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Purpose: Healthy diets are believed to be associated with a reduced risk of experiencing common mental disorders (CMDs) and related symptomatology (such as ruminative thinking), and with healthier brain chemistry and structure, especially in the frontal regions implicated in CMDs, cognitive control, and food choice. Nevertheless, there is very limited research on the relationship between diet health/quality and brain function. In this study we assessed the associations between adherence to the Mediterranean diet and resting state functional connectivity (rs-FC) of the prefrontal cortex (PFC) with the whole brain and whether this connectivity would be associated with ruminative thinking as a transdiagnostic factor for CMDs., Methods: Thirty-seven adults (Mean Age = 25.57, SD = 7.18) completed the Mediterranean Diet Adherence Screener (MEDAS) and were classified into high- and low-quality diet groups and completed the Ruminative Response Scale. All participants underwent resting-state functional MRI (fMRI) to determine whole-brain rs-FC of the medial prefrontal cortex (mPFC)., Results: Participants in the high MEDAS group (vs. low MEDAS group) exhibited significantly greater rs-FC of the mPFC seed with the thalamus, caudate and putamen. Additionally, the strength of rs-FC of the mPFC seed with these regions was positively associated with the MEDAS scores across groups in both crude and adjusted models. There were no significant associations between the strength of rs-FC of the mPFC seed with the cluster of voxels with the thalamus, caudate, and putamen and ruminative thinking., Discussion: This work shows that healthy dietary patterns are associated with rs-FC in the frontal-subcortical circuitry in healthy volunteers. Considering the implications of the dysregulation of this circuity, adhering to healthy dietary patterns may offer a promising alternative/complementary method to improve CMDs, cognitive control, and food choices., Competing Interests: Declarations. Ethics approval: The research protocol was approved by the Ethical committee at the University of Roehampton (Reference: PSYC 22/ 444) on 30/01/2023. The study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All participants provided informed consent. Conflict of interest: PH, AC, and PA have received research funding, consultancy, travel support, and speaking honoraria from various industrial companies. MHS is employed by FrieslandCampina, Amersfoort, the Netherlands. Other authors declare that they have no conflicts of interest. Funding for this study was provided by FrieslandCampina whom had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication (Ref: 3129AQ00)., (© 2024. The Author(s).)

Rationale and Objectives: The mechanism of comorbidity between alcohol dependence and depressive disorders are not well understood. This study investigated differences in the brain function of alcohol-dependent patients with and without depression by performing functional connectivity analysis using resting-state functional magnetic resonance imaging., Materials and Methods: A total of 29 alcohol-dependent patients with depression, 31 alcohol-dependent patients without depression and 31 healthy control subjects were included in this study. The resting-state functional connectivity between the amygdala and the whole brain was compared among the three groups. Additionally, we examined the correlation between functional connectivity values in significantly different brain regions and levels of alcohol dependence and depression., Results: The resting-state functional connectivity between the left amygdala and the right caudate nucleus was decreased in alcohol-dependent patients. Additionally, the resting-state functional connectivity of the right amygdala with the right caudate nucleus, right transverse temporal gyrus, right temporal pole: superior temporal gyrus were also decreased. In alcohol-dependent patients with depression, not only was functional connectivity between the above brain regions significantly decreased, but so was functional connectivity between the right amygdala and the left middle temporal gyrus. Also, there was no significant correlation between the resting-state functional connectivity values in statistically significant brain regions and the levels of alcohol dependence and depression., Conclusion: The impairment of the functional connectivity of the amygdala with caudate nucleus and partial temporal lobe may be involved in the neural mechanism of alcohol dependence comorbidity depressive disorders., Competing Interests: Declaration of Competing Interest The authors have declared that there are no conflicts of interest in relation to the subject of this study., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Having multiple previous generations with depression in the family increases offspring risk for psychopathology. Parental depression has been associated with smaller subcortical brain volumes in their children, but whether two prior generations with depression is associated with further decreases is unclear., Methods: Using two independent cohorts, 1) a Three-Generation Study (TGS, N = 65) with direct clinical interviews of adults and children