Midcingulate Cortex Research Articles

The Neural Correlates of Individual Differences in Reinforcement Learning during Pain Avoidance and Reward Seeking.

Organisms learn to gain reward and avoid punishment through action-outcome associations. Reinforcement learning (RL) offers a critical framework to understand individual differences in this associative learning by assessing learning rate, action bias, pavlovian factor (i.e., the extent to which action values are influenced by stimulus values), and subjective impact of outcomes (i.e., motivation to seek reward and avoid punishment). Nevertheless, how these individual-level metrics are represented in the brain remains unclear. The current study leveraged fMRI in healthy humans and a probabilistic learning go/no-go task to characterize the neural correlates involved in learning to seek reward and avoid pain. Behaviorally, participants showed a higher learning rate during pain avoidance relative to reward seeking. Additionally, the subjective impact of outcomes was greater for reward trials and associated with lower response randomness. Our imaging findings showed that individual differences in learning rate and performance accuracy during avoidance learning were positively associated with activities of the dorsal anterior cingulate cortex, midcingulate cortex, and postcentral gyrus. In contrast, the pavlovian factor was represented in the precentral gyrus and superior frontal gyrus (SFG) during pain avoidance and reward seeking, respectively. Individual variation of the subjective impact of outcomes was positively predicted by activation of the left posterior cingulate cortex. Finally, action bias was represented by the supplementary motor area (SMA) and pre-SMA whereas the SFG played a role in restraining this action tendency. Together, these findings highlight for the first time the neural substrates of individual differences in the computational processes during RL.

The parietal cortex has a causal role in ambiguity computations in humans.

Humans often face the challenge of making decisions between ambiguous options. The level of ambiguity in decision-making has been linked to activity in the parietal cortex, but its exact computational role remains elusive. To test the hypothesis that the parietal cortex plays a causal role in computing ambiguous probabilities, we conducted consecutive fMRI and TMS-EEG studies. We found that participants assigned unknown probabilities to objective probabilities, elevating the uncertainty of their decisions. Parietal cortex activity correlated with the objective degree of ambiguity and with a process that underestimates the uncertainty during decision-making. Conversely, the midcingulate cortex (MCC) encodes prediction errors and increases its connectivity with the parietal cortex during outcome processing. Disruption of the parietal activity increased the uncertainty evaluation of the options, decreasing cingulate cortex oscillations during outcome evaluation and lateral frontal oscillations related to value ambiguous probability. These results provide evidence for a causal role of the parietal cortex in computing uncertainty during ambiguous decisions made by humans.

Irritable Bowel Syndrome Is Associated With Brain Health by Neuroimaging, Behavioral, Biochemical, and Genetic Analyses

BackgroundIrritable bowel syndrome (IBS) interacts with psychopathology in a complex way; however, little is known about the underlying brain, biochemical, and genetic mechanisms. MethodsTo clarify the phenotypic and genetic associations between IBS and brain health, we performed a comprehensive retrospective cohort study on a large population. Our study included 171,104 participants from the UK Biobank who underwent a thorough assessment of IBS, with the majority also providing neuroimaging, behavioral, biochemical, and genetic information. Multistage linked analyses were conducted, including phenome-wide association analysis, polygenic risk score calculation, and 2-sample Mendelian randomization analysis. ResultsThe phenome-wide association analysis showed that IBS was linked to brain health problems, including anxiety and depression, and poor cognitive performance. Significantly lower brain volumes associated with more severe IBS were found in key areas related to emotional regulation and higher-order cognition, including the medial orbitofrontal cortex/ventromedial prefrontal cortex, anterior insula, anterior and mid-cingulate cortices, dorsolateral prefrontal cortex, and hippocampus. Higher triglycerides, lower high-intensity lipoprotein, and lower platelets were also related (p < 1 × 10−10) to more severe IBS. Finally, Mendelian randomization analyses demonstrated potential causal relationships between IBS and brain health and indicated possible mediating effects of dyslipidemia and inflammation. ConclusionsFor the first time, this study provides a comprehensive understanding of the relationship between IBS and brain health phenotypes, integrating perspectives from neuroimaging, behavioral performance, biochemical factors, and genetics, which is of great significance for clinical applications to potentially address brain health impairments in patients with IBS.

