Limbic Research Articles

Cingulate microstimulation induces negative decision-making via reduced top-down influence on primate fronto-cingulo-striatal network.

The dorsolateral prefrontal cortex (dlPFC) is crucial for regulation of emotion that is known to aid prevention of depression. The broader fronto-cingulo-striatal (FCS) network, including cognitive dlPFC and limbic cingulo-striatal regions, has been associated with a negative evaluation bias often seen in depression. The mechanism by which dlPFC regulates the limbic system remains largely unclear. Here we have successfully induced a negative bias in decision-making in female primates performing a conflict decision-making task, by directly microstimulating the subgenual cingulate cortex while simultaneously recording FCS local field potentials (LFPs). The artificially induced negative bias in decision-making was associated with a significant decrease in functional connectivity from cognitive to limbic FCS regions, represented by a reduction in Granger causality in beta-range LFPs from the dlPFC to the other regions. The loss of top-down directional influence from cognitive to limbic regions, we suggest, could underlie negative biases in decision-making as observed in depressive states.

Modeling brain sex in the limbic system as phenotype for female-prevalent mental disorders

BackgroundSex differences exist in the prevalence and clinical manifestation of several mental disorders, suggesting that sex-specific brain phenotypes may play key roles. Previous research used machine learning models to classify sex from imaging data of the whole brain and studied the association of class probabilities with mental health, potentially overlooking regional specific characteristics.MethodsWe here investigated if a regionally constrained model of brain volumetric imaging data may provide estimates that are more sensitive to mental health than whole brain-based estimates. Given its known role in emotional processing and mood disorders, we focused on the limbic system. Using two different cohorts of healthy subjects, the Human Connectome Project and the Queensland Twin IMaging, we investigated sex differences and heritability of brain volumes of limbic structures compared to non-limbic structures, and subsequently applied regionally constrained machine learning models trained solely on limbic or non-limbic features. To investigate the biological underpinnings of such models, we assessed the heritability of the obtained sex class probability estimates, and we investigated the association with major depression diagnosis in an independent clinical sample. All analyses were performed both with and without controlling for estimated total intracranial volume (eTIV).ResultsLimbic structures show greater sex differences and are more heritable compared to non-limbic structures in both analyses, with and without eTIV control. Consequently, machine learning models performed well at classifying sex based solely on limbic structures and achieved performance as high as those on non-limbic or whole brain data, despite the much smaller number of features in the limbic system. The resulting class probabilities were heritable, suggesting potentially meaningful underlying biological information. Applied to an independent population with major depressive disorder, we found that depression is associated with male–female class probabilities, with largest effects obtained using the limbic model. This association was significant for models not controlling for eTIV whereas in those controlling for eTIV the associations did not pass significance correction.ConclusionsOverall, our results highlight the potential utility of regionally constrained models of brain sex to better understand the link between sex differences in the brain and mental disorders.

Multiscale brain age prediction reveals region-specific accelerated brain aging in Parkinson's disease

Brain biological age, which measures the aging process in the brain using neuroimaging data, has been used to assess advanced brain aging in neurodegenerative diseases, including Parkinson disease (PD). However, assuming that whole brain degeneration is uniform may not be sufficient for assessing the complex neurodegenerative processes in PD. In this study we constructed a multiscale brain age prediction models based on structural MRI of 1240 healthy participants. To assess the brain aging patterns using the brain age prediction model, 93 PD patients and 91 healthy controls matching for sex and age were included. We found increased global and regional brain age in PD patients. The advanced aging regions were predominantly noted in the frontal and temporal cortices, limbic system, basal ganglia, thalamus, and cerebellum. Furthermore, region-level rather than global brain age in PD patients was associated with disease severity. Our multiscale brain age prediction model could aid in the development of objective image-based biomarkers to detect advanced brain aging in neurodegenerative diseases.