across all three generations, and 2) the Adolescent Brain Cognitive Development Study (ABCD, N = 10,626) of 9-10 year-old children with family history assessed by a caregiver, we tested whether having more generations of depression in the family was associated with smaller subcortical volumes (using structural MRI)., Results: In TGS, caudate, pallidum and putamen showed decreasing volumes with higher familial risk for depression. Having a parent and a grandparent with depression was associated with decreased volume compared to having no familial depression in these regions. Putamen volume was associated with depression at eight-year follow-up. In ABCD, smaller pallidum and putamen were associated with family history, which was driven by parental depression, regardless of grandparental depression., Limitations: Discrepancies between cohorts could be due to interview type (clinical or self-report) and informant (individual or common informant), sample size or age. Future analyses of follow-up ABCD waves will be able to assess whether effects of grandparental depression on brain markers become more apparent as the children enter young adulthood., Conclusions: Basal ganglia regional volumes are significantly smaller in offspring with a family history of depression in two independent cohorts., Competing Interests: Declaration of competing interest Dr. Weissman receives funds from NIMH and Columbia University Institute for Developmental Sciences and book royalties from Perseus Press and Oxford Press. Dr. Posner has received research support from Takeda (formerly Shire) and Aevi Genomics and consultancy fees from Innovative Science and AlphaSights. None of these present a conflict of interest with or have influenced the research presented in this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The perimenopausal transition is marked by an increased risk for affective dysregulation and major depressive disorder (MDD), with hormone replacement therapy using estradiol (E2) showing promise for alleviating symptoms of perimenopausal-onset MDD (PO-MDD). Although E2's effectiveness is recognized, its mechanisms underlying mood symptom modulation remain to be fully elucidated. Building on previous research suggesting that E2 may influence mood by altering cortico-subcortical connectivity, this study investigated the effects of transdermal E2 on resting-state functional connectivity (rsFC) in perimenopausal women with and without PO-MDD, focusing on rsFC changes using seed regions within reward and emotion processing networks. In this pharmaco-fMRI study, 16 participants with PO-MDD and 18 controls underwent rsFC analysis before and after three weeks of transdermal E2 administration. Pre-E2 results showed that the PO-MDD group, compared to controls, exhibited increased connectivity between the right amygdala (seed) and medial prefrontal cortex and anterior cingulate cortex, and decreased connectivity with the supplementary motor area. Comparing groups on change from pre-E2 to post-E2 revealed several significant E2-induced changes in connectivity between the PO-MDD and control groups: PO-MDD showed increased connectivity between the right caudate nucleus (seed) and left insula, and decreased connectivity between the right putamen (seed) and left hippocampus, and the right amygdala (seed) and left ventromedial prefrontal cortex. Notably, changes in connectivity were predictive of symptom trajectories across anhedonia, depressive mood, somatic, and vasomotor domains in the PO-MDD group. These findings enrich our understanding of PO-MDD by highlighting distinct rsFC patterns characteristic of the disorder and their shifts in response to E2 treatment, suggesting potential neural mechanisms underlying E2's mood-modulating effects., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Published by Elsevier B.V.)

Anorexia nervosa (AN) is associated with food restriction and significantly low body weight, but the neurobiology of food avoidance in AN is unknown. Animal research suggests that food avoidance can be triggered by conditioned fear that engages the anterior cingulate and nucleus accumbens. We hypothesized that the neural activation during food avoidance in AN could be modeled based on aversive goal value processing. Nineteen females with AN and thirty healthy controls matched for age underwent functional magnetic resonance brain imaging while conducting a food avoidance task. During active control free-bid and computer-generated forced-bid trials, participants bid money to avoid eating food items. Brain activation was parametrically modulated with the trial-by-trial placed bids. During free-bid trials, the AN group engaged the caudate nucleus, nucleus accumbens, ventral anterior cingulate, and inferior and medial orbitofrontal cortex more than the control group. High- versus low-bid trials in the AN group were associated with higher caudate nucleus response. Emotion dysregulation and intolerance of uncertainty scores were inversely associated with nucleus accumbens free-bid trial brain response in AN. This study supports the idea that food avoidance behavior in AN involves aversive goal value computation in the nucleus accumbens, caudate nucleus, anterior cingulate, and orbitofrontal cortex.

