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Infant cerebral blood flow (CBF) delivers nutrients and oxygen to fulfill brain energy consumption requirements for the fastest period of postnatal brain development across the lifespan. However, organizing principle of whole-brain CBF dynamics during infancy remains obscure. Leveraging a unique cohort of 100+ infants with high-resolution arterial spin labeled MRI, we find the emergence of the cortical hierarchy revealed by the highest-resolution infant CBF maps available to date. Infant CBF across cortical regions increases in a biphasic pattern featured by initial rapid and subsequently slower rate, and break-point ages increasing along the limbic-sensorimotor-association cortical gradient. Increases in CBF in sensorimotor cortices are associated with enhanced language and motor skills, and frontoparietal association cortices with cognitive skills. The study discovers emergence of the hierarchical limbic-sensorimotor-association cortical gradient in infancy and offers standardized reference of infant brain CBF and insight into the physiological basis of cortical specialization and real-world infant developmental functioning., (© 2024. The Author(s).)

Pain is a complex experience that involves sensory, emotional, and motivational components. It has been suggested that pain arising from the head and orofacial regions evokes stronger emotional responses than pain from the body. Indeed, recent work in rodents reports different patterns of activation in ascending pain pathways during noxious stimulation of the skin of the face when compared to noxious stimulation of the body. Such differences may dictate different activation patterns in higher brain regions, specifically in those areas processing the affective component of pain. We aimed to use ultra-high field functional magnetic resonance imaging (fMRI at 7-Tesla) to determine whether noxious thermal stimuli applied to the surface of the face and body evoke differential activation patterns within the ascending pain pathway in awake humans (n=16). Compared to the body, noxious heat stimulation to the face evoked more widespread signal changes in prefrontal cortical regions and numerous brainstem and subcortical limbic areas. Moreover, facial pain evoked significantly different signal changes in the lateral parabrachial nucleus, substantia nigra, paraventricular hypothalamus, and paraventricular thalamus, to those evoked by body pain. These results are consistent with recent preclinical findings of differential activation in the brainstem and subcortical limbic nuclei and associated cortices during cutaneous pain of the face when compared with the body. The findings suggest one potential mechanism by which facial pain could evoke a greater emotional impact than that evoked by body pain., Competing Interests: Declaration of competing interest The authors declare there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Experiencing highly stressful events can have detrimental and lasting effects on brain morphology. The current study explores the effects of stress during childhood and adulthood on grey matter macro- and microstructure using a sub-sample of 720 participants from the UK Biobank with very high or very low childhood and adulthood stress scores. We used T1-weighted and diffusion MRI data to assess grey matter macro- and microstructure within bilateral hippocampus, amygdala and thalamus. Findings showed that childhood stress is associated with changes in microstructural measures bilaterally within the hippocampus and amygdala. No effects of adulthood stress on brain microstructure were found. No interaction effects between sex and stress (either childhood or adulthood) were observed for any brain imaging measure. Analysis of sub-segments of the hippocampus showed that childhood stress predominantly impacted the bilateral heads of the hippocampus. Overall, these findings suggest that highly stressful experiences during childhood, but not adulthood, have lasting impact on brain microstructure. The effects of these experiences in childhood appear to persist regardless of experiences of high or low stress in adulthood., (© 2024. The Author(s).)

Background: Abnormal reward sensitivity is a risk factor for psychiatric disorders, including eating disorders such as overeating and binge-eating disorder, but the brain structural mechanisms that underlie it are not completely understood. Here, we sought to investigate the relationship between multimodal whole-brain structural features and reward sensitivity in nonhuman primates., Methods: Reward sensitivity was evaluated through behavioral economic analysis in which monkeys (adult rhesus macaques; 7 female, 5 male) responded for sweetened condensed milk (10%, 30%, 56%), Gatorade, or water using an operant procedure in which the response requirement increased incrementally across sessions (i.e., fixed ratio 1, 3, 10). Animals were divided into high (n = 6) or low (n = 6) reward sensitivity groups based on essential value for 30% milk. Multimodal magnetic resonance imaging was used to measure gray matter volume and white matter microstructure. Brain structural features were compared between groups, and their correlations with reward sensitivity for various stimuli was investigated., Results: Animals in the high sensitivity group had greater dorsolateral prefrontal cortex, centromedial amygdaloid complex, and middle cingulate cortex volumes than animals in the low sensitivity group. Furthermore, compared with monkeys in the low sensitivity group, high sensitivity monkeys had lower fractional anisotropy in the left dorsal cingulate bundle connecting the centromedial amygdaloid complex and middle cingulate cortex to the dorsolateral prefrontal cortex, and in the left superior longitudinal fasciculus 1 connecting the middle cingulate cortex to the dorsolateral prefrontal cortex., Conclusions: These results suggest that neuroanatomical variation in prefrontal-limbic circuitry is associated with reward sensitivity. These brain structural features may serve as predictive biomarkers for vulnerability to food-based and other reward-related disorders., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Aberrant structural covariance (SC) in the medial prefrontal cortex (mPFC) is believed to play a crucial role in adolescent-onset major depressive disorder (AO-MDD). However, the effect of childhood abuse (CA) on SC in AO-MDD patients is still unknown. Here, we measured anomalous SC in the mPFC of AO-MDD patients and assessed the potential modulation of this feature by CA. We acquired T1-weighted structural images of AO-MDD patients (n = 93) and healthy controls (HCs, n = 81). Using voxel-based morphometry analysis, we calculated gray matter volumes for each subject. Subsequently, we classified abnormal SC in the mPFC into three subtypes according to overall CA. Compared with HCs, AO-MDD patients showed alterations in the structural covariance network of the mPFC, which is a central region in the default mode network (DMN). We also found an anterior-posterior dissociation in the structural covariance connectivity of the DMN. A history of CA modulated bilateral mPFC SC. These changes were primarily focused on the SC between the mPFC and the limbic system, indicating a gap in the rate of neural maturation between these regions. In summary, the DMN and frontal-limbic system, which are involved in emotional processing, appear to play a significant role in the development of AO-MDD. These findings highlight the crucial effects of CA on neurophysiological alterations in individuals with AO-MDD., Competing Interests: Declaration of competing interest The authors declare no potential or actual conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: As a more common but easily neglected disorder, minimal depressive symptoms (MDS), it is unclear whether and why it increases the risk of cognitive progression in non-dementia elderly., Methods: The Alzheimer's disease Neuroimaging Initiative (ADNI) database was used to assign 1065 non-dementia elderly into normal control (n = 380) and MDS (n = 685) groups via the Geriatric Depression Scale (GDS). Blood neutrophils, transcriptomics and metabolomics, cerebrospinal fluid (CSF) proteomics, and magnetic resonance imaging (MRI) data were analyzed., Results: MDS was found to increase the risk of cognitive progression independently of multiple psychological symptoms. Increased levels of blood neutrophils were associated with cognitive progression in MDS, as supported by neutrophil-related pathways by transcriptomic enrichment analysis and multi-omics joint analysis. A disrupted frontolimbic circuit was associated with neutrophil activation in MDS., Limitations: The heterogeneity of the sample limited the generalizability of results, and the lack of follow-up data limited the research on the mechanism of neutrophil activation influencing cognitive function in MDS., Conclusions: Cognitive progression occurs as early as the MDS stage. And this phenomenon may attribute to the neutrophil activation and the related disrupted frontolimbic circuit., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Maternal adverse childhood experiences (ACEs) are robust predictors of mental health for both the exposed individual and the next generation; however, the pathway through which such intergenerational risk is conferred remains unknown. The current study evaluated the association between maternal ACEs and infant brain development, including an a priori focus on circuits implicated in emotional and sensory processing., Methods: The sample included 101 mother-infant dyads from a longitudinal study. Maternal ACEs were assessed with the Adverse Childhood Questionnaire dichotomized into low (0 or 1) and high (≥2) groups. White matter microstructure, as indexed by fractional anisotropy (FA), was assessed using structural magnetic resonance imaging in infants (41.6-46.0 weeks' postconceptional age) within a priori tracts (the cingulum, fornix, uncinate, inferior frontal occipital fasciculus, and inferior longitudinal fasciculus). Exploratory analyses were also conducted across the whole brain., Results: High maternal ACEs (≥2) were associated with decreased infant left inferior longitudinal fasciculus (ILF) FA (F(1,94) = 7.78, p < .006) relative to infants of low ACE mothers. No group difference was observed within the right ILF following correction for multiple comparisons (F(1,95) = 4.29, p < .041). Follow-up analyses within the left ILF demonstrated associations between high maternal ACEs and increased left radial diffusivity (F(1,95) = 5.10, p < .006). Exploratory analyses demonstrated preliminary support for differences in visual processing networks (e.g., optic tract) as well as additional circuits less frequently examined in the context of early life adversity exposure (e.g., corticothalamic tract)., Conclusions: Maternal ACEs predict neural circuit development of the inferior longitudinal fasciculus. Findings suggest that early developing sensory circuits within the infant brain are susceptible to maternal adverse childhood experiences and may have implications for the maturation of higher-order emotional and cognitive circuits., Competing Interests: Declaration of competing interest CNE was an investigator for a multisite clinical trial conducted by Sage Therapeutics. She is also a consultant to EmbarkNeuro, Skyland Trail, and Health Rhythms and a member of the scientific advisory board of Babyscripts. No funding or involvement from these entities was used to support the current work, and all views expressed are solely those of the authors. All other authors have no conflicts of interest or relevant disclosures., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