Mendelian randomization analyses support causal relationships between tinnitus of different stages and severity and structural characteristics of specific brain regions

This study aims to delineate the causal relationships between idiopathic tinnitus in different stages and severity and the morphological properties in specific brain regions. We utilized a two-sample bidirectional Mendelian randomization (MR) analysis to ascertain the causal effects of brain structural attributes on varying severities and stages of tinnitus. Our approach involved harnessing genetic variables derived from extensive genome-wide association studies as instrumental variables, centered mainly on pertinent single-nucleotide polymorphisms associated with tinnitus. Subsequently, we integrated this data with brain structural imaging inputs to facilitate the MR analysis. We also applied reverse MR analysis to pinpoint the critical brain regions implicated in the onset of tinnitus. Our analysis revealed a demonstrable causal relationship between tinnitus and brain structural alterations, including changes primarily within the auditory cortex and hub regions of the limbic system, as well as portions of the frontal-temporal-occipital circuit. We found that individuals exhibiting cortical thickness alterations in the bilateral peri-calcarine and right superior occipital gyrus might have previously experienced tinnitus. Changes in the cortical areas of the right rectus, left inferior frontal gyrus, and right pars-orbitalis appeared unrelated to tinnitus. Furthermore, moderate tinnitus patients showed more pronounced structural alterations. This study substantiates that tinnitus could instigate substantial structural alterations mainly within the auditory-limbic-frontal-visual system, while the reciprocal causality was not supported. Moreover, the data underscores that moderate, rather than severe, tinnitus precipitates the most significant structural changes. Morphological alterations in several specific brain areas either indicate a history of tinnitus or bear no relation to it.

The psychophysiology of music-based interventions and the experience of pain.

In modern times there is increasing acceptance that music-based interventions are useful aids in the clinical treatment of a range of neurological and psychiatric conditions, including helping to reduce the perception of pain. Indeed, the belief that music, whether listening or performing, can alter human pain experiences has a long history, dating back to the ancient Greeks, and its potential healing properties have long been appreciated by indigenous cultures around the world. The subjective experience of acute or chronic pain is complex, influenced by many intersecting physiological and psychological factors, and it is therefore to be expected that the impact of music therapy on the pain experience may vary from one situation to another, and from one person to another. Where pain persists and becomes chronic, aberrant central processing is a key feature associated with the ongoing pain experience. Nonetheless, beneficial effects of exposure to music on pain relief have been reported across a wide range of acute and chronic conditions, and it has been shown to be effective in neonates, children and adults. In this comprehensive review we examine the various neurochemical, physiological and psychological factors that underpin the impact of music on the pain experience, factors that potentially operate at many levels - the periphery, spinal cord, brainstem, limbic system and multiple areas of cerebral cortex. We discuss the extent to which these factors, individually or in combination, influence how music affects both the quality and intensity of pain, noting that there remains controversy about the respective roles that diverse central and peripheral processes play in this experience. Better understanding of the mechanisms that underlie music's impact on pain perception together with insights into central processing of pain should aid in developing more effective synergistic approaches when music therapy is combined with clinical treatments. The ubiquitous nature of music also facilitates application from the therapeutic environment into daily life, for ongoing individual and social benefit.

RETRACTED: Left hemisphere lateralization of the limbic system and frontoparietal network (FPN) correlates with positive and negative symptom improvement following cannabidiol (CBD) administration in psychosis and ultra-high risk (UHR) populations: A voxel-wise meta-analysis

This voxel-wise meta-analysis assesses current findings about the neural correlates of cannabidiol on the positive and negative symptoms among individuals with psychosis or ultra-high risk (UHR) for psychosis. We used PubMed, EMBASE, and ScienceDirect as primary databases and initially retrieved 157 studies. After applying our eligibility criteria, 13 studies remained for inclusion. Ten studies focused on psychosis. Three studies focused on UHR. Quality assessment was performed for included articles using the RoB2 instrument. Statistical analysis implicated a voxel-wise meta-analysis of different task paradigms (emotion recognition, verbal memory recall, and inhibitory control) with a jackknife sensitivity measure, Egger's test of random effects, and a meta-regression with relevant covariates. Article quality was determined to be primarily low risk of bias, with some elements of unclear bias figuring across studies. Our results showed robust, convergent correlations between CBD administration and left hemisphere lateralization of limbic system and frontoparietal network (FPN) subregions across task paradigms in psychosis and UHR populations. Our meta-regression revealed that decreased limbic system activity correlated with positive symptom improvements, and decreased FPN activity correlated with negative symptom improvements. Lastly, sensitivity analyses determined that there was minimal risk bias or risk of confounding variables unduly influencing our meta-analyses (p > 0.05).