Shared and distinctive dysconnectivity patterns underlying pure generalized anxiety disorder (GAD) and comorbid GAD and depressive symptoms

The resting-state connectivity features underlying pure generalized anxiety disorder (GAD, G1) and comorbid GAD and depressive symptoms (G2) have not been directly compared. Furthermore, it is unclear whether these features might serve as potential prognostic biomarkers and change with treatment. Degree centrality (DC) in G1 (40 subjects), G2 (58 subjects), and healthy controls (HCs, 54 subjects) was compared before treatment, and the DC of G1 or G2 at baseline was compared with that after 4 weeks of paroxetine treatment. Using support vector regression (SVR), voxel-wise DC across the entire brain and abnormal DC at baseline were employed to predict treatment response. At baseline, G1 and G2 exhibited lower DC in the left mid-cingulate cortex and vermis IV/V compared to HCs. Additionally, compared to HCs, G1 had lower DC in the left middle temporal gyrus, while G2 showed higher DC in the right inferior temporal/fusiform gyrus. However, there was no significant difference in DC between G1 and G2. The SVR based on abnormal DC at baseline could successfully predict treatment response in responders in G2 or in G1 and G2. Notably, the predictive performance based on abnormal DC at baseline surpassed that based on DC across the entire brain. After treatment, G2 responders showed lower DC in the right medial orbital frontal gyrus, while no change in DC was identified in G1 responders. The G1 and G2 showed common and distinct dysconnectivity patterns and they could potentially serve as prognostic biomarkers. Furthermore, DC in patients with GAD could change with treatment.

Reduced Cortico-Cortical Resting-State Connectivity in Sensory Systems Related to Bodily Pain in Juvenile Fibromyalgia.

Juvenile-onset fibromyalgia (JFM) is a paradigmatic chronic pain condition for which the underlying neurobiological substrates are poorly understood. This study examined, for the first time, data-driven resting-state functional connectivity (rsFC) alterations in 37 female adolescents with JFM compared with 43 healthy female adolescents and identified associations with bodily pain. Whole-brain voxel-wise rsFC alterations were assessed using the intrinsic connectivity contrast, a measure of node centrality at each voxel, and seed-based analyses for interpretability. We studied the relationship between rsFC alterations in somatosensory systems and the location and extension of bodily pain. Adolescents with JFM had voxel-wise rsFC reductions in the paracentral lobule (PCL)/primary somatosensory cortex (S1) (T=4.89, family-wise error corrected p-value (pFWE)< 0.001) and left midcingulate cortex (T=4.67, pFWE=0.043). Post hoc analyses revealed reduced rsFC spanning major cortical sensory hubs (T > 4.4, pFWE < 0.030). Cortico-cortical rsFC reductions within PCL/S1 in JFM occurred in locations innervated by bodily areas where the pain was most frequent (F=3.15; positive false discovery rate=0.029) and predicted widespread pain (T > 4.4, pFWE < 0.045). Conversely, adolescents with JFM had increases in PCL/S1-thalamus (T=4.75, pFWE=0.046) and PCL/S1-anterior insula rsFC (T=5.13, pFWE=0.039). Reduced cortico-cortical sensory integration involving PCL/S1 and spanning the sensory systems may underly critical pain sensory features in youth with JFM. Reduced sensory integration is paralleled by augmented cross-talk between sensory and affective/salience-processing regions, potentially indicating a shift toward more affectively colored sensory experiences to the detriment of specific sensory discrimination.

Acetaldehyde-mediated increase in glutamatergic and N-acetylaspartate neurometabolite levels in the midcingulate cortex of ALDH2*1/*2 heterozygous young adults.

