Meso-cortical pathway damage in cognition, apathy and gait in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is known to contribute to cognitive impairment, apathy, and gait dysfunction. Although associations between cognitive impairment and either apathy or gait dysfunction have been shown in SVD, the inter-relations among these three clinical features and their potential common neural basis remains unexplored. The dopaminergic meso-cortical and meso-limbic pathways have been known as the important brain circuits for both cognitive control, emotion regulation and motor function. Here, we investigated the potential inter-relations between cognitive impairment, apathy, and gait dysfunction, with a specific focus on determining whether these clinical features are associated with damage to the meso-cortical and meso-limbic pathways in SVD. In this cross-sectional study, we included 213 participants with SVD in whom MRI scans and comprehensive neurobehavioral assessments were administered. These assessments comprised of six clinical measures: processing speed, executive function, memory, apathy (based on the Apathy Evaluation Scale), and gait function (based on the time and steps in Timed Up and Go test). We reconstructed five tracts connecting ventral tegmental area (VTA) and the dorsolateral prefrontal cortex (dlPFC), ventral lateral PFC (vlPFC), medial orbitofrontal cortex (mOFC), anterior cingulate cortex (ACC) and nucleus accumbens (NAc) within meso-cortical and meso-limbic pathways using diffusion weighted imaging. The damage along the five tracts was quantified using the free water (FW) and FW-corrected mean diffusivity (MD-t) indices. Furthermore, we explored the inter-correlations among the six clinical measures and identified their common components using principal component analysis (PCA). Linear regression analyses showed that higher FW values of tracts within meso-cortical pathways were related to these clinical measures in cognition, apathy, and gait (all P-corrected values < 0.05). PCA showed strong inter-associations among these clinical measures and identified a common component wherein all six clinical measures loaded on. Higher FW values of tracts within meso-cortical pathways were related to the PCA-derived common component (all P-corrected values < 0.05). Moreover, FW values of VTA-ACC tract showed the strongest contribution to the PCA-derived common component over all other neuroimaging features. In conclusion, our study showed that the three clinical features (cognitive impairment, apathy, and gait dysfunction) of SVD are strongly inter-related and that the damage in meso-cortical pathway could be the common neural basis underlying the three features in SVD. These findings advance our understanding of the mechanisms behind these clinical features of SVD and have the potential to inform novel management and intervention strategies for SVD.

Six types of loves differentially recruit reward and social cognition brain areas.

Feelings of love are among the most significant human phenomena. Love informs the formation and maintenance of pair bonds, parent-offspring attachments, and influences relationships with others and even nature. However, little is known about the neural mechanisms of love beyond romantic and maternal types. Here, we characterize the brain areas involved in love for six different objects: romantic partner, one's children, friends, strangers, pets, and nature. We used functional magnetic resonance imaging (fMRI) to measure brain activity, while we induced feelings of love using short stories. Our results show that neural activity during a feeling of love depends on its object. Interpersonal love recruited social cognition brain areas in the temporoparietal junction and midline structures significantly more than love for pets or nature. In pet owners, love for pets activated these same regions significantly more than in participants without pets. Love in closer affiliative bonds was associated with significantly stronger and more widespread activation in the brain's reward system than love for strangers, pets, or nature. We suggest that the experience of love is shaped by both biological and cultural factors, originating from fundamental neurobiological mechanisms of attachment.

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.

Cortico-limbic interactions and carotid atherosclerotic burden during chronic stress exposure.