Altered fornix integrity is associated with sleep apnea-related hypoxemia in mild cognitive impairment.

The limbic system is critical for memory function and degenerates early in the Alzheimer's disease continuum. Whether obstructive sleep apnea (OSA) is associated with alterations in the limbic white matter tracts remains understudied. Polysomnography, neurocognitive assessment, and brain magnetic resonance imaging (MRI) were performed in 126 individuals aged 55-86 years, including 70 cognitively unimpaired participants and 56 participants with mild cognitive impairment (MCI). OSA measures of interest were the apnea-hypopnea index and composite variables of sleep fragmentation and hypoxemia. Microstructural properties of the cingulum, fornix, and uncinate fasciculus were estimated using free water-corrected diffusion tensor imaging. Higher levels of OSA-related hypoxemia were associated with higher left fornix diffusivities only in participants with MCI. Microstructure of the other white matter tracts was not associated with OSA measures. Higher left fornix diffusivities correlated with poorer episodic verbal memory. OSA may contribute to fornix damage and memory dysfunction in MCI. Sleep apnea-related hypoxemia was associated with altered fornix integrity in MCI. Altered fornix integrity correlated with poorer memory function. Sleep apnea may contribute to fornix damage and memory dysfunction in MCI.

Vestibular system and human cognitive functions

The article is a review of scientific research on the influence of the vestibular system on human cognitive functions. The vestibular apparatus is well studied. Research in recent decades using functional tomography techniques has shown that it has extensive connections with the subcortical and cortical structures of the brain that provide cognitive activity. Hypotheses are put forward that the conduction and processing of bioelectric impulses by the brain, which are recorded by the vestibular apparatus, creates the necessary background for the course of all cognitive processes. The vestibular apparatus has connections with the limbic system, hippocampus, striatum and neocortex. Therefore, vestibular dysfunctions can reduce the ability to learn, cause impaired attention, memory, executive functions, cause disorientation, and affect stress levels. An urgent area of research is the study of the influence of vestibular sensory reactivity on children’s learning ability. This influence has long been underestimated, since it was generally assumed that motor and cognitive development occur independently of each other. The mechanisms linking vestibular dysfunction with cognitive impairment have not yet been sufficiently studied. Further studies are needed to assess the possible impact of vestibular dysfunctions on attention, memory, and speech. Such studies are already underway. Their results are most relevant for patients with neurodegenerative disorders and for children with special needs.

Neuroanatomical Substrates of Circuit-Specific Cholinergic Modulation across the Primate Anterior Cingulate Cortex.

Acetylcholine is a robust neuromodulator of the limbic system and a critical regulator of arousal and emotions. The anterior cingulate cortex (ACC) and the amygdala (AMY) are key limbic structures that are both densely innervated by cholinergic afferents and interact with each other for emotional regulation. The ACC is composed of functionally distinct dorsal (A24), rostral (A32), and ventral (A25) areas that differ in their connections with the AMY. The structural substrates of cholinergic modulation of distinct ACC microcircuits and outputs to AMY are thought to depend on the laminar and subcellular localization of cholinergic receptors. The present study examines the distribution of muscarinic acetylcholine receptors, m1 and m2, on distinct excitatory and inhibitory neurons and on AMY-targeting projection neurons within ACC areas, via immunohistochemistry and injections of neural tracers into the basolateral AMY in adult rhesus monkeys of both sexes. We found that laminar densities of m1+ and m2+ expressing excitatory and inhibitory neurons depended on area and cell type. Among the ACC areas, ventral subgenual ACC A25 exhibited greater m2+ localization on presynaptic inhibitory axon terminals and greater density of m1+ and m2+ expressing AMY-targeting (tracer+) pyramidal neurons. These patterns suggest robust cholinergic disinhibition and potentiation of amygdalar outputs from the limbic ventral ACC, which may be linked to the hyperexcitability of this subgenual ACC area in depression. These findings reveal the anatomical substrate of diverse cholinergic modulation of specific ACC microcircuits and amygdalar outputs that mediate cognitive-emotional integration and dysfunctions underlying stress and affective disorders.