To elucidate the neurobiology underlying alcohol's effect on the human brain, we examined the acute effects of moderate alcohol administration on levels of glutamatergic neurometabolites and N-acetylaspartate, an amino acid found in neurons, may reflect disordered neuronal integrity. Eighteen healthy Japanese participants (7 males/11 females) aged 20-30 years who were heterozygous for an inactive allele of acetaldehyde dehydrogenase-2 (ALDH/*1/*2) were included. Participants underwent an intravenous alcohol infusion using the clamp method at a target blood alcohol concentration (BAC) of 0.50 mg/mL for 90 min within a range of ±0.05 mg/mL. We examined glutamate + glutamine (Glx) and N-acetylaspartate N-acetylaspartylglutamate (NAA) levels in the midcingulate cortex (MCC) using 3 T 1 H-MRS PRESS at baseline, 90 min, and 180 min (i.e., 90 min after alcohol infusion was finished). A two-way repeated-measures analysis of variance was used to assess longitudinal changes in Glx and NAA levels, with time and sex as within- and between-subject factors, respectively. Pearson's correlation coefficients were calculated among neurometabolite levels and BAC or blood acetaldehyde concentration (BAAC). Both Glx (F(2,32) = 8.15, p = 0.004, η2 = 0.15) and NAA (F(2,32) = 5.01, p = 0.04, η2 = 0.07) levels were increased after alcohol injection. There were no sex or time × sex interaction effects observed. NAA levels were positively correlated with BAAC at 90 min (r(13) = 0.77, p = 0.01). There were no associations between neurometabolite levels and BAC. Both Glx and NAA levels in the MCC increased in response to the administration of moderate concentrations of alcohol. Given positive associations between NAA levels and BAAC and the hypothetical glutamate release via dopamine pathways, the effects of drinking on the MCC in the acute phase may be ascribed to acetaldehyde metabolized from alcohol.

Heart Rate Variability during Slow Wave Sleep is Linked to Resting‐state Functional Connectivity in the Central Autonomic Network among Older Adults ‘at‐risk’ of Dementia

AbstractBackgroundReduced heart rate variability (HRV) can be an early sign of autonomic dysfunction in neurodegenerative diseases, and may be related to brain dysfunction in the central autonomic network (CAN). As yet, such autonomic dysfunction has not been examined during sleep – which is an ideal physiological state to study brain‐heart interaction as both the central and peripheral nervous systems behave differently compared to during wakefulness. Therefore, we aimed to examine whether nocturnal HRV, especially slow wave sleep (SWS), is associated with CAN functional connectivity in older adults ‘at‐risk’ of dementia.MethodOlder adults (n = 78; age range = 50‐88 years; 64% female) attending a memory clinic for cognitive concerns underwent resting‐state functional magnetic resonance imaging and an overnight polysomnography. From these, CAN functional connectivity strength and HRV data during sleep were derived, respectively. High‐frequency heart rate variability (HF‐HRV) was extracted to index parasympathetic activity during distinct periods of sleep, including SWS as well as secondary outcomes of non‐rapid eye movement sleep, wake after sleep onset, and rapid eye movement sleep. General linear models were used to examine associations between CAN functional connectivity and HF‐HRV.ResultAnalyses revealed that increased HF‐HRV during SWS was associated with stronger functional connectivity (F = 3.98, p = 0.022) in two core brain regions within the CAN, the right anterior insular and posterior midcingulate cortex, as well as stronger functional connectivity (F = 6.21, p = 0.005) between broader CAN brain regions – the right amygdala with three sub‐nuclei of the thalamus. There were no significant associations between HF‐HRV and CAN functional connectivity during wake after sleep onset or rapid eye movement sleep.ConclusionThese findings show that in older adults ‘at‐risk’ of dementia, parasympathetic regulation during SWS is uniquely linked to differential functional connectivity within both core and broader CAN brain regions. It is possible that dysfunctional brain‐heart interactions manifest primarily during this specific period of sleep known for its role in memory and metabolic clearance. Further studies elucidating the pathophysiology and directionality of this relationship should be conducted to determine if HRV drives neurodegeneration, or if brain degeneration within the CAN promotes aberrant HRV.