The complexity of brain activity reflects its ability to process information, adapt to environmental changes, and transition between states. However, it remains unclear how schizophrenia (SZ) affects brain activity complexity, particularly its dynamic changes. This study aimed to investigate the abnormal patterns of brain activity complexity in SZ, their relationship with cognitive deficits, and the impact of antipsychotic medication. Forty-four drug-naive first-episode (DNFE) SZ patients and thirty demographically matched healthy controls (HC) were included. Functional MRI-based sliding window analysis was utilized for the first time to calculate weighted permutation entropy to characterize complex patterns of brain activity in SZ patients before and after 12 weeks of risperidone treatment. Results revealed reduced complexity in the caudate, putamen, and pallidum at baseline in SZ patients compared to HC, with reduced complexity in the left caudate positively correlated with Continuous Performance Test (CPT) and Category Fluency Test scores. After treatment, the complexity of the left caudate increased. Regions with abnormal complexity showed decreased functional connectivity, with complexity positively correlated with connectivity strength. We observed that the dynamic complexity of the brain exhibited the characteristic of spontaneous, recurring "complexity drop", potentially reflecting transient state transitions in the resting brain. Compared to HC, patients exhibited reduced scope, intensity, and duration of complexity drop, all of which improved after treatment. Reduced duration was negatively correlated with CPT scores and positively with clinical symptoms. The results suggest that abnormalities in brain activity complexity and its dynamic changes may underlie cognitive deficits and clinical symptoms in SZ patients. Antipsychotic treatment partially restores these abnormalities, highlighting their potential as indicators of treatment efficacy and biomarkers for personalized therapy., (© 2024. The Author(s).)

Suicide is the second leading cause of death in youth, and depression is a strong proximal predictor of adolescent suicide. It is important to identify psychological factors that may protect against suicide ideation in depressed adolescents. Self-compassion may be such a factor. Converging evidence indicates the inverse association between self-compassion and suicide ideation, but the neural mechanisms underlying their link remain unknown. Because self-referential caudate activity is associated with both self-compassion and suicide ideation, its functional connectivity might explain their relationship. In this study, we examined the relationship between self-compassion and caudate functional connectivity during self-appraisals, a typical self-referential paradigm, and their associations with suicide ideation in both depressed and healthy youth. In the scanner, 79 depressed youth and 36 healthy controls evaluated, from various perspectives, whether phrases they heard were self-descriptive. Self-compassion and suicide ideation were rated with self-report and interview-based measures. We found that self-compassion was associated with stronger left caudate functional connectivity with bilateral posterior superior temporal sulcus/temporoparietal junction, the left middle temporal gyrus (MTG), and the left middle occipital gyrus during positive versus negative self-appraisals. Stronger left caudate connectivity with the left MTG explained the association between higher self-compassion and lower suicide ideation, even controlling for non-suicide ideation depression severity, anxiety severity, and non-suicidal self-injurious behavior. The findings suggest that the left caudate to MTG connectivity during positive versus negative self-referential processing could be a biomarker to be targeted by neural stimulation interventions for reducing suicide ideation in depressed youth, combined with self-compassion interventions., (© 2024. The Author(s).)

Background: Anorexia nervosa (AN) is a serious psychiatric illness that remains difficult to treat. Elucidating the neural mechanisms of AN is necessary to identify novel treatment targets and improve outcomes. A growing body of literature points to a role for dorsal fronto-striatal circuitry in the pathophysiology of AN, with increasing evidence of abnormal task-based fMRI activation within this network among patients with AN. Whether these abnormalities are present at rest and reflect fundamental differences in brain organization is unclear., Methods: The current study combined resting-state fMRI data from patients with AN ( n = 89) and healthy controls (HC; n = 92) across four studies, removing site effects using ComBat harmonization. First, the a priori hypothesis that dorsal fronto-striatal connectivity strength - specifically between the anterior caudate and dlPFC - differed between patients and HC was tested using seed-based functional connectivity analysis with small-volume correction. To assess specificity of effects, exploratory analyses examined anterior caudate whole-brain connectivity, amplitude of low-frequency fluctuations (ALFF), and node centrality., Results: Compared to HC, patients showed significantly reduced right, but not left, anterior caudate-dlPFC connectivity ( p = 0.002) in small-volume corrected analyses. Whole-brain analyses also identified reduced connectivity between the right anterior caudate and left superior frontal and middle frontal gyri ( p = 0.028) and increased connectivity between the right anterior caudate and right occipital cortex ( p = 0.038). No group differences were found in analyses of anterior caudate ALFF and node centrality., Conclusions: Decreased coupling of dorsal fronto-striatal regions indicates that circuit-based abnormalities persist at rest and suggests this network may be a potential treatment target.

