Lateral septum as a possible regulatory center of maternal behaviors.

The lateral septum (LS) is involved in controlling anxiety, aggression, feeding, and other motivated behaviors. Lesion studies have also implicated the LS in various forms of caring behaviors. Recently, novel experimental tools have provided a more detailed insight into the function of the LS, including the specific role of distinct cell types and their neuronal connections in behavioral regulations, in which the LS participates. This article discusses the regulation of different types of maternal behavioral alterations using the distributions of established maternal hormones such as prolactin, estrogens, and the neuropeptide oxytocin. It also considers the distribution of neurons activated in mothers in response to pups and other maternal activities, as well as gene expressional alterations in the maternal LS. Finally, this paper proposes further research directions to keep up with the rapidly developing knowledge on maternal behavioral control in other maternal brain regions.

A theory of the neural mechanisms underlying negative cognitive bias in major depression.

The widely acknowledged cognitive theory of depression, developed by Aaron Beck, focused on biased information processing that emphasizes the negative aspects of affective and conceptual information. Current attempts to discover the neurological mechanism underlying such cognitive and affective bias have successfully identified various brain regions associated with severally biased functions such as emotion, attention, rumination, and inhibition control. However, the neurobiological mechanisms of how individuals in depression develop this selective processing toward negative is still under question. This paper introduces a neurological framework centered around the frontal-limbic circuit, specifically analyzing and synthesizing the activity and functional connectivity within the amygdala, hippocampus, and medial prefrontal cortex. Firstly, a possible explanation of how the positive feedback loop contributes to the persistent hyperactivity of the amygdala in depression at an automatic level is established. Building upon this, two hypotheses are presented: hypothesis 1 revolves around the bidirectional amygdalohippocampal projection facilitating the amplification of negative emotions and memories while concurrently contributing to the impediment of the retrieval of opposing information in the hippocampus attractor network. Hypothesis 2 highlights the involvement of the ventromedial prefrontal cortex in the establishment of a negative cognitive framework through the generalization of conceptual and emotional information in conjunction with the amygdala and hippocampus. The primary objective of this study is to improve and complement existing pathological models of depression, pushing the frontiers of current understanding in neuroscience of affective disorders, and eventually contributing to successful recovery from the debilitating affective disorders.

The relationship of personality, alexithymia, anxiety symptoms, and odor awareness: a mediation analysis.

OBJECTIVE: Personality, emotions, and olfaction exhibit partial anatomical overlap in the limbic system structure, establishing potential mechanisms between personality, affective disorders, and olfactory-related aspects. Thus, this study aims to investigate the associations among the Big Five personality traits, alexithymia, anxiety symptoms, and odor awareness. METHODS: A total of 863 college participants were recruited for this study. All participants completed the Chinese Big Five Personality Inventory-15, the Odor Awareness Scale (OAS), the Toronto Alexithymia Scale-20, and the Generalized Anxiety Disorder Screener-7. Structural equation modeling was employed to examine the hypothesized mediated model. RESULTS: The findings revealed the majority of significant intercorrelations among the dimensions of the Big Five personality traits, alexithymia, anxiety symptoms, and OAS (|r| = 0.072-0.567, p < 0.05). Alexithymia and anxiety symptoms exhibited a serial mediation effect between neuroticism and OAS (95%CI[0.001, 0.014]), conscientiousness and OAS (95%CI[-0.008, -0.001]), and extraversion and OAS (95%CI[-0.006, -0.001]). Anxiety symptoms mediated the relationship between agreeableness and OAS (95%CI[-0.023, -0.001]) and between openness and OAS (95%CI [0.004, 0.024]). CONCLUSION: The mediating roles of alexithymia and anxiety symptoms between the Big Five personality traits and odor awareness support the idea of a certain level of association among personality, emotions, and olfaction, with the underlying role of the limbic system structure. This enhances our understanding of personality, emotions, and olfaction and provides insights for future intervention measures for affective disorders and olfactory dysfunctions.

Damage to the Locus Coeruleus Alters the Expression of Key Proteins in Limbic Neurodegeneration.