A role for retro-splenial cortex in the task-related P3 network

ObjectiveThe P3 is an event-related response observed in relation to task-relevant sensory events. Despite its ubiquitous presence, the neural generators of the P3 are controversial and not well identified. MethodsWe compared source analysis of combined magneto- and electroencephalography (M/EEG) data with functional magnetic resonance imaging (fMRI) and simulation studies to better understand the sources of the P3 in an auditory oddball paradigm. ResultsOur results suggest that the dominant source of the classical, postero-central P3 lies in the retro-splenial cortex of the ventral cingulate gyrus. A second P3 source in the anterior insular cortex contributes little to the postero-central maximum. Multiple other sources in the auditory, somatosensory, and anterior midcingulate cortex are active in an overlapping time window but can be functionally dissociated based on their activation time courses. ConclusionsThe retro-splenial cortex is a dominant source of the parietal P3 maximum in EEG. SignificanceThese results provide a new perspective for the interpretation of the extensive research based on the P3 response.

Projections from anteromedial thalamus nucleus to the midcingulate cortex mediate pain and anxiety-like behaviors in mice

Prior research has demonstrated the involvement of the midcingulate cortex (MCC) and its downstream pathway in pain regulation. However, the mechanism via which pain information is conveyed to the MCC remains unclear. The present study utilized immunohistochemistry, chemogenetics, optogenetics, and behavior detection methods to explore the involvement of MCC, anteromedial thalamus nucleus (AM), and AM-MCC pathway in pain and emotional regulation. Chemogenetics or optogenetics methods were employed to activate/inhibit MCCCaMKIIα, AMCaMKIIα, AMCaMKIIα-MCC pathway. This manipulation evokes/relieves mechanical and partial heat hyperalgesia, as well as anxiety-like behaviors. In the complete Freund,s adjuvant (CFA) inflammatory pain model, chemogenetic inhibition of the AMCaMKIIα-MCCCaMKIIα pathway contributed to pain relief. Notably, this study presented the first evidence implicating the AM in the regulation of nociception and negative emotions. Additionally, it was observed that the MCC primarily receives projections from the AM, highlighting the crucial role of this pathway in the transmission of pain and emotional information.

Cerebral glucose hypometabolism and hypoperfusion of cingulate gyrus: an imaging biomarker of autoimmune encephalitis with psychiatric symptoms

BackgroundAbout 60% of autoimmune encephalitis (AE) patients present psychiatric symptoms, but the underlying mechanism remains unknown. This study examined the role of the cingulate cortex in such patients to identify predictive poor psychiatric factors.MethodsIn this study, 49 AE patients and 39 healthy controls were enrolled. AE patients were further divided into two groups based on the presence/absence of psychiatric symptoms. The ratio of the standardized uptake value (SUVR) and relative cerebral blood flow (rCBF) in different regions of the cingulate cortex were calculated through positron emission tomography–computed tomography (PET/CT) and arterial spin labeling (ASL) MRI, and the results were compared among the three groups. In addition, we followed-up on the psychiatric outcomes and identified the risk factors for poor psychiatric prognosis, focusing on the cingulate cortex.ResultsMore than half of the AE patients (27/49) exhibited psychiatric symptoms. Agitation and thought blocking were typical psychiatric phenotypes, except for anti-glutamic acid decarboxylase 65 (GAD65) encephalitis, which mainly presented with catatonia and a depressed mood. AE patients with psychiatric symptoms experienced reduced metabolism and perfusion of the anterior cingulate cortex (ACC), midcingulate cortex (MCC), and posterior cingulate cortex (PCC). The SUVR of ACC can be used as an independent risk factor of poor psychiatric outcomes, which had an area under the ROC curve (AUC) of 0.865.ConclusionImpaired cingulate cortex function in AE may be the potential mechanism of psychiatric symptoms. Hypometabolism of ACC is an independent prognostic factor predicting an unfavorable psychiatric prognosis in AE.