BACKGROUND AND AIMS: Chronic stress associates with cardiovascular disease, but mechanisms remain incompletely defined. Advanced imaging was used to identify stress-related neural imaging phenotypes associated with atherosclerosis. METHODS: Twenty-seven individuals with post-traumatic stress disorder (PTSD), 45 trauma-exposed controls without PTSD, and 22 healthy controls underwent 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI). Atherosclerotic inflammation and burden were assessed using 18F-FDG PET (as maximal target-to-background ratio, TBR max) and MRI, respectively. Inflammation was assessed using high-sensitivity C-reactive protein (hsCRP) and leucopoietic imaging (18F-FDG PET uptake in spleen and bone marrow). Stress-associated neural network activity (SNA) was assessed on 18F-FDG PET as amygdala relative to ventromedial prefrontal cortex (vmPFC) activity. MRI diffusion tensor imaging assessed the axonal integrity (AI) of the uncinate fasciculus (major white matter tract connecting vmPFC and amygdala). RESULTS: Median age was 37 years old and 54% of participants were female. There were no significant differences in atherosclerotic inflammation between participants with PTSD and controls; adjusted mean difference in TBR max (95% confidence interval) of the aorta 0.020 (-0.098, 0.138), and of the carotids 0.014 (-0.091, 0.119). Participants with PTSD had higher hsCRP, spleen activity, and aorta atherosclerotic burden (normalized wall index). Participants with PTSD also had higher SNA and lower AI. Across the cohort, carotid atherosclerotic burden (standard deviation of wall thickness) associated positively with SNA and negatively with AI independent of Framingham risk score. CONCLUSIONS: In this study of limited size, participants with PTSD did not have higher atherosclerotic inflammation than controls. Notably, impaired cortico-limbic interactions (higher amygdala relative to vmPFC activity or disruption of their intercommunication) associated with carotid atherosclerotic burden. Larger studies are needed to refine these findings.

Signatures of Electrical Stimulation Driven Network Interactions in the Human Limbic System.

Stimulation-evoked signals are starting to be used as biomarkers to indicate the state and health of brain networks. The human limbic network, often targeted for brain stimulation therapy, is involved in emotion and memory processing. Previous anatomic, neurophysiological, and functional studies suggest distinct subsystems within the limbic network (Rolls, 2015). Studies using intracranial electrical stimulation, however, have emphasized the similarities of the evoked waveforms across the limbic network. We test whether these subsystems have distinct stimulation-driven signatures. In eight patients (four male, four female) with drug-resistant epilepsy, we stimulated the limbic system with single-pulse electrical stimulation. Reliable corticocortical evoked potentials (CCEPs) were measured between hippocampus and the posterior cingulate cortex (PCC) and between the amygdala and the anterior cingulate cortex (ACC). However, the CCEP waveform in the PCC after hippocampal stimulation showed a unique and reliable morphology, which we term the "limbic Hippocampus-Anterior nucleus of the thalamus-Posterior cingulate, HAP-wave." This limbic HAP-wave was visually distinct and separately decoded from the CCEP waveform in ACC after amygdala stimulation. Diffusion MRI data show that the measured end points in the PCC overlap with the end points of the parolfactory cingulum bundle rather than the parahippocampal cingulum, suggesting that the limbic HAP-wave may travel through fornix, mammillary bodies, and the anterior nucleus of the thalamus (ANT). This was further confirmed by stimulating the ANT, which evoked the same limbic HAP-wave but with an earlier latency. Limbic subsystems have unique stimulation-evoked signatures that may be used in the future to help network pathology diagnosis.SIGNIFICANCE STATEMENT The limbic system is often compromised in diverse clinical conditions, such as epilepsy or Alzheimer's disease, and characterizing its typical circuit responses may provide diagnostic insight. Stimulation-evoked waveforms have been used in the motor system to diagnose circuit pathology. We translate this framework to limbic subsystems using human intracranial stereo EEG (sEEG) recordings that measure deeper brain areas. Our sEEG recordings describe a stimulation-evoked waveform characteristic to the memory and spatial subsystem of the limbic network that we term the "limbic HAP-wave." The limbic HAP-wave follows anatomic white matter pathways from hippocampus to thalamus to the posterior cingulum and shows promise as a distinct biomarker of signaling in the human brain memory and spatial limbic network.

Stress in Musicians with and Without Focal Dystonia Is Not Reflected in Limbic Circuit Activation.

