocampus (VH). CBD potentiated this effect in the ACC, AIC, BLA, DH, and VH regions. These results provide substantial evidence of the role of the ACC-AIC-BLA corticolimbic circuit, and BLA-VH for pain regulation. These results can be clinically relevant since they contribute to the evidence of CBD's beneficial effects on treating chronic pain and associated comorbidities such as anxiety.

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Increase in proton concentration [H+] or decrease in local and global extracellular pH occurs in both physiological and pathological conditions. Acid-sensing ion channels (ASICs), belonging to the ENaC/Deg superfamily, play an important role in signal transduction as proton sensor. ASICs and in particular ASIC1a (one of the six ASICs subunits) which is permeable to Ca2+, are involved in many physiological processes including synaptic plasticity and neurodegenerative diseases. Activity-dependent long-term potentiation (LTP) is a major type of long-lasting synaptic plasticity in the CNS, associated with learning, memory, development, fear and persistent pain. Neurons in the anterior cingulate cortex (ACC) play critical roles in pain perception and chronic pain and express ASIC1a channels. During synaptic transmission, acidification of the synaptic cleft presumably due to the co-release of neurotransmitter and H+ from synaptic vesicles activates postsynaptic ASIC1a channels in ACC of mice. This generates ASIC1a synaptic currents that add to the glutamatergic excitatory postsynaptic currents (EPSCs). Here we report that modulators like histamine and corticosterone, acting through ASIC1a regulate synaptic plasticity, reducing the threshold for LTP induction of glutamatergic EPSCs. Our findings suggest a new role for ASIC1a mediating the neuromodulator action of histamine and corticosterone regulating specific forms of synaptic plasticity in the mouse ACC.

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BACKGROUND: Childhood abuse (CA) is a risk factor for a number of psychiatric disorders and has been associated with higher risk of developing bipolar disorders (BD). CA in BD has been associated with more severe clinical outcomes, but the neurobiological explanation for this is unknown. Few studies have explored in vivo measurement of brain metabolites using proton magnetic resonance spectroscopy (1H-MRS) in CA and no studies have investigated the association of CA severity with brain neurometabolites in BD. OBJECTIVE: To investigate whether CA severity is associated with changes in anterior cingulate cortex (ACC) neurometabolite profile in BD and HC subjects. METHODS: Fifty-nine BD I euthymic patients and fifty-nine HC subjects were assessed using the Childhood Trauma Questionnaire (CTQ) and underwent a 3-Tesla 1H-MRS scan. Severity of childhood abuse (physical, sexual and emotional) and its association with levels of brain metabolites was analyzed within each group. RESULTS: BD patients had higher total scores on the CTQ and higher severity rates of sexual and physical abuse compared to HC subjects. Greater severity of physical and sexual abuse was associated with increased ACC PCr level and lower Cr/PCr ratio in the BD group only. CONCLUSION: Sexual and physical abuse in BD patients, but not in HC subjects, appeared to be associated with creatine metabolism in the ACC, which can influence neuronal mitochondrial energy production. Further studies should investigate whether this is the mechanism underlying the association between CA and worse clinical outcomes in BD.

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