(1) Background: Many studies link food intake with clinical cognitive outcomes, but evidence for brain biomarkers, such as memory-related limbic white matter (WM) tracts, is limited. We examined the association between food groups, limbic WM tracts integrity, and memory performance in community-dwelling individuals. (2) Methods: We included 117 non-demented individuals (ALBION study). Verbal and visual episodic memory tests were administered, and a composite z-score was calculated. Diffusion tensor imaging tractography was applied for limbic WM tracts (fornix-FX, cingulum bundle-CB, uncinate fasciculus-UF, hippocampal perforant pathway zone-hPPZ). Food intake was evaluated through four 24-h recalls. We applied linear regression models adjusted for demographics and energy intake. (3) Results: We found significant associations between (a) higher low-to-moderate alcohol intake and higher FX fractional anisotropy (FA), (b) higher full-fat dairy intake and lower hPPZ FA, and (c) higher red meat and cold cuts intake and lower hPPZ FA. None of the food groups was associated with memory performance. (4) Conclusions: Despite non-significant associations between food groups and memory, possibly due to participants' cognitive profile and/or compensatory mechanisms, the study documented a possible beneficial role of low-to-moderate alcohol and a harmful role of full-fat dairy and red meat and cold cuts on limbic WM tracts.

Mild traumatic brain injury (mTBI) is a known risk factor for neurodegenerative diseases, yet the precise pathophysiological mechanisms remain poorly understand, often obscured by group-level analysis in non-invasive neuroimaging studies. Individual-based method is critical to exploring heterogeneity in mTBI. We recruited 80 mTBI patients and 40 matched healthy controls, obtaining high-resolution structural MRI for constructing Individual Differential Structural Covariance Networks (IDSCN). Comparisons were conducted at both the individual and group levels. Connectome-based Predictive Modeling (CPM) was applied to predict cognitive performance based on whole-brain connectivity. During the acute stage of mTBI, patients exhibited significant heterogeneity in the count and direction of altered edges, obscured by group-level analysis. In the chronic stage, the number of altered edges decreased and became more consistent, aligning with clinical observations of acute cognitive impairment and gradual improvement. Subgroup analysis based on loss of consciousness/post-traumatic amnesia revealed distinct patterns of alterations. The temporal lobe, particularly regions related to the limbic system, significantly predicted cognitive function from acute to chronic stage. The use of IDSCN and CPM has provided valuable individual-level insights, reconciling discrepancies from previous studies. Additionally, the limbic system may be an appropriate target for future intervention efforts., Competing Interests: Declaration of Competing Interest There was no conflict of interest of all the authors., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives: Psychogenic nonepileptic (functional) seizures (FS) clinically resemble epileptic seizures (ES) with both often preceded by traumatic brain injury (TBI). FS and ES emergence and occurrence after TBI may be linked to aberrant neurobehavioral stress responses. We hypothesized that neural activity signatures in response to a psychosocial stress task would differ between TBI + FS and TBI + ES after controlling for TBI status (TBI-only)., Methods: In the current multicenter study, participants were recruited prospectively from Rhode Island Hospital, Providence Rhode Island Veterans Administration Medical Center, and the University of Alabama at Birmingham Medical Center. Previous diagnoses of TBI, ES, and FS were verified based on data collected from participants, medical chart and record review, and, where indicated, results of EEG and/or video-EEG confirmatory diagnosis. TBI + ES (N = 21) and TBI + FS (N = 21) were matched for age and sex and combined into an initial group (TBI + SZ; N = 42). A TBI-only group (N = 42) was age and sex matched to the TBI with seizures (TBI + SZ) group. All participants completed an fMRI control math task (CMT) and stress math task (SMT) based on the Montreal Imaging Stress Task (MIST)., Results: The TBI + SZ group (n = 24 female) did not differ in mood or anxiety severity compared to TBI-only group (n = 24 female). However, TBI + FS group (n = 11 female) reported greater severity of these symptoms compared to TBI + ES (n = 13 female). The linear mixed effects analysis identified neural responses that differed between TBI-only and TBI + SZ during math performance within the left premotor cortex and during auditory feedback within bilateral prefrontal cortex and hippocampus/amygdala regions. Additionally, neural responses differed between TBI + ES and TBI + FS during math performance within the right dorsolateral prefrontal cortex and bilateral amygdala during auditory feedback within the supplementary motor area. All tests comparing neural stress responses to psychiatric symptom severity failed to reach significance., Discussion: Controlling for TBI and seizure status, these findings implicate specific nodes within frontal, limbic, and sensorimotor networks that may maintain functional neurological symptoms and possibly distinguish FS from ES. This study provides class II evidence of differences in neural responses to psychosocial stress between ES and FS after TBI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Limbic predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is common in older adults and is associated with neurodegeneration, cognitive decline and dementia. In this MRI and pathology investigation we tested the hypothesis that LATE-NC is associated with abnormalities in white matter structural integrity and connectivity of a network of brain regions typically harboring TDP-43 inclusions in LATE, referred to here as the "LATE-NC network". Ex-vivo diffusion MRI and detailed neuropathological data were collected on 184 community-based older adults. Linear regression revealed an independent association of higher LATE-NC stage with lower diffusion anisotropy in a set of white matter connections forming a pattern of connectivity that is consistent with the stereotypical spread of this pathology in the brain. Graph theory analysis revealed an association of higher LATE-NC stage with weaker integration and segregation in the LATE-NC network. Abnormalities were significant in stage 3, suggesting that they are detectable in later stages of the disease. Finally, LATE-NC network abnormalities were associated with faster cognitive decline, specifically in episodic and semantic memory., Competing Interests: Conflict of interest statement The authors have no financial interests or relationships to disclose with regard to the subject matter of this manuscript. Disclosure statement The authors have no financial interests or relationships to disclose with regard to the subject matter of this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Autonomic symptoms in Parkinson's disease result from variable involvement of the central and peripheral systems, but many aspects remain unclear. The analysis of functional connectivity has shown promising results in assessing the pathophysiology of Parkinson's disease. This study aims to investigate the association between autonomic symptoms and cortical functional connectivity in early Parkinson's disease patients using high-density EEG. 53 early Parkinson's disease patients (F/M 18/35) and 49 controls (F/M 20/29) were included. Autonomic symptoms were evaluated using the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score. Data were recorded with a 64-channel EEG system. We analyzed cortical functional connectivity, based on weighted phase-lag index, in θ-α-β-low-γ bands. A network-based statistic was used to perform linear regression between Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and functional connectivity in Parkinson's disease patients. We observed a positive relation between the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and α-functional connectivity (network τ = 2.8, P = 0.038). Regions with higher degrees were insula and limbic lobe. Moreover, we found positive correlations between the mean connectivity of this network and the gastrointestinal, cardiovascular, and thermoregulatory domains of Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction. Our results revealed abnormal functional connectivity in specific areas in Parkinson's disease patients with greater autonomic symptoms. Insula and limbic areas play a significant role in the regulation of the autonomic system. Increased functional connectivity in these regions might represent the central compensatory mechanism of peripheral autonomic dysfunction in Parkinson's disease., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Impaired cognition has been demonstrated in pediatric bipolar disorder (PBD). The subcortical limbic structures play a key role in PBD. However, alternations of anatomical and functional characteristics of subcortical limbic structures and their relationship with neurocognition of PBD remain unclear., Methods: Thirty-six PBD type I (PBD-I) (15.36 ± 0.32 years old), twenty PBD type II (PBD-II) (14.80 ± 0.32 years old) and nineteen age-gender matched healthy controls (HCs) (14.16 ± 0.36 years old) were enlisted. Primarily, the volumes of the subcortical limbic structures were obtained and differences in the volumes were evaluated. Then, these structures served as seeds of regions of interest to calculate the voxel-wised functional connectivity (FC). After that, correlation analysis was completed between volumes and FC of brain regions showing significant differences and neuropsychological tests., Results: Compared to HCs, both PBD-I and PBD-II patients showed a decrease in the Stroop color word test (SCWT) and digit span backward test scores. Compared with HCs, PBD-II patients exhibited a significantly increased volume of right septal nuclei, and PBD-I patients presented increased FC of right nucleus accumbens and bilateral pallidum, of right basal forebrain with right putamen and left pallidum. Both the significantly altered volumes and FC were negatively correlated with SCWT scores., Significance: The study revealed the role of subcortical limbic structural and functional abnormalities on cognitive impairments in PBD patients. These may have far-reaching significance for the etiology of PBD and provide neuroimaging clues for the differential diagnosis of PBD subtypes., Conclusions: Distinctive features of neural structure and function in PBD subtypes may contribute to better comprehending the potential mechanisms of PBD., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors have declared no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., (© 2024. The Author(s).)