The present investigation was designed based on the evidence that, in neurodegenerative disorders, such as Alzheimer's dementia (AD) and Parkinson's disease (PD), damage to the locus coeruleus (LC) arising norepinephrine (NE) axons (LC-NE) is documented and hypothesized to foster the onset and progression of neurodegeneration within target regions. Specifically, the present experiments were designed to assess whether selective damage to LC-NE axons may alter key proteins involved in neurodegeneration within specific limbic regions, such as the hippocampus and piriform cortex, compared with the dorsal striatum. To achieve this, a loss of LC-NE axons was induced by the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) in C57 Black mice, as assessed by a loss of NE and dopamine-beta-hydroxylase within target regions. In these experimental conditions, the amount of alpha-synuclein (alpha-syn) protein levels were increased along with alpha-syn expressing neurons within the hippocampus and piriform cortex. Similar findings were obtained concerning phospho-Tau immunoblotting. In contrast, a decrease in inducible HSP70-expressing neurons and a loss of sequestosome (p62)-expressing cells, along with a loss of these proteins at immunoblotting, were reported. The present data provide further evidence to understand why a loss of LC-NE axons may foster limbic neurodegeneration in AD and limbic engagement during PD.

Systemic lupus erythematosus-related brain abnormalities in the default mode network and the limbic system: A resting-state fMRI meta-analysis.

BACKGROUND: Systemic lupus erythematosus (SLE) is an immune-mediated and multi-systemic disease which may affect the nervous system, causing neuropsychiatric SLE (NPSLE). Recent neuroimaging studies have examined brain functional alterations in SLE. However, discrepant findings were reported. This meta-analysis aims to identify consistent resting-state functional abnormalities in SLE. METHODS: PubMed and Web of Science were searched to identify candidate resting-state functional MRI studies assessing SLE. A voxel-based meta-analysis was performed using the anisotropic effect-size version of the seed-based d mapping (AES-SDM). The abnormal intrinsic functional patterns extracted from SDM were mapped onto the brain functional network atlas to determine brain abnormalities at a network level. RESULTS: Twelve studies evaluating fifteen datasets were included in this meta-analysis, comprising 572 SLE patients and 436 healthy controls (HCs). Compared with HCs, SLE patients showed increased brain activity in the bilateral hippocampus and right superior temporal gyrus, and decreased brain activity in the left superior frontal gyrus, left middle temporal gyrus, bilateral thalamus, left inferior frontal gyrus and right cerebellum. Mapping the abnormal patterns to the network atlas revealed the default mode network and the limbic system as core neural systems commonly affected in SLE. LIMITATIONS: The number of included studies is relatively small, with heterogeneous analytic methods and a risk of publication bias. CONCLUSIONS: Brain functional alterations in SLE are predominantly found in the default mode network and the limbic system. These findings uncovered a consistent pattern of resting-state functional network abnormalities in SLE which may serve as a potential objective neuroimaging biomarker.

Abnormal functional connectivity of the intrinsic networks in adolescent bipolar I versus bipolar II disorder.

BACKGROUND: The symptoms of pediatric bipolar disorder (PBD)-I and PBD-II differ, but accurate identification at an early stage is difficult and may prevent effective treatment of this disorder. Therefore, it is urgent to elucidate a biological marker based on objective imaging indicators to help distinguish the two. Therefore, this research aims to compare the functional connectivity between PBD-I patient and PBD-II patient in different brain networks. METHODS: Our study enrolled 31 PBD-I and 23 PBD-II patients from 12 to 17 years of age. They were analyzed by resting state-functional connectivity through Independent component analysis (ICA). RESULTS: We found differences between PBD-I and PBD-II in functional connectivity of the default network, frontoparietal network, salience network and limbic system. In addition, the clinical features, cognitive functions are associated with the functional connectivity of the intrinsic networks in PBD-I and PBD-II separately. CONCLUSION: This research is the first to find differences in functional connectivity between PBD-I and PBD-II, suggesting that abnormality of the functional connectivity within large networks may be biomarkers that help differentiate PBD-I from PBD-II in the future.

Unraveling the relations between post-traumatic stress symptoms, neurocognitive functioning, and limbic white matter in pediatric brain tumor patients.