Neural tracking ofsocial hierarchies inadolescents' real-world social networks.

In the current study, we combined sociometric nominations and neuroimaging techniques to examine adolescents' neural tracking of peers from their real-world social network that varied in social preferences and popularity. Adolescent participants from an entire school district (N = 873) completed peer sociometric nominations of their grade at school, and a subset of participants (N = 117, Mage = 13.59 years) completed a neuroimaging task in which they viewed peer faces from their social networks. We revealed two neural processes by which adolescents track social preference: (1) the fusiform face area, an important region for early visual perception and social categorization, simultaneously represented both peers high in social preference and low in social preference; (2) the dorsolateral prefrontal cortex (DLPFC), which was differentially engaged in tracking peers high and low in social preference. No regions specifically tracked peers high in popularity and only the inferior parietal lobe, temporoparietal junction, midcingulate cortex and insula were involved in tracking unpopular peers. This is the first study to examine the neural circuits that support adolescents' perception of peer-based social networks. These findings identify the neural processes that allow youths to spontaneously keep track of peers' social value within their social network.

Peripheral Pain Captured Centrally: Altered Brain Morphology on MRI in Small Fiber Neuropathy Patients With and Without an SCN9A Gene Variant

The current study aims to characterize brain morphology of pain as reported by small fiber neuropathy (SFN) patients with or without a gain-of-function variant involving the SCN9A gene and compare these with findings in healthy controls without pain. The Neuropathic Pain Scale was used in patients with idiopathic SFN (N = 20) and SCN9A-associated SFN (N = 12) to capture pain phenotype. T1-weighted, structural magnetic resonance imaging (MRI) data were collected in patients and healthy controls (N = 21) to 1) compare cortical thickness and subcortical volumes and 2) quantify the association between severity, quality, and duration of pain with morphological properties. SCN9A-associated SFN patients showed significant (P < .017, Bonferroni corrected) higher cortical thickness in sensorimotor regions, compared to idiopathic SFN patients, while lower cortical thickness was found in more functionally diverse regions (eg, posterior cingulate cortex). SFN patient groups combined demonstrated a significant (Spearman’s ρ = .44–.55, P = .005–.049) correlation among itch sensations (Neuropathic Pain Scale-7) and thickness of the left precentral gyrus, and midcingulate cortices. Significant associations were found between thalamic volumes and duration of pain (left: ρ = −.37, P = .043; right: ρ = −.40, P = .025). No associations were found between morphological properties and other pain qualities. In conclusion, in SCN9A-associated SFN, profound morphological alterations anchored within the pain matrix are present. The association between itch sensations of pain and sensorimotor and midcingulate structures provides a novel basis for further examining neurobiological underpinnings of itch in SFN. PerspectiveCortical thickness and subcortical volume alterations in SFN patients were found in pain hubs, more profound in SCN9A-associated neuropathy, and correlated with itch and durations of pain. These findings contribute to our understanding of the pathophysiological pathways underlying chronic neuropathic pain and symptoms of itch in SFN.

The remodeling of metabolic brain pattern in patients with extracranial diffuse large B-cell lymphoma

