Anterior Cingulate Areas Research Articles

Causal relationship between cortical structural changes and onset of anxiety disorder: evidence from Mendelian randomization.

Previous studies have reported a correlation between anxiety disorders and changes in brain structure, yet the specific alterations in brain region volumes remain unclear. This study aimed to infer the causal relationship between anxiety disorders and changes in brain structure volume through Mendelian Randomization analysis. We selected 63 cortical structure volumes from the GWAS database as exposure data and anxiety disorder data from the FinnGen and UK Biobank databases as outcomes. We found a significant correlation between atrophy in the Left precentral volume area (Odds Ratio [OR] = 0.935, 95% Confidence intervals [CI]: 0.891-0.981, P value, P = 0.007) and an increased risk of anxiety disorders. Additionally, changes identified in specific brain regions, such as atrophy in the Right rostral anterior cingulate area (OR = 0.993, 95% CI: 0.987-0.999, P = 0.025) and increased volume in the Left superior parietal area (OR = 1.001, 95% CI: 1.000-1.001, P = 0.028), may correlate with an increased risk of anxiety disorders. Furthermore, both phenotypes demonstrated directional consistency in their respective and overall meta-analyzed OR values pre- and post-merger, enhancing the reliability of the results. This study elucidates the causal relationship between anxiety disorders and specific brain structures, providing new insights for further research into psychiatric disorders.

Limbic Network Derangement Mediates Unawareness of Apathy in Mild Cognitive Impairment due to Alzheimer's Disease: Clues from [18F]FDG PET Voxel-Wise Analysis.

Discrepancy between caregiver and patient assessments of apathy in mild cognitive impairment (MCI) is considered an index of apathy unawareness, independently predicting progression to AD dementia. However, its neural underpinning are uninvestigated. To explore the [18F]FDG PET-based metabolic correlates of apathy unawareness measured through the discrepancy between caregiver and patient self-report, in patients diagnosed with MCI. We retrospectively studied 28 patients with an intermediate or high likelihood of MCI-AD, progressed to dementia over an average of two years, whose degree of apathy was evaluated by means of the Apathy Evaluation Scale (AES) for both patients (PT-AES) and caregivers (CG-AES). Voxel-based analysis at baseline was used to obtain distinct volumes of interest (VOIs) correlated with PT-AES, CG-AES, or their absolute difference (DISCR-AES). The resulting DISCR-AES VOI count densities were used as covariates in an inter-regional correlation analysis (IRCA) in MCI-AD patients and a group of matched healthy controls (HC). DISCR-AES negatively correlated with metabolism in bilateral parahippocampal gyrus, posterior cingulate cortex, and thalamus, PT-AES score with frontal and anterior cingulate areas, while there was no significant correlation between CG-AES and brain metabolism. IRCA revealed that MCI-AD patients exhibited reduced metabolic/functional correlations of the DISCR-AES VOI with the right cingulate gyrus and its anterior projections compared to HC. Apathy unawareness entails early disruption of the limbic circuitry rather than the classical frontal-subcortical pathways typically associated with apathy. This reaffirms apathy unawareness as an early and independent measure in MCI-AD, marked by distinct pathophysiological alterations.

Associations between low-moderate prenatal alcohol exposure and brain development in childhood

BackgroundThe effects of low-moderate prenatal alcohol exposure (PAE) on brain development have been infrequently studied. AimTo compare cortical and white matter structure between children aged 6 to 8 years with low-moderate PAE in trimester 1 only, low-moderate PAE throughout gestation, or no PAE. MethodsWomen reported quantity and frequency of alcohol consumption before and during pregnancy. Magnetic resonance imaging was undertaken for 143 children aged 6 to 8 years with PAE during trimester 1 only (n = 44), PAE throughout gestation (n = 58), and no PAE (n = 41). T1-weighted images were processed using FreeSurfer, obtaining brain volume, area, and thickness of 34 cortical regions per hemisphere. Fibre density (FD), fibre cross-section (FC) and fibre density and cross-section (FDC) metrics were computed for diffusion images. Brain measures were compared between PAE groups adjusted for age and sex, then additionally for intracranial volume. ResultsAfter adjustments, the right caudal anterior cingulate cortex volume (pFDR = 0.045) and area (pFDR = 0.008), and right cingulum tract cross-sectional area (pFWE < 0.05) were smaller in children exposed to alcohol throughout gestation compared with no PAE. ConclusionThis study reports a relationship between low-moderate PAE throughout gestation and cingulate cortex and cingulum tract alterations, suggesting a teratogenic vulnerability. Further investigation is warranted.