Measures of fMRI resting-state functional connectivity (rs-FC) are an essential tool for basic and clinical investigations of fronto-limbic circuits. Understanding the relationship between rs-FC and the underlying patterns of neural activity in these circuits is therefore vital. Here we introduced inhibitory designer receptors exclusively activated by designer drugs (DREADDs) into the amygdala of two male macaques. We evaluated the causal effect of activating the DREADD receptors on rs-FC and neural activity within circuits connecting amygdala and frontal cortex. Activating the inhibitory DREADD increased rs-FC between amygdala and ventrolateral prefrontal cortex. Neurophysiological recordings revealed that the DREADD-induced increase in fMRI rs-FC was associated with increased local field potential coherency in the alpha band (6.5-14.5 Hz) between amygdala and ventrolateral prefrontal cortex. Thus, our multi-modal approach reveals the specific signature of neuronal activity that underlies rs-FC in fronto-limbic circuits., (© 2024. The Author(s).)

Background: Sex 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., Methods: We 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)., Results: Limbic 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., Conclusions: Overall, 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., (© 2024. The Author(s).)

Background: Previous 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., Methods: In 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., Results: In 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., Conclusion: Our 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., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Attention deficit hyperactivity disorder (ADHD) is a common childhood developmental disorder. In recent years, pattern recognition methods have been increasingly applied to neuroimaging studies of ADHD. However, these methods often suffer from limited accuracy and interpretability, impeding their contribution to the identification of ADHD-related biomarkers. To address these limitations, we applied the amplitude of low-frequency fluctuation (ALFF) results for the limbic system and cerebellar network as input data and conducted a binary hypothesis testing framework for ADHD biomarker detection. Our study on the ADHD-200 dataset at multiple sites resulted in an average classification accuracy of 93%, indicating strong discriminative power of the input brain regions between the ADHD and control groups. Moreover, our approach identified critical brain regions, including the thalamus, hippocampal gyrus, and cerebellum Crus 2, as biomarkers. Overall, this investigation uncovered potential ADHD biomarkers in the limbic system and cerebellar network through the use of ALFF realizing highly credible results, which can provide new insights for ADHD diagnosis and treatment.

Background: Low back pain (LBP) is a major public health issue that influences physical and emotional factors integral to the limbic system. This study aims to investigate the association between LBP and brain morphometry alterations as the duration of LBP increases (acute vs. chronic)., Methods: We used the UK Biobank data to investigate the morphological features of the limbic system in acute LBP (N = 115), chronic LBP (N = 243) and controls (N = 358), and tried to replicate our findings with an independent dataset composed of 45 acute LBP participants evaluated at different timepoints throughout 1 year from the OpenPain database., Results: We found that in comparison with chronic LBP and pain-free controls, acute LBP was associated with increased volumes of the nucleus accumbens, amygdala, hippocampus, and thalamus, and increased grey matter volumes in the hippocampus and posterior cingulate gyrus. In the replication cohort, we found non-significantly larger hippocampus and thalamus volumes in the 3-month visit (acute LBP) compared to the 1-year visit (chronic LBP), with similar effect sizes as the UK Biobank dataset., Conclusions: Our results suggest that acute LBP is associated with dramatic morphometric increases in the limbic system and mesolimbic pathway, which may reflect an active brain response and self-regulation in the early stage of LBP., Significance: Our study suggests that LBP in the acute phase is associated with the brain morphometric changes (increase) in some limbic areas, indicating that the acute phase of LBP may represent a crucial stage of self-regulation and active response to the disease's onset., (© 2023 European Pain Federation - EFIC®.)