BackgroundOwing to the advances in diagnosis and therapy, survival or remission rates for lymphoma have improved prominently. Apart from the lymphoma- and chemotherapy-related somatic symptom burden, increasing attention has been drawn to the health-related quality of life. The application of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) has been routinely recommended for the staging and response assessment of FDG-avid lymphoma. However, up till now, only a few researches have investigated the brain metabolic impairments in patients with pre-treatment lymphoma. The determination of the lymphoma-related metabolic brain pattern would facilitate exploring the tailored therapeutic regimen to alleviate not only the physiological, but also the psychological symptoms. In this retrospective study, we aimed to establish the diffuse large B-cell lymphoma-related pattern (DLBCLRP) of metabolic brain network and investigate the correlations between DLBCLRP and several indexes of the staging and response assessment.ResultsThe established DLBCLRP was characterized by the increased metabolic activity in bilateral cerebellum, brainstem, thalamus, striatum, hippocampus, amygdala, parahippocampal gyrus and right middle temporal gyrus and by the decreased metabolic activity in bilateral occipital lobe, parietal lobe, anterior cingulate gyrus, midcingulate cortex and medial frontal gyrus. Significant difference in the baseline expression of DLBCLRP was found among complete metabolic response (CMR), partial metabolic response (PMR) and progressive metabolic disease (PMD) groups (P < 0.01). DLBCLRP expressions were also significantly or tended to be positively correlated with international prognostic index (IPI) (rs = 0.306, P < 0.05), lg(total metabolic tumor volume, TMTV) (r = 0.298, P < 0.05) and lg(total lesion glycolysis, TLG) (r = 0.233, P = 0.064). Though no significant correlation of DLBCLRP expression was found with Ann Arbor staging or tumor SUVmax (P > 0.05), the post-treatment declines of DLBCLRP expression were significantly positively correlated with Ann Arbor staging (rs = 0.284, P < 0.05) and IPI (rs = 0.297, P < 0.05).ConclusionsThe proposed DLBCLRP would lay the foundation for further investigating the cerebral dysfunction related to DLBCL itself and/or treatments. Besides, the expression of DLBCLRP was associated with the tumor burden of lymphoma, implying a potential biomarker for prognosis.

Cholinergic centro-cingulate network in Parkinson disease and normal aging.

Decreased cholinergic binding within the recently identified centro-cingulate brain network robustly has been shown to robustly correlate with the severity of cognitive impairment in Parkinson disease (PD). This network with key hubs within the cingulum, operculum and peri-central cortical regions also correlates with elements of parkinsonian motor impairments, including postural instability and gait difficulties, such as falls or freezing. MRI neuroimaging studies have shown that the anterior midcingulate cortex is a key node for cognitive aspects of movement generation, i.e., intentional motor control. Recent evidence also suggests a novel aspect of organization of primary motor cortex, describing "effector" regions for fine movement control intercalated with interlinked "inter-effector" regions devoted to whole-body control. A distinguishing feature of inter-effector regions is tight linkage to the cingular and opercular regions. Such inter-effector regions have been proposed to be part of a greater somato-cognitive action network necessary for integration of goals and movement. Recent evidence also points to vulnerabilities of cholinergic nerve terminals in the centro-cingulate network in older non-PD adults. These features of normal aging underscore that cortical cholinergic terminal losses in age-associated neurodegenerative disorders are likely not exclusively the result of disease-specific etiologies but also related to otherwise normal aging. Practical implications of this overlap are that addressing disease-specific and general aging etiologies involved in neurodegeneration, may be of benefit in age-associated neurodegenerative disorders where significant cholinergic systems degeneration is present.

Different cortical connectivities in human females and males relate to differences in strength and body composition, reward and emotional systems, and memory.

Sex differences in human brain structure and function are important, partly because they are likely to be relevant to the male-female differences in behavior and in mental health. To analyse sex differences in cortical function, functional connectivity was measured in 36,531 participants (53% female) in the UK Biobank (mean age 69) using the Human Connectome Project multimodal parcellation atlas with 360 well-specified cortical regions. Most of the functional connectivities were lower in females (Bonferroni corrected), with the mean Cohen's d = - 0.18. Removing these as covariates reduced the difference of functional connectivities for females-males from d = - 0.18 to - 0.06. The lower functional connectivities in females were especially of somatosensory/premotor regions including the insula, opercular cortex, paracentral lobule and mid-cingulate cortex, and were correlated with lower maximum workload (r = 0.17), and with higher whole body fat mass (r = - 0.17). But some functional connectivities were higher in females, involving especially the ventromedial prefrontal cortex and posterior cingulate cortex, and these were correlated with higher liking for some rewards such as sweet foods, higher happiness/subjective well-being, and with better memory-related functions. The main findings were replicated in 1000 individuals (532 females, mean age 29) from the Human Connectome Project. This investigation shows the cortical systems with different functional connectivity between females and males, and also provides for the first time a foundation for understanding the implications for behavior of these differences between females and males.