Aging modulates frontal lobes involvement in emotion regulation processing.

Emotion regulation (ER) is the process by which individuals can modulate the intensity of their emotional experience and it plays a crucial role in daily life. So far, behavioral analyses seem to suggest that ER ability remains stable throughout the lifespan. However, imaging studies evaluating the neural correlates of ER performance during the aging process have shown mixed results. In this study, we used the "Cambridge Centre for Ageing and Neuroscience cohort sample" to investigate: (1) ER behavioral performance and (2) the differential association between brain measures (based on both structural and functional connectivity data) and ER performance, in a group of younger/middle-aged participants (N = 159; age range: 18y < x < 58y) relative to a group of older healthy subjects (N = 136; age range: 58y < =x < 89y). Whereas we found no group-related differences either in ER behavioral data or the association between ER performance and structural data, we did observe that ER performance was differentially correlated in our two study groups to functional connectivity measures in the fronto-insular-temporal network, which has been shown to be involved in emotional processing. Group-related differences were specifically localized in a cluster of voxels within the anterior cingulate areas which revealed a reverse pattern between our study groups: in younger/middle-aged participants better ER performance was associated with increase connectivity, whereas among older participants better ER performance was related to reduced connectivity. Based on our results, we suggest that a de-differentiation mechanism, known to affect the frontal lobes brain activity and connectivity in older subjects, might explain our findings.

Harnessing axonal transport to map reward circuitry: Differing brain-wide projections from medial prefrontal cortical domains.

Neurons project long axons that contact other distant neurons. Neurons in the medial prefrontal cortex project into the limbic system to regulate responses to reward or threat. Diminished neural activity in prefrontal cortex is associated with loss of executive function leading to drug use, yet the specific circuitry that mediate these effects is unknown. Different regions within the medial prefrontal cortex may project to differing limbic system nuclei. Here, we exploited the cell biology of intracellular membrane trafficking, fast axonal transport, to map projections from two adjacent medial prefrontal cortical regions. We used Mn(II), a calcium analog, to trace medial prefrontal cortical projections in the living animal by magnetic resonance imaging (MRI). Mn(II), a contrast agent for MRI, enters neurons through voltage-activated calcium channels and relies on kinesin-1 and amyloid-precursor protein to transport out axons to distal destinations. Aqueous MnCl2 together with fluorescent dextran (3--5nL) was stereotactically injected precisely into two adjacent regions of the medial prefrontal cortex: anterior cingulate area (ACA) or infralimbic/prelimbic (IL/PL) region. Projections were traced, first live by manganese-enhanced MRI (MEMRI) at four time points in 3D, and then after fixation by microscopy. Data-driven unbiased voxel-wise statistical maps of aligned normalized MR images after either ACA or IL/PL injections revealed statistically significant progression of Mn(II) over time into deeper brain regions: dorsal striatum, globus pallidus, amygdala, hypothalamus, substantia nigra, dorsal raphe and locus coeruleus. Quantitative comparisons of these distal accumulations at 24h revealed dramatic differences between ACA and IL/PL injection groups throughout the limbic system, and most particularly in subdomains of the hypothalamus. ACA projections targeted dorsomedial nucleus of the hypothalamus, posterior part of the periventricular region and mammillary body nuclei as well as periaqueductal gray, while IL/PL projections accumulated in anterior hypothalamic areas and lateral hypothalamic nuclei as well as amygdala. As hypothalamic subsegments relay CNS activity to the body, our results suggest new concepts about mind-body relationships and specific roles of distinct yet adjacent medial prefrontal cortical segments. Our MR imaging strategy, when applied to follow other cell biological processes in the living organism, will undoubtedly lead to an expanded perspective on how minute details of cellular processes influence whole body health and wellbeing.