BACKGROUND: Musicians' dystonia (MD) is a movement disorder with several established risk factors, but the exact pathophysiology remains unknown. Recent research suggests dysfunction in sensory-motor, basal ganglia, cerebellar, and limbic loops as potential causes. Adverse childhood experiences are also considered risk factors. OBJECTIVE: This study aimed to investigate whether MD patients have experienced more childhood trauma, leading to increased stress reactivity and neural vulnerability to movement disorders. METHODS: Using functional magnetic resonance imaging and the Montreal Imaging Stress Task, 40 MD patients were compared with 39 healthy musicians (HMs). Whole-brain analysis and regions of interest analysis were performed. Parameter estimates and subjective stress levels were compared between groups and correlated with the Childhood Trauma Questionnaire. RESULTS: MD patients reported significantly higher childhood trauma scores than healthy control subjects, but they did not differ in their subjective stress experiences. Stress-related activity of limbic areas was neither found in the whole sample nor between the two groups. Instead, increased activity of visual association and temporal areas was observed, but this activation did not differ between patients and HMs. However, patients showed a tendency toward reduced precuneus activity under stress. Adverse childhood experiences were negatively correlated with precuneus, thalamus, and substantia nigra activity across all participants. CONCLUSIONS: Overall, MD patients and HMs had similar subjective and neurological reactions to stress but differed in childhood trauma experiences and precuneus activity under stress. Further research about the functional connectivity between precuneus, cerebellum, thalamus, and basal ganglia in musicians is needed. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Proteomic evidence of depression-associated astrocytic dysfunction in the human male olfactory bulb.

The olfactory bulb (OB), a major structure of the limbic system, has been understudied in human investigations of psychopathologies such as depression. To explore more directly the molecular features of the OB in depression, a global comparative proteome analysis was carried out with human post-mortem OB samples from 11 males having suffered from depression and 12 healthy controls. We identified 188 differentially abundant proteins (with adjusted p < 0.05) between depressed cases and controls. Gene ontology and gene enrichment analyses suggested that these proteins are involved in biological processes including the complement and coagulation cascades. Cell type enrichment analysis displayed a significant reduction in several canonical astrocytic proteins in OBs from depressed patients. Furthermore, using RNA-fluorescence in-situ hybridization, we observed a decrease in the percentage of ALDH1L1+ cells expressing canonical astrocytic markers including ALDOC, NFIA, GJA1 (connexin 43) and SLC1A3 (EAAT1). These results are consistent with previous reports of downregulated astrocytic marker expression in other brain regions in depressed patients. We also conducted a comparative phosphoproteomic analysis of OB samples and found a dysregulation of proteins involved in neuronal and astrocytic functions. To determine whether OB astrocytic abnormalities is specific to humans, we also performed proteomics on the OB of socially defeated male mice, a commonly used model of depression. Cell-type specific analysis revealed that in socially defeated animals, the most striking OB protein alterations were associated with oligodendrocyte-lineage cells rather than with astrocytes, highlighting an important species difference. Overall, this study further highlights cerebral astrocytic abnormalities as a consistent feature of depression in humans.

Structural hyperconnectivity of the subthalamic area with limbic cortices underpins anxiety and impulsivity in Tourette syndrome.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics, which is often associated with psychiatric comorbidities. Dysfunction of basal ganglia pathways might account for the wide spectrum of symptoms in TS patients. Although psychiatric symptoms may be related to limbic networks, the specific contribution of different limbic structures remains unclear. We used tractography to investigate cortical connectivity with the striatal area (caudate, putamen, core and shell of the nucleus accumbens), the subthalamic nucleus (STN), and the adjacent medial subthalamic region (MSR) in 58 TS patients and 35 healthy volunteers. 82% of TS patients showed psychiatric comorbidities, with significantly higher levels of anxiety and impulsivity compared to controls. Tractography analysis revealed significantly increased limbic cortical connectivity of the left MSR with the entorhinal (BA34), insular (BA48), and temporal (BA38) cortices in TS patients compared to controls. Furthermore, we found that left insular-STN connectivity was positively correlated with impulsivity scores for all subjects and with anxiety scores for all subjects, particularly for TS. Our study highlights a heterogenous modification of limbic structure connectivity in TS, with specific abnormalities found for the subthalamic area. Abnormal connectivity with the insular cortex might underpin the higher level of impulsivity and anxiety observed in TS.