Successful cognitive aging is associated with thicker anterior cingulate cortex and lower tau deposition compared to typical aging.

There is no consensus on either the definition of successful cognitive aging (SA) or the underlying neural mechanisms. We examined the agreement between new and existing definitions using: (1) a novel measure, the cognitive age gap (SA-CAG, cognitive-predicted age minus chronological age), (2) composite scores for episodic memory (SA-EM), (3) non-memory cognition (SA-NM), and (4) the California Verbal Learning Test (SA-CVLT). Fair to moderate strength of agreement was found between the four definitions. Most SA groups showed greater cortical thickness compared to typical aging (TA), especially in the anterior cingulate and midcingulate cortices and medial temporal lobes. Greater hippocampal volume was found in all SA groups except SA-NM. Lower entorhinal 18 F-Flortaucipir (FTP) uptake was found in all SA groups. These findings suggest that a feature of SA, regardless of its exact definition, is resistance to tau pathology and preserved cortical integrity, especially in the anterior cingulate and midcingulate cortices. Different approaches have been used to define successful cognitive aging (SA). Regardless of definition, different SA groups have similar brain features. SA individuals have greater anterior cingulate thickness and hippocampal volume. Lower entorhinal tau deposition, but not amyloid beta is related to SA. A combination of cortical integrity and resistance to tau may be features of SA.

Microglial and Astrocytic Responses in the Human Midcingulate Cortex in Huntington's Disease.

Patients with Huntington's disease can present with variable difficulties of motor functioning, mood, and cognition. Neurodegeneration occurs in the anterior cingulate cortex of some patients with Huntington's disease and is linked to the presentation of mood symptomatology. Neuroinflammation, perpetrated by activated microglia and astrocytes, has been reported in Huntington's disease and may contribute to disease progression and presentation. This study sought to quantify the density of mutant huntingtin protein and neuroinflammatory glial changes in the midcingulate cortex of postmortem patients with Huntington's disease and determine if either correlates with the presentation of mood, motor, or mixed symptomatology. Free-floating immunohistochemistry quantified 1C2 immunolabeling density as an indicative marker of mutant huntingtin protein, and protein and morphological markers of astrocyte (EAAT2, Cx43, and GFAP), and microglial (Iba1 and HLA-DP/DQ/DR) activation. Relationships among the level of microglial activation, mutant huntingtin burden, and case characteristics were explored using correlative analysis. We report alterations in activated microglia number and morphology in the midcingulate cortex of Huntington's disease cases with predominant mood symptomatology. An increased proportion of activated microglia was observed in the midcingulate of all Huntington's disease cases and positively correlated with 1C2 burden. Alterations in the astrocytic glutamate transporter EAAT2 were observed in the midcingulate cortex of patients associated with mood symptoms. This study presents pathological changes in microglia and astrocytes in the midcingulate cortex in Huntington's disease, which coincide with mood symptom presentation. These findings further the understanding of neuroinflammation in Huntington's disease, a necessary step for developing inflammation-targeted therapeutics. ANN NEUROL 2023;94:895-910.