Cardiac interoception in Anorexia Nervosa: A resting-state heartbeat-evoked potential study.

A deficit in interoception - the ability to perceive, interpret and integrate afferent signals about the physiological state of the body - has been shown in Anorexia Nervosa (AN), and linked to altered hunger sensations, body dysmorphia, and abnormal emotional awareness. The present high-density electroencephalography (hdEEG) study aims to assess cardiac interoception in AN and to investigate its neural correlates, using an objective neurophysiological measure. Heartbeat-evoked potentials (HEPs) were computed from 5min of resting-state EEG and electrocardiogram (ECG) data and compared between individuals with AN (N=22) and healthy controls (HC) (N=19) with waveform, topographic, and source imaging analyses. Differences in the cortical representation of heartbeats were present between AN and HC at a time window of 332-348ms after the ECG R-peak. Source imaging analyses revealed a right-sided hypoactivation in AN of brain regions linked to interoceptive processing, such as the anterior cingulate and orbitofrontal areas. To the best of our knowledge, this is the first study using hdEEG to localise the underlying sources of HEPs in AN. Results point to altered interoceptive processing during resting-state in AN. As our participants had a short duration of illness, this might not be the consequence of prolonged starvation. Interventions targeted at interoception could provide an additional tool to facilitate recovery.

Action observation and motor imagery improve motor imagery abilities in patients with Parkinson’s disease – A functional MRI study

IntroductionMotor imagery (MI) skills can be affected in Parkinson's disease (PD). We aimed at assessing MI and brain functional changes after action observation and MI training (AOT-MI) associated with gait/balance exercises in PD patients with postural instability and gait disorders (PD-PIGD). MethodsTwenty-five PD-PIGD patients were randomized into two groups: DUAL-TASK + AOT-MI group performed 6-week gait/balance training combined with AOT-MI; DUAL-TASK group performed the same exercises without AOT-MI. Before and after training, MI was assessed using Kinesthetic-and-Visual-Imagery Questionnaire (KVIQ) and a MI functional MRI (fMRI) task. During fMRI, subjects were asked to watch first-person perspective videos representing gait/balance tasks and mentally simulate their execution. At baseline patients were compared with 23 healthy controls. ResultsPD groups did not differ in the MI scores. Both patient groups increased kinesthetic KVIQ score after training, while only DUAL-TASK + AOT-MI group improved visual and total KVIQ scores. At baseline, both PD groups showed reduced fMRI activity of sensorimotor, temporal and cerebellar areas relative to controls. After training, DUAL-TASK + AOT-MI patients increased activity of anterior cingulate, fronto-temporal and motor cerebellar areas, and reduced the recruitment of cognitive cerebellar regions. DUAL-TASK group showed increased recruitment of occipito-temporal areas and reduced activity of cerebellum crus-I. DUAL-TASK + AOT-MI relative to DUAL-TASK group had increased activity of cerebellum VIII-IX. In DUAL-TASK + AOT-MI group, KVIQ improvement correlated with increased activity of cerebellum IX and anterior cingulate, and with reduced activity of crus-I. ConclusionsAOT-MI improves MI abilities in PD-PIGD patients, promoting the functional plasticity of brain areas involved in MI processes and gait/balance control.