Connectome-based predictive modeling predicts paranoid ideation in young men with paranoid personality disorder: a resting-state functional magnetic resonance imaging study.

Paranoid personality disorder (PPD), a mental disorder that affects interpersonal relationships and work, is frequently neglected during diagnosis and evaluation at the individual-level. This preliminary study aimed to investigate whether connectome-based predictive modeling (CPM) can predict paranoia scores of young men with PPD using whole-brain resting-state functional connectivity (rs-FC). College students with paranoid tendencies were screened using paranoia scores ≥60 derived from the Minnesota Multiphasic Personality Inventory; 18 participants were ultimately diagnosed with PPD according to the Diagnostic and Statistical Manual of Mental Disorders and subsequently underwent resting-state functional magnetic resonance imaging. Whole-brain rs-FC was constructed, and the ability of this rs-FC to predict paranoia scores was evaluated using CPM. The significance of the models was assessed using permutation tests. The model constructed based on the negative prediction network involving the limbic system-temporal lobe was observed to have significant predictive ability for paranoia scores, whereas the model constructed using the positive and combined prediction network had no significant predictive ability. In conclusion, using CPM, whole-brain rs-FC predicted the paranoia score of patients with PPD. The limbic system-temporal lobe FC pattern is expected to become an important neurological marker for evaluating paranoid ideation.

Adaptive control of functional connectivity: dorsal and ventral limbic divisions regulate the dorsal and ventral neocortical networks.

The connectional anatomy of the primate cortex is now well-defined by the Structural Model, in which adjacent cortical areas are interconnected in an organized network hierarchy of communication and control. The computational theory of "active inference" can be aligned with this architecture, proposing that predictions descend from higher association areas to be updated by ascending prediction errors from lower (i.e. primary) sensory and motor areas. Given the connectivity, the limbic networks at the apex of the cerebral hierarchy must then be responsible for the most general expectancies, which are propagated through the hierarchy to organize the multiple component network levels of experience and behavior. Anatomical evidence suggests that there are dual limbic divisions, reflecting archicortical (dorsal) and paleocortical (ventral) derivations, resulting in fundamentally different neural mechanisms for managing expectancies across the corticolimbic hierarchy. In the functional connectivity literature, the dorsal attention network is seen to provide top-down or endogenous control of attention, whereas the ventral attention network provides stimulus bound or exogenous attentional control. We review evidence indicating that the dorsal, archicortical division of the limbic system provides a feedforward, impulsive, endogenous mode of motive control, whereas the ventral, paleocortical limbic division provides feedback constraint linked to exogenous events.

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.

Secretagogin marks amygdaloid PKCδ interneurons and modulates NMDA receptor availability.

The perception of and response to danger is critical for an individual's survival and is encoded by subcortical neurocircuits. The amygdaloid complex is the primary neuronal site that initiates bodily reactions upon external threat with local-circuit interneurons scaling output to effector pathways. Here, we categorize central amygdala neurons that express secretagogin (Scgn), a Ca2+-sensor protein, as a subset of protein kinase Cδ (PKCδ)+ interneurons, likely "off cells." Chemogenetic inactivation of Scgn+/PKCδ+ cells augmented conditioned response to perceived danger in vivo. While Ca2+-sensor proteins are typically implicated in shaping neurotransmitter release presynaptically, Scgn instead localized to postsynaptic compartments. Characterizing its role in the postsynapse, we found that Scgn regulates the cell-surface availability of NMDA receptor 2B subunits (GluN2B) with its genetic deletion leading to reduced cell membrane delivery of GluN2B, at least in vitro. Conclusively, we describe a select cell population, which gates danger avoidance behavior with secretagogin being both a selective marker and regulatory protein in their excitatory postsynaptic machinery.