Tracts in the limbic system show microstructural alterations post COVID-19 recovery.

Delirium, memory loss, attention deficit and fatigue are frequently reported by COVID survivors, yet the neurological pathways underlying these symptoms are not well understood. To study the possible mechanisms for these long-term sequelae after COVID-19 recovery, we investigated the microstructural properties of white matter in Indian cohorts of COVID-recovered patients and healthy controls. For the cross-sectional study presented here, we recruited 44 COVID-recovered patients and 29 healthy controls in New Delhi, India. Using deterministic whole-brain tractography on the acquired diffusion MRI scans, we traced 20 white matter tracts and compared fractional anisotropy, axial, mean and radial diffusivity between the cohorts. Our results revealed statistically significant differences (PFWE < 0.01) in the uncinate fasciculus, cingulum cingulate, cingulum hippocampus and arcuate fasciculus in COVID survivors, suggesting the presence of microstructural abnormalities. Additionally, in a subsequent subgroup analysis based on infection severity (healthy control, non-hospitalized patients and hospitalized patients), we observed a correlation between tract diffusion measures and COVID-19 infection severity. Although there were significant differences between healthy controls and infected groups, we found no significant differences between hospitalized and non-hospitalized COVID patients. Notably, the identified tracts are part of the limbic system and orbitofrontal cortex, indicating microstructural differences in neural circuits associated with memory and emotion. The observed white matter alterations in the limbic system resonate strongly with the functional deficits reported in Long COVID. Overall, our study provides additional evidence that damage to the limbic system could be a neuroimaging signature of Long COVID. The findings identify targets for follow-up studies investigating the long-term physiological and psychological impact of COVID-19.

Fractional amplitude of low-frequency fluctuations in sensory-motor networks and limbic system as a potential predictor of treatment response in patients with schizophrenia

BackgroundPrevious investigations have revealed substantial differences in neuroimaging characteristics between healthy controls (HCs) and individuals diagnosed with schizophrenia (SCZ). However, we are not entirely sure how brain activity links to symptoms in schizophrenia, and there is a need for reliable brain imaging markers for treatment prediction. MethodsIn this longitudinal study, we examined 56 individuals diagnosed with 56 SCZ and 51 HCs. The SCZ patients underwent a three-month course of antipsychotic treatment. We employed resting-state functional magnetic resonance imaging (fMRI) along with fractional Amplitude of Low Frequency Fluctuations (fALFF) and support vector regression (SVR) methods for data acquisition and subsequent analysis. ResultsIn this study, we initially noted lower fALFF values in the right postcentral/precentral gyrus and left postcentral gyrus, coupled with higher fALFF values in the left hippocampus and right putamen in SCZ patients compared to the HCs at baseline. However, when comparing fALFF values in brain regions with abnormal baseline fALFF values for SCZ patients who completed the follow-up, no significant differences in fALFF values were observed after 3 months of treatment compared to baseline data. The fALFF values in the right postcentral/precentral gyrus and left postcentral gyrus, and the left postcentral gyrus were useful in predicting treatment effects. ConclusionOur findings suggest that reduced fALFF values in the sensory-motor networks and increased fALFF values in the limbic system may constitute distinctive neurobiological features in SCZ patients. These findings may serve as potential neuroimaging markers for the prognosis of SCZ patients.

Andrographolide exerts an anxiolytic-like effect possibly via regulation of the hypothalamic-orexinergic system

Background: Anxiety is a psychiatric disorder that causes many problems in life such as poor concentration, sleep disturbance, and feelings of unease to anticipate future threats. The hypothalamus is a part of the limbic system that regulates stress. The orexinergic system, naturally produced in the hypothalamus, is associated with anxiety and depression which is induced by stress. Andrographolide has antioxidants and anti-inflammation properties that are possibly effective in preventing stress-induced anxiety. Objective: This study was designed to investigate the effect of andrographolide on anxiety-like behaviour and orexinergic systems. Method: The ddY strain mice were exposed to electrical footshock stress for five days. The light was used as a contextual fear conditioning during stress exposure. Exactly 50 mg/kg of Andrographolide was given intraperitoneally, along with stress induction. The anxiety-like behaviour was investigated using two approaches: the duration of the freezing behaviour and the mice’s natural aversion to exploring open space. The hypothalamus was collected to examine the orexinergic systems. Result: Stress induction developed an anxiety-like behaviour in mice while administering andrographolide attenuated this effect. Additionally, andrographolide administration stimulated the hypothalamic orexinergic system. Conclusion: Andrographolide exerts an anxiolytic effect possibly via regulation of the hypothalamic orexinergic system.