Top-down input modulates visual context processing through an interneuron-specific circuit

Visual stimuli that deviate from the current context elicit augmented responses in the primary visual cortex (V1). These heightened responses, known as "deviance detection," require local inhibition in the V1 and top-down input from the anterior cingulate area (ACa). Here, we investigated the mechanisms by which the ACa and V1 interact to support deviance detection. Local field potential recordings in mice during an oddball paradigm showed that ACa-V1 synchrony peaks in the theta/alpha band (≈10Hz). Two-photon imaging in the V1 revealed that mainly pyramidal neurons exhibited deviance detection, while contextually redundant stimuli increased vasoactive intestinal peptide (VIP)-positive interneuron (VIP) activity and decreased somatostatin-positive interneuron (SST) activity. Optogenetic drive of ACa-V1 inputs at 10Hz activated V1-VIPs but inhibited V1-SSTs, mirroring the dynamics present during the oddball paradigm. Chemogenetic inhibition of V1-VIPs disrupted Aca-V1 synchrony and deviance detection in the V1. These results outline temporal and interneuron-specific mechanisms of top-down modulation that support visual context processing.

A frontal transcallosal inhibition loop mediates interhemispheric balance in visuospatial processing

Interhemispheric communication through the corpus callosum is required for both sensory and cognitive processes. Impaired transcallosal inhibition causing interhemispheric imbalance is believed to underlie visuospatial bias after frontoparietal cortical damage, but the synaptic circuits involved remain largely unknown. Here, we show that lesions in the mouse anterior cingulate area (ACA) cause severe visuospatial bias mediated by a transcallosal inhibition loop. In a visual-change-detection task, ACA callosal-projection neurons (CPNs) were more active with contralateral visual field changes than with ipsilateral changes. Unilateral CPN inactivation impaired contralateral change detection but improved ipsilateral detection by altering interhemispheric interaction through callosal projections. CPNs strongly activated contralateral parvalbumin-positive (PV+) neurons, and callosal-input-driven PV+ neurons preferentially inhibited ipsilateral CPNs, thus mediating transcallosal inhibition. Unilateral PV+ neuron activation caused a similar behavioral bias to contralateral CPN activation and ipsilateral CPN inactivation, and bilateral PV+ neuron activation eliminated this bias. Notably, restoring interhemispheric balance by activating contralesional PV+ neurons significantly improved contralesional detection in ACA-lesioned animals. Thus, a frontal transcallosal inhibition loop comprising CPNs and callosal-input-driven PV+ neurons mediates interhemispheric balance in visuospatial processing, and enhancing contralesional transcallosal inhibition restores interhemispheric balance while also reversing lesion-induced bias.

Longitudinal developmental trajectories of functional connectivity reveal regional distribution of distinct age effects in infancy.

Prior work has shown that different functional brain networks exhibit different maturation rates, but little is known about whether and how different brain areas may differ in the exact shape of longitudinal functional connectivity growth trajectories during infancy. We used resting-state functional magnetic resonance imaging (fMRI) during natural sleep to characterize developmental trajectories of different regions using a longitudinal cohort of infants at 3weeks (neonate), 1year, and 2years of age (n = 90; all with usable data at three time points). A novel whole brain heatmap analysis was performed with four mixed-effect models to determine the best fit of age-related changes for each functional connection: (i) growth effects: positive-linear-age, (ii) emergent effects: positive-log-age, (iii) pruning effects: negative-quadratic-age, and (iv) transient effects: positive-quadratic-age. Our results revealed that emergent (logarithmic) effects dominated developmental trajectory patterns, but significant pruning and transient effects were also observed, particularly in connections centered on inferior frontal and anterior cingulate areas that support social learning and conflict monitoring. Overall, unique global distribution patterns were observed for each growth model indicating that developmental trajectories for different connections are heterogeneous. All models showed significant effects concentrated in association areas, highlighting the dominance of higher-order social/cognitive development during the first 2 years of life.

No evidence from complementary data sources of a direct glutamatergic projection from the mouse anterior cingulate area to the hippocampal formation.