Background: Pediatric brain tumor patients are at risk of developing neurocognitive impairments and associated white matter alterations. In other populations, post-traumatic stress symptoms (PTSS) impact cognition and white matter. This study aims to investigate the effect of PTSS on neurocognitive functioning and limbic white matter in pediatric brain tumor patients. Methods: Sixty-six patients (6-16 years) completed neuropsychological assessment and brain MRI (1-year post-diagnosis) and parents completed PTSS proxy questionnaires (CRIES-13; 1-3 months and 1-year post-diagnosis). Mean Z-scores and percentage impaired (>1SD) for attention, processing speed, executive functioning, and memory were compared to normscores (t-tests, chi-square tests). Multi-shell diffusion MRI data were analyzed for white matter tractography (fractional anisotropy/axial diffusivity). Effects of PTSS on neurocognition and white matter were explored with linear regression models (FDR correction for multiple testing), including age at diagnosis, treatment intensity, and tumor location as covariates. Neurocognition and limbic white matter associations were explored with correlations. Results: Attention (M = -0.49, 33% impaired; P < .05) and processing speed (M = -0.57, 34% impaired; P < .05) were significantly lower than healthy peers. PTSS was associated with poorer processing speed (ß = -0.64, P < .01). Treatment intensity, age at diagnosis, and tumor location, but not PTSS, were associated with limbic white matter metrics. Neurocognition and white matter metrics were not associated. Conclusions: Higher PTSS was associated with poorer processing speed, highlighting the need for monitoring, and timely referrals to optimize psychological well-being and neurocognitive functioning. Future research should focus on longitudinal follow-up and explore the impact of PTSS interventions on neurocognitive performance.

Acute amnestic syndrome in fornix lesions: a systematic review of reported cases with a focus on differential diagnosis.

Introduction: Acute amnestic syndrome is an uncommon clinical presentation of neurological disease. Differential diagnosis encompasses several syndromes including Wernicke-Korsakoff and transient global amnesia (TGA). Structural lesions of the fornix account for a minority of cases of acute amnestic syndromes. Etiology varies from iatrogenic injury to ischemic, inflammatory, or neoplastic lesions. A prompt diagnosis of the underlying pathology is essential but challenging. The aim of this review is to systematically review the existing literature regarding cases of acute amnestic syndrome associated with non-iatrogenic lesions of the fornix. Methods: We performed a systematic literature search on PubMed, Scopus, and Web of Science up to September 2023 to identify case reports and case series of patients with amnestic syndrome due to fornix lesions. The systematic review was conducted according to PRISMA guidelines. The research was limited to articles written in English. Cases of fornix damage directly ascribable to a surgical procedure were excluded. Results: A total of 52 publications reporting 55 cases were included in the review. Focusing on acute/subacute onset, vascular etiology was highly prevalent, being responsible for 78% of cases, 40/55 (74%) of which were due to acute ischemic stroke. The amnestic syndrome was characterized by anterograde amnesia in all patients, associated with retrograde amnesia in 27% of cases. Amnesia was an isolated presentation in most cases. Up to two thirds of patients had persistent memory deficits of any severity at follow-up. Discussion: Acute amnestic syndrome can be rarely caused by fornix lesions. In most cases of acute/subacute presentation, the etiology is ischemic stroke, mainly caused by strokes involving the subcallosal artery territory. The differential diagnosis is challenging and a distinction from common mimics is often difficult on a clinical basis. A high index of suspicion should be maintained to avoid misdiagnosis and provide adequate acute treatment to patients with time-dependent disease, also employing advanced neuroimaging. More research is needed to better understand the outcome and identify prognostic factors in patients with amnestic syndrome due to fornix lesions.

The Limbic System in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder: A Longitudinal Structural Magnetic Resonance Imaging Analysis.