Background: Major depressive disorder (MDD) and anxiety disorders (ANX) are psychiatric disorders with high mutual comorbidity rates that might indicate some shared neurobiological pathways between them, but they retain diverse phenotypes that characterize themselves specifically. However, no consistent evidence exists for common and disorder-specific gray matter volume (GMV) alternations between them., Methods: A systematic review and meta-analysis on voxel-based morphometry studies of patients with MDD and ANX were performed. The effect of comorbidity was explicitly controlled during disorder-specific analysis and particularly investigated in patient with comorbidity., Results: A total of 45 studies with 54 datasets comprising 2196 patients and 2055 healthy participants met the inclusion criteria. Deficits in the orbitofrontal cortex, striatum, and limbic regions were found in MDD and ANX. The disorder-specific analyses showed decreased GMV in the bilateral anterior cingulate cortex, right striatum, hippocampus, and cerebellum in MDD, while decreased GMV in the left striatum, amygdala, insula, and increased cerebellar volume in ANX. A totally different GMV alternation pattern was shown involving bilateral temporal and parietal gyri and left fusiform gyrus in patients with comorbidity., Limitations: Owing to the design of included studies, only partial patients in the comorbid group had a secondary comorbidity diagnosis., Conclusion: Patients with MDD and ANX shared a structural disruption in the orbitofrontal-limbic-striatal system. The disorder-specific effects manifested their greatest severity in distinct lateralization and directionality of these changes that differentiate MDD from ANX. The comorbid group showed a totally different GMV alternation pattern, possibly suggesting another illness subtype that requires further investigation., Competing Interests: Declaration of competing interest Dr. Wenjing Zhang consults to VeraSci. The remaining authors have no competing interests or financial support to disclose., (Copyright © 2024. Published by Elsevier B.V.)

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

Background: Widespread functional alterations have been implicated in patients with generalized anxiety disorder (GAD). However, most studies have primarily focused on static brain network features in patients with GAD. The current research focused on exploring the dynamics within functional brain networks among individuals diagnosed with GAD., Methods: Seventy-five participants were divided into patients with GAD and healthy controls (HCs), and resting-state functional magnetic resonance imaging data were collected. The severity of symptoms was measured using the Hamilton Anxiety Scale and the Patient Health Questionnaire. Co-activation pattern (CAP) analysis, centered on the bed nucleus of the stria terminalis, was applied to explore network dynamics. The capability of these dynamic characteristics to distinguish between patients with GAD and HCs was evaluated using a support vector machine., Results: Patients with GAD exhibited disruptions in the limbic-prefrontal and limbic-default-mode network circuits. Particularly noteworthy was the marked reduction in dynamic indicators such as occurrence, EntriesFromBaseline, ExitsToBaseline, in-degree, out-degree, and resilience. Moreover, these decreased dynamic features effectively distinguished the GAD group from the HC in this study., Conclusions: The current findings revealed the underlying brain networks associated with compromised emotion regulation in individuals with GAD. The dynamic reduction in connectivity between the limbic-default mode network and limbic-prefrontal networks could potentially act as a biomarker and therapeutic target for GAD in the future., (Copyright © 2024. Published by Elsevier Inc.)

In progressive supranuclear palsy (PSP), subcortical tau and cortical perfusion can be assessed using the tracer [18F]PI-2620. We investigated if subcortical tau (globus pallidus internus, dentate nucleus) and frontal/limbic perfusion correlate in a cohort of 32 PSP patients. Tau in subcortical regions showed significant negative correlation with perfusion in limbic cortex. Perfusion in frontal regions was negatively associated with tau in both subcortical regions, but the significance threshold was only passed for the dentate nucleus. A reason could be a diaschisis-like phenomenon; that is, subcortical tau could lead to reduced connectivity to frontal regions and, thereby, to decreased perfusion.

Objective: Deep brain stimulation (DBS) is an effective treatment for medically refractory Tourette syndrome (TS). Several effective targets have been reported, but there is still controversy about the networks involved in the efficacy of DBS for TS. Here, the authors aimed to identify the basal ganglia-thalamo-cortical networks associated with tic and obsessive-compulsive behavior (OCB) improvement and the network link between the two main targets for TS., Methods: A retrospective analysis of 21 patients treated with pallidal and thalamic DBS was performed. Tics and OCB scores were recorded before and after DBS. The authors localized the electrodes in standard MNI (Montreal Neurological Institute) space and calculated the volume of tissue activated with the settings at the last follow-up to obtain areas of maximal improvement ("sweet spots") among all patients for the pallidal and thalamic targets. Tractography was used to show the white matter pathways associated with maximal tic and OCB improvement., Results: Ten patients treated with pallidal DBS and 11 patients treated with thalamic DBS were included. Responder rates were 80% in the pallidal and 64% in the thalamic target groups. Sweet spots for tics and OCB clustered in several areas across the basal ganglia and thalamus delineated two main networks. Tic reduction in the pallidal target mapped to a limbic pallidothalamic network and in the thalamic target to the premotor thalamocortical network. Putting these two networks together will form the main output of the so-called limbic-motor interface network. However, OCB reduction mapped a dorsomedial prefrontal cortex/dorsal anterior cingulate (dmPFC/dACC) network., Conclusions: The authors demonstrated the involvement of the limbic-motor interface network during effective DBS for tics in patients with TS. OCB redution was associated with the additional involvement of dmPFC/dACC connections passing dorsal to the head of the globus pallidus pars externa on its way to the thalamus and midbrain.