Multiple cholinergic receptor subtypes coordinate dual modulation of acetylcholine on anterior and posterior paraventricular thalamic neurons.

Paraventricular thalamus (PVT) plays important roles in the regulation of emotion and motivation through connecting many brain structures including the midbrain and the limbic system. Although acetylcholine (ACh) neurons of the midbrain were reported to send projections to PVT, little is known about how cholinergic signaling regulates PVT neurons. Here, we used both RNAscope and slice patch-clamp recordings to characterize cholinergic receptor expression and ACh modulation of PVT neurons in mice. We found ACh excited a majority of anterior PVT (aPVT) neurons but predominantly inhibited posterior PVT (pPVT) neurons. Compared to pPVT with more inhibitory M2 receptors, aPVT expressed higher levels of all excitatory receptor subtypes including nicotinic α4, α7, and muscarinic M1 and M3. The ACh-induced excitation was mimicked by nicotine and antagonized by selective blockers for α4β2 and α7 nicotinic ACh receptor (nAChR) subtypes as well as selective antagonists for M1 and M3 muscarinic ACh receptors (mAChR). The ACh-induced inhibition was attenuated by selective M2 and M4 mAChR receptor antagonists. Furthermore, we found ACh increased the frequency of excitatory postsynaptic currents (EPSCs) on a majority of aPVT neurons but decreased EPSC frequency on a larger number of pPVT neurons. In addition, ACh caused an acute increase followed by a lasting reduction in inhibitory postsynaptic currents (IPSCs) on PVT neurons of both subregions. Together, these data suggest that multiple AChR subtypes coordinate a differential modulation of ACh on aPVT and pPVT neurons.

Functional anatomy of the limbic system structures involved in the development of post-traumatic stress disorder: analysis of anatomical and clinical studies

We present an analysis of anatomical and clinical studies investigating the morphological and functional characteristics of various structures of the limbic system involved in the development of post-traumatic stress disorder (PTSD). Understanding the structural organization and functional interactions of this system will provide new insights into the mechanisms underlying PTSD. The results of various morphological and clinical studies are considered, including information on the architecture and interconnections of the structures of the limbic system and their alteration by traumatic events. The generalized results provide new data on the role of the individual structures of the limbic system in the development of PTSD, enabling more accurate prediction of the development of PTSD and prompt appropriate measures to alleviate the course of this disorder

S-3,4-DCPG, a potent orthosteric agonist for the mGlu8 receptor, facilitates extinction and inhibits the reinstatement of morphine-induced conditioned place preference in male rats

The limbic system, particularly the NAc, shows a high concentration of metabotropic glutamate receptors (mGluRs). Recent evidence suggests the significant involvement of mGluRs in mental disorders, including substance abuse and addiction. The objective of this study was to examine the involvement of mGlu8 receptors in the NAc in the mechanisms underlying the extinction and reinstatement of conditioned place preference (CPP) induced by morphine. Male Wistar rats underwent surgical implantation of bilateral cannulas in the NAc and were assessed in a CPP protocol. In study 1 at the same time as the extinction phase, the rats were given varying doses of S-3,4-DCPG (0.03, 0.3, and 3 μg/0.5 μl). In study 2, rats that had undergone CPP extinction were given S-3,4-DCPG (0.03, 0.3, and 3 μg/0.5 μl) five minutes prior to receiving a subthreshold dose of morphine (1 mg/kg) in order to reactivate the previously extinguished morphine response. The findings demonstrated that administering S-3,4-DCPG directly into the accumbens nucleus resulted in a decrease in the duration of the CPP extinction phase. Moreover, dose-dependent administration of S-3,4-DCPG into the NAc inhibited CPP reinstatement. The observations imply that microinjection of S-3,4-DCPG as a potent orthosteric agonist with high selectivity for the mGlu8 receptor into the NAc promotes the process of extinction while concurrently exerting inhibitory effects on the reinstatement of morphine-induced CPP. This effect may be associated with the modulation of glutamate engagement within the NAc and the plasticity of reward pathways at the synaptic level.