Background: During childhood and adolescence, attention-deficit/hyperactivity disorder (ADHD) is associated with changes in symptoms and brain structures, but the link between brain structure and function remains unclear. The limbic system, often termed the "emotional network," plays an important role in a number of neurodevelopmental disorders, yet this brain network remains largely unexplored in ADHD. Investigating the developmental trajectories of key limbic system structures during childhood and adolescence will provide novel insights into the neurobiological underpinnings of ADHD. Methods: Structural magnetic resonance imaging data (380 scans), emotional regulation (Affective Reactivity Index), and ADHD symptom severity (Conners 3 ADHD Index) were measured at up to 3 time points between 9 and 14 years of age in a sample of children and adolescents with ADHD (n = 57) and control children (n = 109). Results: Compared with the control group, the ADHD group had lower volume of the amygdala (left: ß standardized [ß_std] = -0.38; right: ß_std = -0.34), hippocampus (left: ß_std = -0.44; right: ß_std = -0.34), cingulate gyrus (left: ß_std = -0.42; right: ß_std = -0.32), and orbitofrontal cortex (right: ß_std = -0.33) across development (9-14 years). There were no significant group-by-age interactions in any of the limbic system structures. Exploratory analysis found a significant Conners 3 ADHD Index-by-age interaction effect on the volume of the left mammillary body (ß_std = 0.17) in the ADHD group across the 3 study time points. Conclusions: Children and adolescents with ADHD displayed lower volume and atypical development in limbic system structures. Furthermore, atypical limbic system development was associated with increased symptom severity, highlighting a potential neurobiological correlate of ADHD severity.

Fetal development of the human amygdala.

The intricate development of the human amygdala involves a complex interplay of diverse processes, varying in speed and duration. In humans, transient cytoarchitectural structures deliquesce, leading to the formation of functionally distinct nuclei as a result of multiple interdependent developmental events. This study compares the amygdala's cytoarchitectural development in conjunction with specific antibody reactivity for neuronal, glial, neuropil, and radial glial fibers, synaptic, extracellular matrix, and myelin components in 39 fetal human brains. We recognized that the early fetal period, as a continuation of the embryonic period, is still dominated by relatively uniform histogenetic processes. The typical appearance of ovoid cell clusters in the lateral nucleus during midfetal period is most likely associated with the cell migration and axonal growth processes in the developing human brain. Notably, synaptic markers are firstly detected in the corticomedial group of nuclei, while immunoreactivity for the panaxonal neurofilament marker SMI 312 is found dorsally. The late fetal period is characterized by a protracted migration process evidenced by the presence of doublecortin and SOX-2 immunoreactivity ventrally, in the prospective paralaminar nucleus, reinforced by vimentin immunoreactivity in the last remaining radial glial fibers. Nearing the term period, SMI 99 immunoreactivity indicates that perinatal myelination becomes prominent primarily along major axonal pathways, laying the foundation for more pronounced functional maturation. This study comprehensively elucidates the rate and sequence of maturational events in the amygdala, highlighting the key role of prenatal development in its behavioral, autonomic, and endocrine regulation, with subsequent implications for both normal functioning and psychiatric disorders.

Estrogen Receptor ß in the Lateral Septum Mediates Estrogen Regulation of Social Anxiety-like Behavior in Male Mice.

17ß-estradiol (E2) regulates various forms of social behavior through the activation of two types of estrogen receptors, ERα and ERß. The lateral septum (LS) is thought to be one of the potential target sites of E2, but the role played by ERα and ERß in this brain area remains largely unknown. In the present study, we first analyzed the distribution of ERα and ERß with double fluorescent immunohistochemistry in a transgenic mouse line in which red fluorescent protein (RFP) signal has been a reliable marker of ERß expression. The overall number of ERß-RFP-expressing cells was significantly higher (about 2.5 times) compared to ERα-expressing cells. The distribution of the two types of ERs was different, with co-expression only seen in about 1.2% of total ER-positive cells. Given these distinctive distribution patterns, we examined the behavioral effects of site-specific knockdown of each ER using viral vector-mediated small interference RNA (siRNA) techniques in male mice. We found ERß-specific behavioral alterations during a social interaction test, suggesting involvement of ERß-expressing LS neurons in the regulation of social anxiety and social interest. Further, we investigated the neuronal projections of ERα- and ERß-expressing LS cells by injecting an anterograde viral tracer in ERα-Cre and ERß-iCre mice. Dense expression of green fluorescence protein (GFP) in synaptic terminals was observed in ERß-iCre mice in areas known to be related to the modulation of anxiety. These findings collectively suggest that ERß expressed in the LS plays a major role in the estrogenic control of social anxiety-like behavior.

Clinical and neuroimaging correlates in a pilot randomized trial of aerobic exercise for major depression.