The connectivity and interplay between the prefrontal cortex and hippocampus underpin various key cognitive processes, with changes in these interactions being implicated in both neurodevelopmental as well as neurodegenerative conditions. Understanding the precise cellular connections through which this circuit is organised is, therefore, vital for understanding these same processes. Overturning earlier findings, a recent study described a novel excitatory projection from anterior cingulate area to dorsal hippocampus. We sought to validate this unexpected finding using multiple, complementary methods: anterograde and retrograde anatomical tracing, using anterograde and retrograde AAVs, monosynaptic rabies tracing and the Fast Blue classical tracer. Additionally, an extensive data search of the Allen Projection Brain Atlas database was conducted to find the stated projection within any of the deposited anatomical studies, as an independent verification of our own results. However, we failed to find any evidence of a direct, monosynaptic glutamatergic projection from mouse anterior cingulate cortex to the hippocampus proper.

Brain structure and working memory adaptations associated with maturation and aging in mice.

As the population skews toward older age, elucidating mechanisms underlying human brain aging becomes imperative. Structural MRI has facilitated non-invasive investigation of lifespan brain morphology changes, yet this domain remains uncharacterized in rodents despite increasing use as models of disordered human brain aging. Young (2m, n = 10), middle-age (10m, n = 10) and old (22m, n = 9) mice were utilized for maturational (young vs. middle-age) and aging-related (middle-age vs. old mice) comparisons. Regional brain volume was averaged across hemispheres and reduced to 32 brain regions. Pairwise group differences in regional volume were tested using general linear models, with total brain volume as a covariate. Sample-wide associations between regional brain volume and Y-maze performance were assessed using logistic regression, residualized for total brain volume. Both analyses corrected for multiple comparisons. Structural covariance networks were generated using the R package "igraph." Group differences in network centrality (degree), integration (mean distance), and segregation (transitivity, modularity) were tested across network densities (5-40%), using 5,000 (1,000 for degree) permutations with significance criteria of p < 0.05 at ≥5 consecutive density thresholds. Widespread significant maturational changes in volume occurred in 18 brain regions, including considerable loss in isocortex regions and increases in brainstem regions and white matter tracts. The aging-related comparison yielded 6 significant changes in brain volume, including further loss in isocortex regions and increases in white matter tracts. No significant volume changes were observed across either comparison for subcortical regions. Additionally, smaller volume of the anterior cingulate area (χ2 = 2.325, pBH = 0.044) and larger volume of the hippocampal formation (χ2 = -2.180, pBH = 0.044) were associated with poorer cognitive performance. Maturational network comparisons yielded significant degree changes in 9 regions, but no aging-related changes, aligning with network stabilization trends in humans. Maturational decline in modularity occurred (24-29% density), mirroring human trends of decreased segregation in young adulthood, while mean distance and transitivity remained stable. These findings offer a foundational account of age effects on brain volume, structural brain networks, and working memory in mice, informing future work in facilitating translation between rodent models and human brain aging.

Increased Excitability of Layer 2 Cortical Pyramidal Neurons in the Supplementary Motor Cortex Underlies High Cocaine-Seeking Behaviors

BackgroundMost efforts in addiction research have focused on the involvement of the medial prefrontal cortex, including the infralimbic, prelimbic, and anterior cingulate cortical areas, in cocaine-seeking behaviors. However, no effective prevention or treatment for drug relapse is available. MethodsWe focused instead on the motor cortex, including both the primary and supplementary motor areas (M1 and M2, respectively). Addiction risk was evaluated by testing cocaine seeking after intravenous self-administration (IVSA) of cocaine in Sprague Dawley rats. The causal relationship between the excitability of cortical pyramidal neurons (CPNs) in M1/M2 and addiction risk was explored by ex vivo whole-cell patch clamp recordings and in vivo pharmacological or chemogenetic manipulation. ResultsOur recordings showed that on withdrawal day 45 (WD45) after IVSA, cocaine, but not saline, increased the excitability of CPNs in the cortical superficial layers (primarily layer 2, denoted L2) but not in layer 5 (L5) in M2. Bilateral microinjection of the GABAA (gamma-aminobutyric acid A) receptor agonist muscimol to the M2 area attenuated cocaine seeking on WD45. More specifically, chemogenetic inhibition of CPN excitability in L2 of M2 (denoted M2-L2) by the DREADD (designer receptor exclusively activated by designer drugs) agonist compound 21 prevented drug seeking on WD45 after cocaine IVSA. This chemogenetic inhibition of M2-L2 CPNs had no effects on sucrose seeking. In addition, neither pharmacological nor chemogenetic inhibition manipulations altered general locomotor activity. ConclusionsOur results indicate that cocaine IVSA induces hyperexcitability in the motor cortex on WD45. Importantly, the increased excitability in M2, particularly in L2, could be a novel target for preventing drug relapse during withdrawal.