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

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: OSA may contribute to fornix damage and memory dysfunction in MCI. HIGHLIGHTS: 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.

Toddler disorganized attachment in relation to cortical thickness and socioemotional problems in late childhood.

Disorganized attachment is a risk for mental health problems, with increasing work focused on understanding biological mechanisms. Examining late childhood brain morphology may be informative - this stage coincides with the onset of many mental health problems. Past late childhood research reveals promising candidates, including frontal lobe cortical thickness and hippocampal volume. However, work has been limited to Western samples and has not investigated mediation or moderation by brain morphology. Furthermore, past cortical thickness research included only 33 participants. The current study utilized data from 166 children from the GUSTO Asian cohort, who participated in strange situations at 18 months and MRI brain imaging at 10.5 years, with 124 administered the Child Behaviour Checklist at 10.5 years. Results demonstrated disorganization liked to internalizing problems, but no mediation or moderation by brain morphology. The association to internalizing (but not externalizing) problems is discussed with reference to the comparatively higher prevalence of internalizing problems in Singapore.

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.

Shifts in structural connectome organization in the limbic and sensory systems of patients with episodic migraine.

Migraine is a complex neurological condition characterized by recurrent headaches, which is often accompanied by various neurological symptoms. Magnetic resonance imaging (MRI) is a powerful tool for investigating whole-brain connectivity patterns; however, systematic assessment of structural connectome organization has rarely been performed. In the present study, we aimed to examine the changes in structural connectivity in patients with episodic migraines using diffusion MRI. First, we computed structural connectivity using diffusion MRI tractography, after which we applied dimensionality reduction techniques to the structural connectivity and generated three low-dimensional eigenvectors. We subsequently calculated the manifold eccentricity, defined as the Euclidean distance between each data point and the center of the data in the manifold space. We then compared the manifold eccentricity between patients with migraines and healthy controls, revealing significant between-group differences in the orbitofrontal cortex, temporal pole, and sensory/motor regions. Between-group differences in subcortico-cortical connectivity further revealed significant changes in the amygdala, accumbens, and caudate nuclei. Finally, supervised machine learning effectively classified patients with migraines and healthy controls using cortical and subcortical structural connectivity features, highlighting the importance of the orbitofrontal and sensory cortices, in addition to the caudate, in distinguishing between the groups. Our findings confirmed that episodic migraine is related to the structural connectome changes in the limbic and sensory systems, suggesting its potential utility as a diagnostic marker for migraine.

Subcortical influences on the topology of cortical networks align with functional processing hierarchies.

fMRI of the human brain reveals spatiotemporal patterns of functional connectivity (FC), forming distinct cortical networks. Lately, subcortical contributions to these configurations are receiving renewed interest, but investigations rarely focus explicitly on their effects on cortico-cortical FC. Here, we employ a straightforward multivariable approach and graph-theoretic tools to assess subcortical impact on topological features of cortical networks. Given recent evidence showing that structures like the thalamus and basal ganglia integrate input from multiple networks, we expect increased segregation between cortical networks after removal of subcortical effects on their FC patterns. We analyze resting state data of young and healthy participants (male and female; N = 100) from the human connectome project. We find that overall, the cortical network architecture becomes less segregated, and more integrated, when subcortical influences are accounted for. Underlying these global effects are the following trends: 'Transmodal' systems become more integrated with the rest of the network, while 'unimodal' networks show the opposite effect. For single nodes this hierarchical organization is reflected by a close correspondence with the spatial layout of the principal gradient of FC (Margulies et al., 2016). Lastly, we show that the limbic system is significantly less coherent with subcortical influences removed. The findings are validated in a (split-sample) replication dataset. Our results provide new insight regarding the interplay between subcortex and cortical networks, by putting the integrative impact of subcortex in the context of macroscale patterns of cortical organization.