BACKGROUND: Aerobic exercise (AE) combined with pharmacotherapy is known to reduce depressive symptoms; however, studies have not focused on long-term AE for volumetric changes of brain regions (amygdala, thalamus, and nucleus accumbens [NAcc]) linked to the control of affective responses and hopelessness in individuals with major depression (MD). In addition, AE with motor complexity (AEMC) would be more effective than AE in causing brain plasticity. We compared the effects of 24 weeks of AE and AEMC combined with pharmacotherapy on clinical and volumetric outcomes in individuals with MD. METHODS: Forty medicated individuals with MD were randomly assigned to nonexercising control (C), AE, and AEMC groups. The training groups exercised for 60 min, twice a week for 24 weeks. Clinical and volumetric outcomes were assessed before and after the 24 weeks. Effect size (ES) and confidence interval (CI) were calculated for within-group and between-groups changes. RESULTS: AE and AEMC reduced hopelessness (ES = -0.73 and ES = -0.62, respectively) and increased affective responses (ES = 1.24 and ES = 1.56, respectively). Only AE increased amygdala (ES = 0.27 left and ES = 0.34 right), thalamus (ES = 0.33 left and ES = 0.26 right) and left NAcc (ES = 0.54) volumes. AE was more effective than the C group in reducing hopelessness and causing brain plasticity. The changes in the right amygdala volume showed a strong trend in explaining 72 % of the changes in affective responses following AE (p = 0.06). LIMITATION: Lack of posttraining follow-up and small sample size. CONCLUSION: These preliminary data indicate that AE combined with pharmacotherapy can cause clinical improvement and brain plasticity in individuals with MD.

Limbic system plasticity after electroacupuncture intervention in knee osteoarthritis rats.

Knee osteoarthritis (KOA) is characterized by debilitating pain. Electroacupuncture (EA), a traditional Chinese medical therapy, has shown promise in KOA pain management. This study investigated the therapeutic potential of EA in KOA and its impact on limbic system neural plasticity. Sixteen rats were randomly assigned into two groups: EA group and sham-EA group. EA or sham-EA interventions were administered at acupoints ST32 (Futu) and ST36 (Zusanli) for three weeks. Post-intervention resting-state fMRI was scanned, assessing parameters including Amplitude of low frequency fluctuations (ALFF), regional homogeneity (ReHo), functional connectivity (FC) and nodal characterizations of network within limbic system. The results showed that EA was strategically directed towards the limbic system, resulting in discernible alterations in neural activity, FC, and network characteristics. Our findings demonstrate that EA had a significant impact on the limbic system neural plasticity in rats with KOA, presenting a novel nonpharmacological approach for KOA treatment.

Concordant dynamic changes of global network properties in the frontoparietal and limbic compartments: An EEG study.

INTRODUCTION: Despite its complexity, deciphering nodal interaction is imperative to understanding a neural network. Network interaction is an even more complicated topic that must be addressed. This study aimed to examine the relationship between the brain waves of two canonical brain structures, i.e., the frontoparietal and limbic compartments, during a resting state. METHODS: Electroencephalography (EEG) of 51 subjects in eye-closed condition was analyzed, and the eLORETA method was applied to convert the signals from the scalp to the brain. By way of community detection, representative neural nodes and the associated mean activities were retrieved. Total and lagged coherences were computed to indicate functional connectivity between those neural nodes. Two global network properties were elucidated based on the connectivity measures, i.e., global efficiency and mean functional connectivity strength. The temporal correlation of the global network indices between the two studied networks was explored. RESULTS: It was found that there was a significant trend of positive correlation across the four metrics (lagged vs. total coherence x global efficiency vs. average connectivity). In other words, when the neural interaction in the FP network was stronger, so did that in the limbic network, and vice versa. Notably, the above interaction was not spectrally specific and only existed at a finer temporal scale (under hundreds of milliseconds level). CONCLUSION: The concordant change in network properties indicates an intricate balance between FP and LM compartments. Possible mechanisms and implications for the findings are discussed.

Exercise therapy for chronic pain: How does exercise change the limbic brain function?