Chemogenetics identifies separate area 25 brain circuits involved in anhedonia and anxiety in marmosets.

Poor outcomes are common in individuals with anxiety and depression, and the brain circuits underlying symptoms and treatment responses remain elusive. To elucidate these neural circuits, experimental studies must specifically manipulate them, which is only possible in animals. Here, we used a chemogenetics strategy involving engineered designer receptors exclusively activated by designer drugs (DREADDs) to activate a region of the marmoset brain that is dysfunctional in human patients with major depressive disorder, called the subcallosal anterior cingulate cortex area 25 (scACC-25). Using this DREADDs system, we identified separate scACC-25 neural circuits that underlie specific components of anhedonia and anxiety in marmosets. Activation of the neural pathway connecting the scACC-25 to the nucleus accumbens (NAc) caused blunting of anticipatory arousal (a form of anhedonia) in marmosets in response to a reward-associated conditioned stimulus in an appetitive Pavlovian discrimination test. Separately, activation of the circuit between the scACC-25 and the amygdala increased a measure of anxiety (the threat response score) when marmosets were presented with an uncertain threat (human intruder test). Using the anhedonia data, we then showed that the fast-acting antidepressant ketamine when infused into the NAc of marmosets prevented anhedonia after scACC-25 activation for more than 1 week. These neurobiological findings provide targets that could contribute to the development of new treatment strategies.

Brain positron emission tomography (PET) and cognitive abnormalities one year after COVID-19.

Emerging evidence indicates that the etiologic agent responsible for coronavirus disease 2019 (COVID-19), can cause neurological complications. COVID-19 may induce cognitive impairment through multiple mechanisms. The aim of the present study was to describe the possible neuropsychological and metabolic neuroimaging consequences of COVID-19 12months after patients' hospital discharge. We retrospectively recruited 7 patients (age [mean ± SD] = 56 years ± 12.39, 4 men) who had been hospitalized for COVID-19 with persistent neuropsychological deficits 12months after hospital discharge. All patients underwent cognitive assessment and brain (18F-FDG) PET/CT, and one also underwent 18F-amyloid PET/CT. Of the seven patients studied, four had normal glucose metabolism in the brain. Three patients showed various brain hypometabolism patterns: (1) unilateral left temporal mesial area hypometabolism; (2) pontine involvement; and (3) bilateral prefrontal area abnormalities with asymmetric parietal impairment. The patient who showed the most widespread glucose hypometabolism in the brain underwent an 18F-amyloid PET/CT to assess the presence of Aβ plaques. This examination showed significant Aβ deposition in the superior and middle frontal cortex, and in the posterior cingulate cortex extending mildly in the rostral and caudal anterior cingulate areas. Although some other reports have already suggested that brain hypometabolism may be associated with cognitive impairment at shorter intervals from SarsCov-2 infection, our study is the first to assess cognitive functions, brain metabolic activity and in a patient also amyloid PET one year after COVID-19, demonstrating that cerebral effects of COVID-19 can largely outlast the acute phase of the disease and even be followed by amyloid deposition.

Progression of regional cortical cholinergic denervation in Parkinson's disease.