0455 Sleep Duration and OSA Severity Is Related to Altered Limbic System Integrity in Cognitively Normal Older Adults

0455 Sleep Duration and OSA Severity Is Related to Altered Limbic System Integrity in Cognitively Normal Older Adults

Presenile dementia concomitant with Sjogren's syndrome：A Case Report

What etiology would you think of apart from classic degenerative cause for a dementia lady to make a diagnosis of AD at her age of 58? It has been reported that a 65-year-old female had got declining speech for the past seven years，concomitant with “rampant caries”in her mouth and “vitiligo”on her skin. She was also allergic to penicillin，together with an abnormal subpopulation of lymphocytes (TBNK) and multiple foci of demyelination seen on her brain CT （limbic system). Finally，a diagnosis of presenile dementia resulting from Sjogren's syndrome was established for this lady，suggesting that the autoimmunity mechanism may be involved in the pathogenesis of presenile dementia in a relatively young person.

Distinct alterations in white matter properties and organization related to maternal treatment initiation in neonates exposed to HIV but uninfected

HIV exposed-uninfected (HEU) infants and children are at risk of developmental delays as compared to HIV uninfected unexposed (HUU) populations. The effects of exposure to in utero HIV and ART regimens on the HEU the developing brain are not well understood. In a cohort of 2-week-old newborns, we used diffusion tensor imaging (DTI) tractography and graph theory to examine the influence of HIV and ART exposure in utero on neonate white matter integrity and organisation. The cohort included HEU infants born to mothers who started ART before conception (HEUpre) and after conception (HEUpost), as well as HUU infants from the same community. We investigated HIV exposure and ART duration group differences in DTI metrics (fractional anisotropy (FA) and mean diffusivity (MD)) and graph measures across white matter. We found increased MD in white matter connections involving the thalamus and limbic system in the HEUpre group compared to HUU. We further identified reduced nodal efficiency in the basal ganglia. Within the HEUpost group, we observed reduced FA in cortical-subcortical and cerebellar connections as well as decreased transitivity in the hindbrain area compared to HUU. Overall, our analysis demonstrated distinct alterations in white matter integrity related to the timing of maternal ART initiation that influence regional brain network properties.

Dopamine D1–D5 Receptors in Brain Nuclei: Implications for Health and Disease

Understanding the intricate role of dopamine D1–D5 receptors is pivotal in addressing the challenges posed by the aging global population, as well as by social stress and advancing therapeutic interventions. Central to diverse brain functions such as movement, cognition, motivation, and reward, dopamine receptors are ubiquitously distributed across various brain nuclei. This comprehensive review explores the nuanced functions of each dopamine receptor, D1, D2, D3, D4, and D5, in distinct brain regions, elucidating the alterations witnessed in several neurological and psychiatric disorders. From the substantia nigra and ventral tegmental area, crucial for motor control and reward processing, to the limbic system influencing emotional responses, motivation, and cognitive functions, each brain nucleus reveals a specific involvement of dopamine receptors. In addition, genetic variations in dopamine receptors affect the risk of developing schizophrenia and parkinsonism. The review further investigates the physiological significance and pathogenic impacts of dopamine receptors in critical areas like the prefrontal cortex, hypothalamus, and striatum. By unraveling the complexities of dopamine receptor biology, especially those focused on different brain nuclei, this review provides a foundation for understanding their varied roles in health and disease, which is essential for the development of targeted therapeutic strategies aimed at mitigating the impact of aging and mental health on neurological well-being.

Proton magnetic resonance spectroscopy in children with some neurological and mental disorders accompanied by mental and speech development delay: a prospective study

Proton magnetic resonance spectroscopy in children with some neurological and mental disorders accompanied by mental and speech development delay: a prospective study