We are exposed to various external and internal threats which might hurt us. The role of taking flexible and appropriate actions against threats is played by "the limbic system" and at the heart of it there is the ventral tegmental area and nucleus accumbens (brain reward system). Pain-related fear causes excessive excitation of amygdala, which in turn causes the suppression of medial prefrontal cortex, leading to chronification of pain. Since the limbic system of chronic pain patients is functionally impaired, they are maladaptive to their situations, unable to take goal-directed behavior and are easily caught by fear-avoidance thinking. We describe the neural mechanisms how exercise activates the brain reward system and enables chronic pain patients to take goal-directed behavior and overcome fear-avoidance thinking. A key to getting out from chronic pain state is to take advantage of the behavioral switching function of the basal nucleus of amygdala. We show that exercise activates positive neurons in this nucleus which project to the nucleus accumbens and promote reward behavior. We also describe fear conditioning and extinction are affected by exercise. In chronic pain patients, the fear response to pain is enhanced and the extinction of fear memories is impaired, so it is difficult to get out of "fear-avoidance thinking". Prolonged avoidance of movement and physical inactivity exacerbate pain and have detrimental effects on the musculoskeletal and cardiovascular systems. Based on the recent findings on multiple bran networks, we propose a well-balanced exercise prescription considering the adherence and pacing of exercise practice. We conclude that therapies targeting the mesocortico-limbic system, such as exercise therapy and cognitive behavioral therapy, may become promising tools in the fight against chronic pain.

Three weeks of exercise therapy altered brain functional connectivity in fibromyalgia inpatients.

Background: Fibromyalgia (FM) is a chronic pain syndrome characterized by widespread pain, tenderness, and fatigue. Patients with FM have no effective medication so far, and their activity of daily living and quality of life are remarkably impaired. Therefore, new therapeutic approaches are awaited. Recently, exercise therapy has been gathering much attention as a promising treatment for FM. However, the underlying mechanisms are not fully understood, particularly, in the central nervous system, including the brain. Therefore, we investigated functional connectivity changes and their relationship with clinical improvement in patients with FM after exercise therapy to investigate the underlying mechanisms in the brain using resting-state fMRI (rs-fMRI) and functional connectivity (FC) analysis. Methods: Seventeen patients with FM participated in this study. They underwent a 3-week exercise therapy on in-patient basis and a 5-min rs-fMRI scan before and after the exercise therapy. We compared the FC strength of sensorimotor regions and the mesocortico-limbic system between two scans. We also performed a multiple regression analysis to examine the relationship between pre-post differences in FC strength and improvement of patients' clinical symptoms or motor abilities. Results: Patients with FM showed significant improvement in clinical symptoms and motor abilities. They also showed a significant pre-post difference in FC of the anterior cingulate cortex and a significant correlation between pre-post FC changes and improvement of clinical symptoms and motor abilities. Although sensorimotor regions tended to be related to the improvement of general disease severity and depression, brain regions belonging to the mesocortico-limbic system tended to be related to the improvement of motor abilities. Conclusion: Our 3-week exercise therapy could ameliorate clinical symptoms and motor abilities of patients with FM, and lead to FC changes in sensorimotor regions and brain regions belonging to the mesocortico-limbic system. Furthermore, these changes were related to improvement of clinical symptoms and motor abilities. Our findings suggest that, as predicted by previous animal studies, spontaneous brain activities modified by exercise therapy, including the mesocortico-limbic system, improve clinical symptoms in patients with FM.

Volume changes of the subcortical limbic structures in major depressive disorder patients with and without anhedonia.

Anhedonia is a core feature of major depressive disorder (MDD) and the limbic system has been indicated to be associated with anhedonia in MDD due to its crucial role within the reward circuit. However, the relationship between different regions of the limbic system and MDD, particularly anhedonic symptoms, remains unclear. Therefore, the purpose of this study was to investigate volume changes of various parts of the subcortical limbic (ScLimbic) system in MDD with and without anhedonia. A total of 120 individuals, including 30 MDD patients with anhedonia, 43 MDD patients without anhedonia, and 47 healthy controls (HCs) were enrolled in this study. All subjects underwent structural magnetic resonance imaging scans. After that, ScLimbic system segmentation was performed using the FreeSurfer pipeline ScLimbic. Analysis of covariance (ANCOVA) was performed to identify brain regions with significant volume differences among three groups, and then, post hoc tests were calculated for inter-group comparisons. Finally, correlations between volumes of different parts of the ScLimbic and clinical characteristics in MDD patients were further analyzed. The ANCOVA revealed significant volume differences of the ScLimbic system among three groups in the bilateral fornix (Fx), and the right basal forebrain (BF). As compared with HCs, both groups of MDD patients showed decreased volume in the right Fx, meanwhile, MDD patients with anhedonia further exhibited volume reductions in the left Fx and right BF. However, no significant difference was found between MDD patients with and without anhedonia. No significant association was observed between subregion volumes of the ScLimbic system and clinical features in MDD. The present findings demonstrated that MDD patients with and without anhedonia exhibited segregated brain structural alterations in the ScLimbic system and volume loss of the ScLimbic system might be fairly extensive in MDD patients with anhedonia.