Aims: This study aimed to identify gray/white matter volume (GMV/WMV) alterations in Internet Gaming Disorder (IGD), with a special focus on the subregions of the mesocorticolimbic dopaminergic system and their clinical association., Results: Compared with healthy controls, IGDs showed bigger GMV in the bilateral caudate and the left nucleus accumbens (NAc), and bigger WMV in the inferior parietal lobule. The comparison of regions of interest (ROI) confirmed increased GMV in the bilateral caudate (including the dorsal anterior, body, and tail) and the left core of NAc in IGD, but no significant WMV alterations in the mesocorticolimbic dopaminergic system. GMVs in the left lateral orbital gyrus of orbitofrontal cortex (OFC) were associated with craving for games, while GMVs in the left anterior insula, right NAc, right caudate, and right OFC were associated with self-control in IGD., Conclusions: IGD was accompanied by changed GMV, but not WMV, in the mesocorticolimbic dopaminergic system. GMV in the mesocorticolimbic dopaminergic system may contribute to impaired self-control and craving in IGD., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Persons with Multiple Sclerosis (PwMS) have a higher rate of anxiety and depression than the general population. Depression has been associated with clinical relapses; temporal lesions were shown to predict depression severity. Anxiety is considerably understudied. The role of MS lesions in the limbic system is also understudied, partly due to difficulties identifying limbic lesions on standard 1.5 and 3 Tesla MRI., Methods: This is a retrospective study of 23 PwMS who underwent 7T MRI on the same day as completing the Hospital Anxiety and Depression Scale (HADS). MRI was performed on a Siemens 7T MRI Plus and an 8-channel transmit coil with 32 receiver channels operating in pTx mode. MP2RAGE and DIR-SPACE sequences were analyzed to determine the number of lesions within the limbic system., Results: The median number of lesions in the limbic system was 2.0 (range 0-7). When comparing the presence or absence of lesions in the limbic system, there was a significant relationship with anxiety (X 2 (1, N = 23)=4.44, p = 0.035), but not for depression., Conclusion: Although only a small sample size, this study provides preliminary evidence that lesions in the limbic system are associated with the presence of anxiety in PwMS. This relationship warrants further investigation., Competing Interests: Declaration of Competing Interest Alexandra Hillyer received one time stipend from American Academy of Neurology for this research. Ravi Menon received research support from Siemens Healthineers. Dr. Sarah A. Morrow, in the past 3 years, has served on advisory boards for Biogen Idec, Celgene/BMS, EMD Serono, Novartis, Roche, Sanofi Genzyme, Teva Neurosciences; Received Investigator Initiated Grant Funds from Biogen Idec, Novartis, Roche, Sanofi Genzyme and acted as site PI for multi-center trials funded by AbbVie, Novartis, Genzyme, Roche, Sanofi Genzyme. All other authors have no disclosures to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Microscopic neuroanatomy of limbic system and basal forebrain on MRI is complex and is a terra incognita for many radiologists, clinicians, and neuroscientists. Interestingly, most of the important structures/at least anatomical regions containing these structures demonstrable on cadaveric and surgical dissections can be identified on clinical MRI, with 3T being much better than 1.5T. This article teaches the practical MRI identification of these structures which will greatly help in evaluating complex ailments like temporal lobe epilepsy, Alzheimer dementia, and other neuropsychiatric disorders. This knowledge will also aid in accurate reporting of tumor spread along the white matter fasciculi in the temporal stem/basal forebrain region. Limbic system includes the mesial temporal structures and their connections, piriform cortex including "area tempestas," and the septal area comprising of subcallosal area and paraterminal gyrus. Basal forebrain includes structures like substantia innominata with basal nucleus of Meynert, diagonal gyrus/diagonal band of Broca, and nucleus accumbens lying in between the anterior perforated substance inferiorly and the anterior commissure superiorly., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Psychosocial stressors characterized by social threat, such as interpersonal loss and social rejection, are associated with depression in adolescents. Few studies, however, have examined whether social threat affects fronto-cingulate-limbic systems implicated in adolescent depression., Methods: We assessed lifetime stressor severity across several domains using the Stress and Adversity Inventory (STRAIN) in 57 depressed adolescents (16.15 ± 1.32 years, 34 females), and examined whether the severity of social threat and non-social threat stressors was associated with gray matter volumes (GMVs) in the anterior cingulate cortex (ACC), amygdala, hippocampus, and nucleus accumbens (NAcc). We also examined how lifetime social threat severity and GMVs in these regions related to depressive symptoms at baseline and over 9 months., Results: General stressor severity was related to greater depression severity at baseline and over 9 months. Moreover, greater severity of social threat (but not non-social threat) stressors was associated with smaller bilateral amygdala and NAcc GMVs, and smaller bilateral surface areas of caudal and rostral ACC (all p FDR ⩽ 0.048). However, neither social threat nor non-social threat stressor severity was related to hippocampal GMVs (all p FDR ⩾ 0.318). All fronto-cingulate-limbic structures that were associated with the severity of social threat were negatively associated with greater depression severity over 9 months (all p FDR ⩽ 0.014). Post-hoc analyses suggested that gray matter morphometry of bilateral amygdala, NAcc, and rostral and caudal ACC mediated the association between social threat and depression severity in adolescents over 9 months (all p FDR < 0.048)., Conclusions: Social threat specifically affects fronto-cingulate-limbic pathways that contribute to the maintenance of depression in adolescents.

Background: Imaging studies found that patients with major depressive disorder (MDD) showed abnormal functional connectivity in the fronto-limbic circuit, including the prefrontal cortex (PFC), anterior cingulate cortex (ACC), and limbic system (amygdala). This study used electroencephalography (EEG) coherence as an indicator of functional connectivity in the fronto-limbic circuit and examined the group differences between the MDD group and healthy controls (HC group), and the associations between EEG coherence and depressive symptoms., Methods: 125 and 132 participants in the MDD and HC groups have measured the symptoms of depression and anxiety, and delta, theta, alpha, and beta1-beta4 EEG coherences in the fronto-limbic circuit and examined the differences between the two groups, and the associations between the EEG coherence and depressive symptoms were examined., Results: Lower theta, alpha, beta1, beta3, and beta4 coherence in the fronto-limbic circuit and higher beta2 coherence between the PFC and limbic system in the MDD group than in the HC group. Negative correlations between delta, theta, beta1, beta3, and beta4 coherence and total depression, cognitive depression, and somatic depression; positive correlations between beta2 coherences in the PFC and limbic system, and total depression and cognitive depression scores in the MDD group., Limitations: Whether low EEG coherence in the fronto-limbic circuit is applicable to other subtypes of MDD requires further study., Conclusions: Low EEG coherences in the fronto-limbic circuit were related to depressive symptoms, and increased functional connectivity in the fronto-limbic circuit can be applied by neurofeedback in future studies., Competing Interests: Conflict of interest All authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The Papez circuit, first proposed by James Papez in 1937, is a circuit believed to control memory and emotions, composed of the cingulate cortex, entorhinal cortex, parahippocampal gyrus, hippocampus, hypothalamus, and thalamus. Pursuant to James Papez, Paul Yakovlev and Paul MacLean incorporated the prefrontal/orbitofrontal cortex, septum, amygdalae, and anterior temporal lobes into the limbic system. Over the past few years, diffusion-weighted tractography techniques revealed additional limbic fiber connectivity, which incorporates multiple circuits to the already known complex limbic network. In the current review, we aimed to comprehensively summarize the anatomy of the limbic system and elaborate on the anatomical connectivity of the limbic circuits based on the published literature as an update to the original Papez circuit., (© 2023. The Author(s).)