Cortical cholinergic deficits contribute to cognitive decline and other deficits in Parkinson's disease. Cross-sectional imaging studies suggest a stereotyped pattern of posterior-to-anterior cortical cholinergic denervation accompanying disease progression in Parkinson's disease. We used serial acetylcholinesterase PET ligand imaging to characterize the trajectory of regional cholinergic synapse deficits in Parkinson's disease, testing the hypothesis of posterior-to-anterior progression of cortical cholinergic deficits. The 16 Parkinson's disease subjects (4 females/12 males; mean age: 64.4 ± 6.7 years; disease duration: 5.5 ± 4.2 years; Hoehn & Yahr stage: 2.3 ± 0.6 at entry) completed serial 11C-methyl-4-piperidinyl propionate acetylcholinesterase PET scans over a 4-8 year period (median 5 years). Three-dimensional stereotactic cortical surface projections and volume-of-interest analyses were performed. Cholinergic synapse integrity was assessed by the magnitude, k 3, of acetylcholinesterase hydrolysis of 11C-methyl-4-piperidinyl propionate. Based on normative data, we generated Z-score maps for both the k 3 and the k 1 parameters, the latter as a proxy for regional cerebral blood flow. Compared with control subjects, baseline scans showed predominantly posterior cortical k 3 deficits in Parkinson's disease subjects. Interval change analyses showed evidence of posterior-to-anterior progression of cholinergic cortical deficits in the posterior cortices. In frontal cortices, an opposite gradient of anterior-to-posterior progression of cholinergic deficits was found. The topography of k 3 changes exhibited regionally specific disconnection from k 1 changes. Interval-change analysis based on k 3/k 1 ratio images (k 3 adjustment for regional cerebral blood flow changes) showed interval reductions (up to 20%) in ventral frontal, anterior cingulate and Brodmann area 6 cortices. In contrast, interval k 3 reductions in the posterior cortices, especially Brodmann areas 17-19, were largely proportional to k 1 changes. Our results partially support the hypothesis of progressive posterior-to-cortical cholinergic denervation in Parkinson's disease. This pattern appears characteristic of posterior cortices. In frontal cortices, an opposite pattern of anterior-to-posterior progression of cholinergic deficits was found. The progressive decline of posterior cortical acetylcholinesterase activity was largely proportional to declining regional cerebral blood flow, suggesting that posterior cortical cholinergic synapse deficits are part of a generalized loss of synapses. The disproportionate decline in regional frontal cortical acetylcholinesterase activity relative to regional cerebral blood flow suggests preferential loss or dysregulation of cholinergic synapses in these regions. Our observations suggest that cortical cholinergic synapse vulnerability in Parkinson's disease is mediated by both diffuse processes affecting cortical synapses and processes specific to subpopulations of cortical cholinergic afferents.

Large-scale networks underlie cognitive insight differs between untreated adolescents ongoing their first schizophrenic episode and their reference non-schizophrenic mates

ObjectivesCognitive insight (CI), the ability to perceive erroneous beliefs and correcting them based on safe experiences, is a common cognitive manifestation among schizophrenic individuals. Even though the functional morphology of the default mode network (DMN), the central executive network (CEN) and the salience network (SN) differs between non-schizophrenic and schizophrenic individuals, it is unclear whether such differences are already in place by the first schizophrenic episode. MethodsForty-two adolescents, including twenty-one AOS subjects was recruited, and performed independent component analysis (ICA) on resting-state fMRI data to explore alterations in the three networks in schizophrenia and the association of network changes with Beck Cognitive Insight Scale (BCIS) scores. ResultsCompared to the non-schizophrenic group, the AOS group showed hyper-connectivity in the left middle temporal gyrus (MTG) and hypo-connectivity in the right parahippocampal gyrus within the DMN; hypo-connectivity in the dorsal anterior cingulate (dACC) and supplementary motor area (SMA) within the SN were also detected in AOS individuals. CI subscores were positively correlated with functional connectivity (FC) in the right parahippocampal gyrus. ConclusionsThe correlations reported here suggest that increased DMN connectivity in the right parahippocampal gyrus might be an early neural correlate of reduced cognitive insight in a number, but not all, adolescent untreated individuals ongoing their first schizophrenic episode.