Synaptic Involvement of the Human Amygdala in Parkinson's Disease.

α-Synuclein, a protein mostly present in presynaptic terminals, accumulates neuropathologically in Parkinson's disease in a 6-stage sequence and propagates in the nervous system in a prion-like manner through neurons and glia. In stage 3, the substantia nigra are affected, provoking motor symptoms and the amygdaloid complex, leading to different nonmotor symptoms; from here, synucleinopathy spreads to the temporal cortex and beyond. The expected increase in Parkinson's disease incidence accelerates the need for detection biomarkers; however, the heterogeneity of this disease, including pathological aggregates and pathophysiological pathways, poses a challenge in the search for new therapeutic targets and biomarkers. Proteomic analyses are lacking, and the literature regarding synucleinopathy, neural and glial involvement, and volume of the human amygdaloid complex is controversial. Therefore, the present study combines both proteomic and stereological probes. Data-independent acquisition-parallel accumulation of serial fragmentation proteomic analysis revealed a remarkable proteomic impact, especially at the synaptic level in the human amygdaloid complex in Parkinson's disease. Among the 199 differentially expressed proteins, guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1), elongation factor 1-alpha 1 (EEF1A1), myelin proteolipid protein (PLP1), neuroplastin (NPTN), 14-3-3 protein eta (YWHAH), gene associated with retinoic and interferon-induced mortality 19 protein (GRIM19), and orosomucoid-2 (ORM2) stand out as potential biomarkers in Parkinson's disease. Stereological analysis, however, did not reveal alterations regarding synucleinopathy, neural or glial populations, or volume changes. To our knowledge, this is the first proteomic study of the human amygdaloid complex in Parkinson's disease, and it identified possible biomarkers of the disease. Lewy pathology could not be sufficient to cause neurodegeneration or alteration of microglial and astroglial populations in the human amygdaloid complex in Parkinson's disease. Nevertheless, damage at the proteomic level is manifest, showing up significant synaptic involvement.

Exploring HD-tDCS Effect on µ-opioid Receptor and Pain Sensitivity in Temporomandibular Disorder: A Pilot Randomized Clinical Trial Study.

This study explored the association between experimentally-induced pain sensitivity and µ-opioid receptor (µOR) availability in patients with temporomandibular disorder (TMD) and further investigated any changes in the pain and µOR availability following high-definition transcranial direct current stimulation (HD-tDCS) over the primary motor cortex (M1) with pilot randomized clinical trials. Seven patients with TMD completed either active (n = 3) or sham treatment (n = 4) for 10 daily sessions and underwent positron emission tomography (PET) scans with [11C]carfentanil, a selective µOR agonist, a week before and after treatment. PET imaging consisted of an early resting and late phase with the sustained masseteric pain challenge by computer-controlled injection of 5% hypertonic saline. We also included 12 patients with TMD, obtained from our previous study, for baseline PET analysis. We observed that patients with more sensitivity to pain, indicated by lower infusion rate, had less µOR availability in the right amygdala during the late phase. Moreover, active M1 HD-tDCS, compared to sham, increased µOR availability post-treatment in the thalamus during the early resting phase and the amygdala, hippocampus, and parahippocampal gyrus during the late pain challenge phase. Importantly, increased µOR availability post-treatment in limbic structures including the amygdala and hippocampus was associated with decreased pain sensitivity. The findings underscore the role of the µOR system in pain regulation and the therapeutic potential of HD-tDCS for TMD. Nonetheless, large-scale studies are necessary to establish the clinical significance of these results. TRIAL REGISTRATION: ClinicalTrial.gov (NCT03724032) PERSPECTIVE: This study links pain sensitivity and µ-opioid receptors in patients with TMD. HD-tDCS over M1 improved µOR availability, which was associated with reduced pain sensitivity. Implications for TMD pain management are promising, but larger clinical trials are essential for validation.