Objective: Pre-eclampsia is a vascular complication of pregnancy, associated with a long-term risk of cerebrovascular and mental disorders. We explored whether formerly pre-eclamptic women exhibit differences in functional brain organization, especially in regions that may explain the commonly reported emotional symptoms and cognitive complaints even years after the pregnancy., Methods: Formerly pre-eclamptic women and control women with a history of normotensive pregnancy underwent structural and functional 7-Tesla magnetic resonance imaging scans. Using graph theoretical analysis, the efficiency and clustering coefficient of the functional brain network were investigated. The study included local analysis focusing on particular brain structures, such as the limbic system and the prefrontal cortex, and global analysis of the whole cerebrum. Univariable and multivariable linear regression was used to investigate the relationship between brain network-related graph measures and the group (formerly pre-eclamptic or control)., Results: A total of 17 control parous women and 55 women with a history of pre-eclampsia were recruited. The time intervals between the index pregnancy and recruitment were 8.0 and 5.6 years for the two groups, respectively. Compared with control women, formerly pre-eclamptic women had higher local efficiency in the prefrontal cortex (P = 0.048) and anterior cingulate cortex (P = 0.03) but lower local efficiency and local clustering coefficient in the amygdala (P = 0.004 and P = 0.02, respectively) and parahippocampal cortex (P = 0.007 and P = 0.008, respectively). No differences were found in the global functional brain organization., Conclusions: Compared to controls with a history of normotensive pregnancy, formerly pre-eclamptic women displayed a different local functional brain organization. These differences in functional connectivity, especially in the limbic regions and the prefrontal cortex, are in line with the psychological and cognitive complaints reported commonly by women with a history of pre-eclampsia. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Dynamic functional connectivity (dFC) has been increasingly used to characterize the brain transient temporal functional patterns and their alterations in diseased brains. Meanwhile, naturalistic neuroimaging paradigms have been an emerging approach for cognitive neuroscience with high ecological validity. However, the test-retest reliability of dFC in naturalistic paradigm neuroimaging is largely unknown. To address this issue, we examined the test-retest reliability of dFC in functional magnetic resonance imaging (fMRI) under natural viewing condition. The intraclass correlation coefficients (ICC) of four dFC statistics including standard deviation (Std), coefficient of variation (COV), amplitude of low frequency fluctuation (ALFF), and excursion (Excursion) were used to measure the test-retest reliability. The test-retest reliability of dFC in naturalistic viewing condition was then compared with that under resting state. Our experimental results showed that: (a) Global test-retest reliability of dFC was much lower than that of static functional connectivity (sFC) in both resting-state and naturalistic viewing conditions; (b) Both global and local (including visual, limbic and default mode networks) test-retest reliability of dFC could be significantly improved in naturalistic viewing condition compared to that in resting state; (c) There existed strong negative correlation between sFC and dFC, weak negative correlation between dFC and dFC-ICC (i.e., ICC of dFC), as well as weak positive correlation between dFC-ICC and sFC-ICC (i.e., ICC of sFC). The present study provides novel evidence for the promotion of naturalistic paradigm fMRI in functional brain network studies., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: An increase in body weight is observed in the majority of patients with Parkinson's disease (PD) who undergo deep brain stimulation (DBS) of the subthalamic nucleus (STN) although the mechanisms are unclear., Objectives: To identify the stimulation-dependent effects on reward-associated and attention-associated neural networks and to determine whether these alterations in functional connectivity are associated with the local impact of DBS on different STN parcellations., Methods: We acquired functional task-related MRI data from 21 patients with PD during active and inactive STN DBS and 19 controls while performing a food viewing paradigm. Electrode placement in the STN was localised using a state-of-the-art approach. Based on the 3D model, the local impact of STN DBS was estimated., Results: STN DBS resulted in a mean improvement of motor function of 22.6%±15.5% (on medication) and an increase of body weight of ~4 kg within 2 years of stimulation. DBS of the limbic proportion of the STN was associated with body weight gain and an increased functional connectivity within the salience network and at the same time with a decreased activity within the reward-related network in the context of sweet food images., Conclusions: Our findings indicate increased selective attention for high-caloric foods and a sweet food seeking-like behaviour after DBS particularly when the limbic proportion of the STN was stimulated., Competing Interests: Competing interests: JKK is a consultant to Medtronic and Boston Scientific., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Psychopathic traits have been suggested to increase the risk of violations of socio-moral norms. Previous studies revealed that abnormal neural signatures are associated with elevated psychopathic traits; however, whether the intrinsic network architecture can predict psychopathic traits at the individual level remains unclear., Methods: The present study utilized connectome-based predictive modeling (CPM) to investigate whether whole-brain resting-state functional connectivity (RSFC) can predict psychopathic traits in the general population. Resting-state fMRI data were collected from 84 college students with varying psychopathic traits measured by the Levenson Self-Report Psychopathy Scale (LSRP)., Results: Functional connections that were negatively correlated with psychopathic traits predicted individual differences in total LSRP and secondary psychopathy score but not primary score. Particularly, nodes with the most connections in the predictive connectome anchored in the prefrontal cortex (e.g., anterior prefrontal cortex and orbitofrontal cortex) and limbic system (e.g., anterior cingulate cortex and insula). In addition, the connections between the occipital network (OCCN) and cingulo-opercular network (CON) served as a significant predictive connectome for total LSRP and secondary psychopathy score., Conclusion: CPM constituted by whole-brain RSFC significantly predicted psychopathic traits individually in the general population. The brain areas including the prefrontal cortex and limbic system and large-scale networks including the CON and OCCN play special roles in the predictive model-possibly reflecting atypical cognitive control and affective processing for individuals with elevated psychopathic traits. These findings may facilitate detection and potential intervention of individuals with maladaptive psychopathic tendency., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Anxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of the neurobiology of anxiety disorders, but research has been limited by small sample sizes and low statistical power, as well as heterogenous imaging methodology. The ENIGMA-Anxiety Working Group has brought together researchers from around the world, in a harmonized and coordinated effort to address these challenges and generate more robust and reproducible findings. This paper elaborates on the concepts and methods informing the work of the working group to date, and describes the initial approach of the four subgroups studying generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia. At present, the ENIGMA-Anxiety database contains information about more than 100 unique samples, from 16 countries and 59 institutes. Future directions include examining additional imaging modalities, integrating imaging and genetic data, and collaborating with other ENIGMA working groups. The ENIGMA consortium creates synergy at the intersection of global mental health and clinical neuroscience, and the ENIGMA-Anxiety Working Group extends the promise of this approach to neuroimaging research on anxiety disorders., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

A tool was developed to automatically segment several subcortical limbic structures (nucleus accumbens, basal forebrain, septal nuclei, hypothalamus without mammillary bodies, the mammillary bodies, and fornix) using only a T1-weighted MRI as input. This tool fills an unmet need as there are few, if any, publicly available tools to segment these clinically relevant structures. A U-Net with spatial, intensity, contrast, and noise augmentation was trained using 39 manually labeled MRI data sets. In general, the Dice scores, true positive rates, false discovery rates, and manual-automatic volume correlation were very good relative to comparable tools for other structures. A diverse data set of 698 subjects were segmented using the tool; evaluation of the resulting labelings showed that the tool failed in less than 1% of cases. Test-retest reliability of the tool was excellent. The automatically segmented volume of all structures except mammillary bodies showed effectiveness at detecting either clinical AD effects, age effects, or both. This tool will be publicly released with FreeSurfer (surfer.nmr.mgh.harvard.edu/fswiki/ScLimbic). Together with the other cortical and subcortical limbic segmentations, this tool will allow FreeSurfer to provide a comprehensive view of the limbic system in an automated way., (Copyright © 2021. Published by Elsevier Inc.)

Background: The prefrontal-limbic-subcortical network has been suggested as an important circuitry in the pathophysiology underlying bipolar disorder during depressive episodes (BDD). However, the relationships between disrupted prefrontal-limbic-subcortical connection and the emotional endophenotypes in BDD patients remain largely unclear., Methods: Forty-three BDD patients and 63 matched healthy controls (HCs) underwent the resting-state functional magnetic resonance imaging scan. The altered clusters were first identified by using a spatial pairwise clustering method and then were extracted as regions of interest to calculate the functional connectivity (FC). Group comparisons were conducted to identify the abnormal FCs. Classification analysis was employed to examine whether the altered FCs could distinguish BDD from HCs. The relationships between FC alterations and the emotional endophenotypes as measured by the Affective Neuroscience Personality Scales (ANPS) were further detected in BDD., Results: Compared with HCs, BDD patients showed abnormal FCs in the prefrontal-limbic-striatum circuit. Importantly, the altered FCs yielded 84.91% accuracy (p< 1/5000) with 93.65% sensitivity and 72.09% specificity in differentiating between BDD and HCs. Moreover, the decreased FCs in the prefrontal-striatum and prefrontal-limbic systems were positively correlated with negative emotional endophenotypes of Sadness and Fear scores., Conclusions: The findings demonstrated that prefrontal-limbic-striatum disconnection may be identified as a potential effective biomarker for BDD, which could help further explain the neurobiological mechanisms underlying BDD., (Copyright © 2021. Published by Elsevier B.V.)