RGS14 expression in CA2 hippocampus, amygdala, and basal ganglia: Implications for human brain physiology and disease.

RGS14 is a multifunctional scaffolding protein that is highly expressed within postsynaptic spines of pyramidal neurons in hippocampal area CA2. Known roles of RGS14 in CA2 include regulating G protein, H-Ras/ERK, and calcium signaling pathways to serve as a natural suppressor of synaptic plasticity and postsynaptic signaling. RGS14 also shows marked postsynaptic expression in major structures of the limbic system and basal ganglia, including the amygdala and both the ventral and dorsal subdivisions of the striatum. In this review, we discuss the signaling functions of RGS14 and its role in postsynaptic strength (long-term potentiation) and spine structural plasticity in CA2 hippocampal neurons, and how RGS14 suppression of plasticity impacts linked behaviors such as spatial learning, object memory, and fear conditioning. We also review RGS14 expression in the limbic system and basal ganglia and speculate on its possible roles in regulating plasticity in these regions, with a focus on behaviors related to emotion and motivation. Finally, we explore the functional implications of RGS14 in various brain circuits and speculate on its possible roles in certain disease states such as hippocampal seizures, addiction, and anxiety disorders.

Dimensional personality impairment is associated with disruptions in intrinsic intralimbic functional connectivity.

BACKGROUND: Recently proposed alternative dimensional models of personality disorder (PD) place the severity of impairments in self and interpersonal functioning at the core of personality pathology. However, associations of these impairments with disturbances in social, cognitive, and affective brain networks remain uninvestigated. METHODS: The present study examined patterns of resting-state functional connectivity (rsFC) in a sample of 74 age- and sex-matched participants (45 inpatients with PD and 29 healthy controls). At a minimum, PD patients carried a diagnosis of borderline PD, although the majority of the sample had one or more additional PDs. rsFC patterns in the following networks were compared between groups and in association with dimensional personality impairments: default mode network (DMN)/core mentalization, frontolimbic, salience, and central executive. Further, the extent to which variation in rsFC was explained by levels of personality impairment as compared to typology-specific borderline PD symptom severity was explored. RESULTS: Relative to controls, the PD group showed disruptions in rsFC within the DMN/core mentalization and frontolimbic networks. Among PD patients, greater severity of dimensional self-interpersonal impairment was associated with stronger intralimbic rsFC. In contrast, severity of borderline PD-specific typology was not associated with any rsFC patterns. CONCLUSIONS: Disruptions in core mentalization and affective networks are present in PD. Higher intralimbic functional connectivity may underlie self-interpersonal personality impairment in PD regardless of diagnostic typology-specific PD symptoms, providing initial neurobiological evidence supporting alternative dimensional conceptualizations of personality pathology.

EEG Spatiotemporal Patterns Underlying Self-other Voice Discrimination.

There is growing evidence showing that the representation of the human "self" recruits special systems across different functions and modalities. Compared to self-face and self-body representations, few studies have investigated neural underpinnings specific to self-voice. Moreover, self-voice stimuli in those studies were consistently presented through air and lacking bone conduction, rendering the sound of self-voice stimuli different to the self-voice heard during natural speech. Here, we combined psychophysics, voice-morphing technology, and high-density EEG in order to identify the spatiotemporal patterns underlying self-other voice discrimination (SOVD) in a population of 26 healthy participants, both with air- and bone-conducted stimuli. We identified a self-voice-specific EEG topographic map occurring around 345 ms post-stimulus and activating a network involving insula, cingulate cortex, and medial temporal lobe structures. Occurrence of this map was modulated both with SOVD task performance and bone conduction. Specifically, the better participants performed at SOVD task, the less frequently they activated this network. In addition, the same network was recruited less frequently with bone conduction, which, accordingly, increased the SOVD task performance. This work could have an important clinical impact. Indeed, it reveals neural correlates of SOVD impairments, believed to account for auditory-verbal hallucinations, a common and highly distressing psychiatric symptom.