Activation of TREK1 Channel in the Anterior Cingulate Cortex Improves Neuropathic Pain in a Rat Model.

Objective. To explore the biological function and mechanism of TREK1 in neuropathic pain. Thirty-two healthy rats and rats with sciatic nerve chronic press-fitting model (chronic constriction injury of the sciatic nerve, CCI) were selected. Western blot, immunofluorescence staining, and patch clamp technique were performed to explore the biological functions of TREK1. The expression of TREK1 was decreased in the CCI model. The TREK1 channel current in the CCI model was decreased. After local administration of TREK1 channel activator in the anterior cingulate cortex area, the pain behavior of CCI rats and the expression of TREK1 protein were reversed. The expression of TREK1 was downregulated in the ACC area of CCI rats and the current of TREK1 was decreased, which played an important role in the regulation of neuropathic pain.

Higher polygenic risk scores for anxiety disorders are associated with reduced area in the anterior cingulate gyrus

Anxiety disorders are heterogeneous, show a moderate genetic contribution and are associated with inconsistent cortical structure alterations. Here, we investigated whether genetic factors for anxiety disorders contribute to cortical alterations by conducting polygenic risk score (PRS) analyses. We calculated PRSs for anxiety disorders at several P value thresholds (from PT ≤ 5.0 × 10−8 to PT ≤ 1.0) based on the latest large-scale genome-wide association study of anxiety disorders from the UK biobank (25,453 cases; 58,113 controls) in an independent sample of psychiatrically and physically healthy subjects (n = 174). Using regression after adjusting for confounding factors, we tested whether these PRSs were associated with the surface area and cortical thickness in 34 bilateral brain regions extracted using FreeSurfer. A higher PRS for anxiety disorders at PT ≤ 1.0 was significantly associated with a reduced right caudal anterior cingulate area (beta = −0.25, puncorrected = 9.51 × 10−4, pcorrected = 0.032). PRSs based on more common SNPs, especially from PT ≤ 0.01 to PT ≤ 1.0, were associated with the right caudal anterior cingulate area (a maximum at PT ≤ 0.5: R2 = 0.066, beta = −0.27, puncorr = 3.81 × 10−4, pcorr = 0.013). Furthermore, individuals in the highest quartile for anxiety disorder PRS had lower surface area and volume in the right anterior cingulate gyrus than those in the lowest quartile. We suggest a shared genetic etiology between anxiety disorders and structural features of the anterior cingulate gyrus, possibly contributing to the pathogenesis of anxiety disorders via emotional dysregulations. Our findings suggest the potential usefulness of PRS to reduce pathological heterogeneity among anxiety disorders.

Distinct and sex-specific expression of mu opioid receptors in anterior cingulate and somatosensory S1 cortical areas.

The anterior cingulate cortex (ACC) processes the affective component of pain, whereas the primary somatosensory cortex (S1) is involved in its sensory-discriminative component. Injection of morphine in the ACC has been reported to be analgesic, and endogenous opioids in this area are required for pain relief. Mu opioid receptors (MORs) are expressed in both ACC and S1; however, the identity of MOR-expressing cortical neurons remains unknown. Using the Oprm1-mCherry mouse line, we performed selective patch clamp recordings of MOR+ neurons, as well as immunohistochemistry with validated neuronal markers, to determine the identity and laminar distribution of MOR+ neurons in ACC and S1. We found that the electrophysiological signatures of MOR+ neurons differ significantly between these 2 areas, with interneuron-like firing patterns more frequent in ACC. While MOR+ somatostatin interneurons are more prominent in ACC, MOR+ excitatory neurons and MOR+ parvalbumin interneurons are more prominent in S1. Our results suggest a differential contribution of MOR-mediated modulation to ACC and S1 outputs. We also found that females had a greater density of MOR+ neurons compared with males in both areas. In summary, we conclude that MOR-dependent opioidergic signaling in the cortex displays sexual dimorphisms and likely evolved to meet the distinct function of pain-processing circuits in limbic and sensory cortical areas.