Background: Functional constipation (FCon) is a common functional gastrointestinal disorder (FGID) with a high prevalence in clinical practice. Previous studies have identified that FCon is associated with functional and structural alterations in the primary brain regions involved in emotional arousal processing, sensory processing, somatic/motor-control, and self-referential processing. However, whether FCon is associated with abnormal structural connectivity (SC) among these brain regions remains unclear., Methods: We selected the brain regions with functional and structural abnormalities as seed regions and employed diffusion tensor imaging (DTI) with probabilistic tractography to investigate SC changes in 29 patients with FCon and 31 healthy controls (HC)., Key Results: Results showed lower fractional anisotropy (FA) in the fibers connecting the thalamus, a region involved in sensory processing, with the amygdala (AMY), hippocampal gyrus (HIPP), precentral (PreCen) and postcentral gyrus (PostCen), supplementary motor area (SMA) and precuneus in patients with FCon compared with HC. FCon had higher mean diffusivity (MD) and radial diffusivity (RD) in the thalamus connected to the AMY and HIPP. In addition, FCon had significantly increased RD of the thalamus-SMA tract. Sensation of incomplete evacuation was negatively correlated with FA of the thalamus-PostCen and thalamus-HIPP tracts, and there was a negative correlation between difficulty of defecation and FA of the thalamus-SMA tract., Conclusions and Inferences: These findings reflected that FCon is associated with alterations in SC between the thalamus and limbic/parietal cortex, highlighting the integrative role of the thalamus in brain structural network., (© 2020 John Wiley & Sons Ltd.)

Characterizing the properties of brain networks across mood states seen in bipolar disorder (BP) can provide a deeper insight into the mechanisms involved in this type of affective disorder. In this study, graph theoretical methods were used to examine global, modular and nodal brain network topology in the resting state using functional magnetic resonance imaging data acquired from 95 participants, including those with bipolar depression (BPD; n = 30) and bipolar mania (BPM; n = 39) and healthy control (HC) subjects (n = 26). The threshold value of the individual subjects' connectivity matrix varied from 0.15 to 0.30 with steps of 0.01. We found that: (1) at the global level, BP patients showed a significantly increased global efficiency and synchronization and a decreased path length; (2) at the nodal level, BP patients showed impaired nodal parameters, predominantly within the frontoparietal and limbic sub-network; (3) at the module level, BP patients were characterized by denser FCs (edges) between Module III (the front-parietal system) and Module V (limbic/paralimbic systems); (4) at the nodal level, the BPD and BPM groups showed state-specific differences in the orbital part of the left superior-frontal gyrus, right putamen, right parahippocampal gyrus and left fusiform gyrus. These results revealed abnormalities in topological organization in the whole brain, especially in the frontoparietal-limbic circuit in both BPD and BPM. These deficits may reflect the pathophysiological processes occurring in BP. In addition, state-specific regional nodal alterations in BP could potentially provide biomarkers of conversion across different mood states., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: Altered functional connectivity (FC) is a common finding in resting-state functional magnetic resonance imaging (rs-fMRI) studies of people with psychosis, yet how FC disturbances evolve in the early stages of illness, and how antipsychotic treatment influences these disturbances, remains unknown., Objective: To investigate longitudinal FC changes in antipsychotic-naive and antipsychotic-treated patients with first-episode psychosis (FEP)., Design, Setting, and Participants: This secondary analysis of a triple-blind, randomized clinical trial was conducted over a 5-year recruitment period between April 2008 and December 2016 with 59 antipsychotic-naive patients with FEP receiving either a second-generation antipsychotic or a placebo pill over a treatment period of 6 months. Participants were required to have low suicidality and aggression, to have a duration of untreated psychosis of less than 6 months, and to be living in stable accommodations with social support. Both FEP groups received intensive psychosocial therapy. A healthy control group was also recruited. Participants completed rs-fMRI scans at baseline, 3 months, and 12 months. Data were analyzed from May 2019 to August 2020., Interventions: Resting-state functional MRI was used to probe brain FC. Patients received either a second-generation antipsychotic or a matched placebo tablet. Both patient groups received a manualized psychosocial intervention., Main Outcomes and Measures: The primary outcomes of this analysis were to investigate (1) FC differences between patients and controls at baseline; (2) FC changes in medicated and unmedicated patients between baseline and 3 months; and (3) associations between longitudinal FC changes and clinical outcomes. An additional aim was to investigate long-term FC changes at 12 months after baseline. These outcomes were not preregistered., Results: Data were analyzed for 59 patients (antipsychotic medication plus psychosocial treatment: 28 [47.5%]; mean [SD] age, 19.5 [3.0] years; 15 men [53.6%]; placebo plus psychosocial treatment: 31 [52.5%]; mean [SD] age, 18.8 [2.7]; 16 men [51.6%]) and 27 control individuals (mean [SD] age, 21.9 [1.9] years). At baseline, patients showed widespread functional dysconnectivity compared with controls, with reductions predominantly affecting interactions between the default mode network, limbic systems, and the rest of the brain. From baseline to 3 months, patients receiving placebo showed increased FC principally within the same systems; some of these changes correlated with improved clinical outcomes (canonical correlation analysis R = 0.901; familywise error-corrected P = .005). Antipsychotic exposure was associated with increased FC primarily between the thalamus and the rest of the brain., Conclusions and Relevance: In this secondary analysis of a clinical trial, antipsychotic-naive patients with FEP showed widespread functional dysconnectivity at baseline, followed by an early normalization of default mode network and cortical limbic dysfunction in patients receiving placebo and psychosocial intervention. Antipsychotic exposure was associated with FC changes concentrated on thalamocortical networks., Trial Registration: ACTRN12607000608460.

We investigate the characteristics of injury of four portions of the Papez circuit in patients with diffuse axonal injury (DAI), using diffusion tensor tractography (DTT). Thirty-four consecutive patients with DAI and 30 normal control subjects were recruited. Four portions of the Papez circuit were reconstructed: the fornix, cingulum, thalamocingulate tract, and mammillothalamic tract. Analysis of DTT parameters [fractional anisotropy (FA) and tract volume (TV)] and configuration (narrowing, discontinuation, or non-reconstruction) was performed for each portion of the Papez circuit. The Memory Assessment Scale (MAS) was used for the estimation of cognitive function. In the group analysis, decreased fractional anisotropy and tract volume of the entire Papez circuit were observed in the patient group compared with the control group (p < 0.05). In the individual analysis, all four portions of the Papez circuit were injured in terms of DTT parameters or configuration. Positive correlation was observed between TV of the fornix and short-term memory on MAS r = 0.618, p < 0.05), and between FA of the fornix and total memory on MAS (r = 0.613, p < 0.05). We found that all four portions of the Papez circuit in the patient group were vulnerable to DAI, and among four portions of the Papez circuit, the fornix was the most vulnerable portion in terms of injury incidence and severity., (© 2020. Belgian Neurological Society.)