Electroacupuncture Inhibits Pain Memory and Related Anxiety-Like Behaviors by Blockading the GABAB Receptor Function in the Midcingulate Cortex

Pain memory is commonly considered an underlying cause of chronic pain and is also responsible for a range of anxiety. Electroacupuncture (EA) has been shown to ameliorate pain memories and exert anti-anxiety effects. Previous research has indicated that GABAergic neurons and/or GABA receptors (GABARs) in the midcingulate cortex (MCC) have potential associations with chronic pain and anxiety. However, there is no known empirical research that has specifically studied the effects of EA on the GABAergic system in the MCC. Here, we used cross-injection of carrageenan to establish the pain memory rats model. Immunofluorescence were used to detect the excitability of GABAergic neurons within MCC. Von Frey filament, elevated zero maze, and open field tests were used to measure mechanical allodynia and anxiety-like behaviors, combined with chemogenetic and pharmacologic technologies. Finally, this study provides evidence that pain memories contribute to generalized negative emotions and that downregulating the activity of GABAergic neurons within MCC could block pain memories and reverse anxiety emotion. Specifically, GABABR is involved in pain memory and related anxiety-like behaviors. Activation of GABAergic neurons in the MCC did not reverse the effects of EA on pain memories and related anxiety-like behaviors, whereas these effects could be reversed by a GABABR agonist. These findings highlight the functional significance of GABABR in the EA-mediated attenuation of pain memories and related anxiety-like behaviors in rats.

Another in need enhances prosociality and modulates frontal theta oscillations in young adults.

Decision-making is a process that can be strongly affected by social factors. Evidence has shown how people deviate from traditional rational-choice predictions under different levels of social interactions. The emergence of prosocial decision-making, defined as any action that is addressed to benefit another individual even at the expense of personal benefits, has been reported as an example of such social influence. Furthermore, brain evidence has shown the involvement of structures such as the prefrontal cortex, anterior insula, and midcingulate cortex during decision settings in which a decision maker interacts with others under physical pain or distress or while being observed by others. Using a slightly modified version of the dictator game and EEG recordings, we tested the hypothesis that the inclusion of another person into the decision setting increases prosocial decisions in young adults and that this increase is higher when the other person is associated with others in need. At the brain level, we hypothesized that the increase in prosocial decisions correlates with frontal theta activity. The results showed that including another person in the decision, setting increased prosocial behavior only when this presence was associated with someone in need. This effect was associated with an increase in frontocentral theta-oscillatory activity. These results suggest that the presence of someone in need enhances empathy concerns and norm compliance, raising the participants' prosocial decision-making.

Cortical structural and functional coupling during development and implications for attention deficit hyperactivity disorder

Functional connectivity is scaffolded by the structural connections of the brain. Disruptions of either structural or functional connectivity can lead to deficits in cognitive functions and increase the risk for neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD). To date, very little research has examined the association between structural and functional connectivity in typical development, while no studies have attempted to understand the development of structure-function coupling in children with ADHD. 175 individuals (84 typically developing children and 91 children with ADHD) participated in a longitudinal neuroimaging study with up to three waves. In total, we collected 278 observations between the ages 9 and 14 (139 each in typically developing controls and ADHD). Regional measures of structure-function coupling were calculated at each timepoint using Spearman’s rank correlation and mixed effect models were used to determine group differences and longitudinal changes in coupling over time. In typically developing children, we observed increases in structure-function coupling strength across multiple higher-order cognitive and sensory regions. Overall, weaker coupling was observed in children with ADHD, mainly in the prefrontal cortex, superior temporal gyrus, and inferior parietal cortex. Further, children with ADHD showed an increased rate of coupling strength predominantly in the inferior frontal gyrus, superior parietal cortex, precuneus, mid-cingulate, and visual cortex, compared to no corresponding change over time in typically developing controls. This study provides evidence of the joint maturation of structural and functional brain connections in typical development across late childhood to mid-adolescence, particularly in regions that support cognitive maturation. Findings also suggest that children with ADHD exhibit different patterns of structure-function coupling, suggesting atypical patterns of coordinated white matter and functional connectivity development predominantly in the regions overlapping with the default mode network, salience network, and dorsal attention network during late childhood to mid-adolescence.