Objective: Gliomas frequently involve the insula both primarily and secondarily by invasion. Despite the high connectivity of the human insula, gliomas do not spread randomly to or from the insula but follow stereotypical anatomical involvement patterns. In the majority of cases, these patterns correspond to the intrinsic connectivity of the limbic system, except for tumors with aggressive biology. On the basis of these observations, the authors hypothesized that these different involvement patterns may be correlated with distinct outcomes and analyzed these correlations in an institutional cohort., Methods: Fifty-nine patients who had undergone surgery for insular diffuse gliomas and had complete demographic, pre- and postoperative imaging, pathology, molecular genetics, and clinical follow-up data were included in the analysis (median age 37 years, range 21-71 years, M/F ratio 1.68). Patients with gliomatosis and those with only minor involvement of the insula were excluded. The presence of T2-hyperintense tumor infiltration was evaluated in 12 anatomical structures. Hierarchical biclustering was used to identify co-involved structures, and the findings were correlated with established functional anatomy knowledge. Overall survival was evaluated using Kaplan-Meier and Cox proportional hazards regression analysis (17 parameters)., Results: The tumors involved the anterior insula (98.3%), posterior insula (67.8%), temporal operculum (47.5%), amygdala (42.4%), frontal operculum (40.7%), temporal pole (39%), parolfactory area (35.6%), hypothalamus (23.7%), hippocampus (16.9%), thalamus (6.8%), striatum (5.1%), and cingulate gyrus (3.4%). A mean 4.2 ± 2.6 structures were involved. On the basis of hierarchical biclustering, 7 involvement patterns were identified and correlated with cortical functional anatomy (pure insular [11.9%], olfactocentric [15.3%], olfactoopercular [33.9%], operculoinsular [15.3%], striatoinsular [3.4%], translimbic [11.9%], and multifocal [8.5%] patterns). Cox regression identified hippocampal involvement (p = 0.006) and postoperative tumor volume (p = 0.027) as significant negative independent prognosticators of overall survival and extent of resection (p = 0.015) as a significant positive independent prognosticator., Conclusions: The study findings indicate that insular gliomas primarily involve the olfactocentric limbic girdle and that involvement in the hippocampocentric limbic girdle is associated with a worse prognosis.

We analyzed interrelations between the cerebral blood flow, cardiac output, and condition of the brain substance in 530 patients with ischemic stroke. Dependencies between the linear blood flow velocities in all arteries supplying the brain, as well as between the total volume blood flow through the internal carotid arteries and left ventricular stroke volume were revealed. The severity of atrophy was maximum in the parietal lobes (median 1.5 (1.0; 2.0)) and minimum in the occipital lobes (median 0.5 (0; 1.0)). Temporal lobes cortical atrophy significantly correlated with changes in the limbic system and in the periventricular and deep white matter; a significant weak inverse correlation of this parameter with blood flow in the middle cerebral artery was also found. Changes in the periventricular white matter (but not in deep white matter) demonstrated a significant inverse correlation with blood flow in the middle and anterior cerebral arteries., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Restless legs syndrome (RLS) in pregnancy is a common disorder with a multifactorial etiology. A neurological and obstetrical cohort of 308 postpartum women was screened for RLS within 1 to 6 days of childbirth and 12 weeks postpartum. Of the 308 young mothers, 57 (prevalence rate 19%) were identified as having been affected by RLS symptoms in the recently completed pregnancy. Structural and functional MRI was obtained from 25 of these 57 participants. A multivariate two-window algorithm was employed to systematically chart the relationship between brain structures and phenotypical predictors of RLS. A decreased volume of the parietal, orbitofrontal and frontal areas shortly after delivery was found to be linked to persistent RLS symptoms up to 12 weeks postpartum, the symptoms' severity and intensity in the most recent pregnancy, and a history of RLS in previous pregnancies. The same negative relationship was observed between brain volume and not being married, not receiving any iron supplement and higher numbers of stressful life events. High cortisol levels, being married and receiving iron supplements, on the other hand, were found to be associated with increased volumes in the bilateral striatum. Investigating RLS symptoms in pregnancy within a brain-phenotype framework may help shed light on the heterogeneity of the condition.

The neuroimaging is an important tool for understanding the biomarkers and predicting treatment responses in major depressive disorder (MDD). The potential biomarkers and prediction of treatment response in MDD will be addressed in the review article. The brain regions of cognitive control and emotion regulation, such as the frontal and limbic regions, might represent the potential targets for MDD biomarkers. The potential targets of frontal lobes might include anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). For the limbic system, hippocampus and amygdala might be the potentially promising targets for MDD. The potential targets of fronto-limbic regions have been found in the studies of several major neuroimaging modalities, such as the magnetic resonance imaging, near-infrared spectroscopy, electroencephalography, positron emission tomography, and single-photon emission computed tomography. Additional regions, such as brainstem and midbrain, might also play a part in the MDD biomarkers. For the prediction of treatment response, the gray matter volumes, white matter tracts, functional representations and receptor bindings of ACC, DLPFC, OFC, amygdala, and hippocampus might play a role in the prediction of antidepressant responses in MDD. For the response prediction of psychotherapies, the fronto-limbic, reward regions, and insula will be the potential targets. For the repetitive transcranial magnetic stimulation, the DLPFC, ACC, limbic, and visuospatial regions might represent the predictive targets for treatment. The neuroimaging targets of MDD might be focused in the fronto-limbic regions. However, the neuroimaging targets for the prediction of treatment responses might be inconclusive and beyond the fronto-limbic regions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe. ClinicalTrials.gov : Treatment Resistant Depression (Pilot), NCT01179009.

Generalized anxiety disorder (GAD) is marked by uncontrollable, persistent worry and exaggerated response to uncertainty. Here, we review and summarize the findings from the GAD literature that employs functional neuroimaging methods. In particular, the present review focuses on task-based blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies. We find that select brain regions often regarded as a part of a corticolimbic circuit (e.g., amygdala, anterior cingulate cortex, prefrontal cortex) are consistently targeted for a priori hypothesis-driven analyses, which, in turn, shows varying degrees of abnormal BOLD responsivity in GAD. Data-driven whole-brain analyses show the insula and the hippocampus, among other regions, to be affected by GAD, depending on the task used in each individual study. Overall, while the heterogeneity of the tasks and sample size limits the generalizability of the findings thus far, some promising convergence can be observed in the form of the altered BOLD responsivity of the corticolimbic circuitry in GAD.

Objective: To determine whether the nucleus basalis of Meynert (NBM) may be a key network structure of altered functional connectivity in temporal lobe epilepsy (TLE), we examined fMRI with network-based analyses., Methods: We acquired resting-state fMRI in 40 adults with TLE and 40 matched healthy control participants. We calculated functional connectivity of NBM and used multiple complementary network-based analyses to explore the importance of NBM in TLE networks without biasing our results by our approach. We compared patients to controls and examined associations of network properties with disease metrics and neurocognitive testing., Results: We observed marked decreases in connectivity between NBM and the rest of the brain in patients with TLE (0.91 ± 0.88, mean ± SD) vs controls (1.96 ± 1.13, p < 0.001, t test). Larger decreases in connectivity between NBM and fronto-parietal-insular regions were associated with higher frequency of consciousness-impairing seizures ( r = -0.41, p = 0.008, Pearson). A core network of altered nodes in TLE included NBM ipsilateral to the epileptogenic side and bilateral limbic structures. Furthermore, normal community affiliation of ipsilateral NBM was lost in patients, and this structure displayed the most altered clustering coefficient of any node examined (3.46 ± 1.17 in controls vs 2.23 ± 0.93 in patients). Abnormal connectivity between NBM and subcortical arousal community was associated with modest neurocognitive deficits. Finally, a logistic regression model incorporating connectivity properties of ipsilateral NBM successfully distinguished patients from control datasets with moderately high accuracy (78%)., Conclusions: These results suggest that while NBM is rarely studied in epilepsy, it may be one of the most perturbed network nodes in TLE, contributing to widespread neural effects in this disabling disorder., (© 2021 American Academy of Neurology.)