We used a virtual navigation paradigm in a city environment to assess neuroanatomical correlates of cognitive deficits in schizophrenia spectrum disorders (SSD). We studied a total of N = 36 subjects: 18 with SSD and 18 matched unaffected controls. Participants completed 10 rapid, single-trial navigation tasks within the virtual city while undergoing functional magnetic resonance imaging (fMRI). All trials tested ability to find different targets seen earlier, during the passive viewing of a path around different city blocks. SSD patients had difficulty finding previously-encountered targets, were less likely to find novel shortcuts to targets, and more likely to attempt retracing of the path observed during passive viewing. Based on a priori region-of-interest analyses, SSD participants had hyperactivation of the left hippocampus when passively viewing turns, hyperactivation of the left caudate when finding targets, and hypoactivation of a focal area of the dorsolateral prefrontal cortex when targets were initially shown during passive viewing. We propose that these brain-behaviour relations may bias or reinforce stimulus-response navigation approaches in SSD and underlie impaired performance when allocentric spatial memory is required, such as when forming efficient shortcuts. This pattern may extend to more general cognitive impairments in SSD that could be used to design remediation strategies., Competing Interests: Declaration of competing interest Dr. Foussias has been involved in research sponsored by Medicure Inc., and Neurocrine Bioscience, has received consultant fees from Roche, and has received speaker fees from Roche, Lundbeck, and Novartis. Dr. Wong is a scientific consultant to Lucid psycheceuticals, a subsidiary of FSD Pharma Inc. The other authors declare no competing financial interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Neuromodulation treatment effect size for bothersome tinnitus may be larger and more predictable by adopting a target selection approach guided by personalized striatal networks or functional connectivity maps. Several corticostriatal mechanisms are likely to play a role in tinnitus, including the dorsal/ventral striatum and the putamen. We examined whether significant tinnitus treatment response by deep brain stimulation (DBS) of the caudate nucleus may be related to striatal network increased functional connectivity with tinnitus networks that involve the auditory cortex or ventral cerebellum. The first study was a cross-sectional 2-by-2 factorial design (tinnitus, no tinnitus; hearing loss, normal hearing, n = 68) to define cohort level abnormal functional connectivity maps using high-field 7.0 T resting-state fMRI. The second study was a pilot case-control series (n = 2) to examine whether tinnitus modulation response to caudate tail subdivision stimulation would be contingent on individual level striatal connectivity map relationships with tinnitus networks. Resting-state fMRI identified five caudate subdivisions with abnormal cohort level functional connectivity maps. Of those, two connectivity maps exhibited increased connectivity with tinnitus networks-dorsal caudate head with Heschl's gyrus and caudate tail with the ventral cerebellum. DBS of the caudate tail in the case-series responder resulted in dramatic reductions in tinnitus severity and loudness, in contrast to the nonresponder who showed no tinnitus modulation. The individual level connectivity map of the responder was in alignment with the cohort expectation connectivity map, where the caudate tail exhibited increased connectivity with tinnitus networks, whereas the nonresponder individual level connectivity map did not., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Neonatal adiposity is associated with a higher risk of obesity and cardiometabolic risk factors in later life. It is however unknown if central food intake regulating networks in the ventral striatum are altered with in-utero abdominal growth, indexed by neonatal adiposity in our current study. We aim to examine the relationship between striatal microstructure and abdominal adipose tissue compartments (AATCs) in Asian neonates from the Growing Up in Singapore Toward healthy Outcomes mother-offspring cohort., Study Design: About 109 neonates were included in this study. Magnetic resonance imaging (MRI) was performed for the brain and abdominal regions between 5 to 17 days of life. Diffusion-weighted imaging of the brain was performed for the derivation of caudate and putamen fractional anisotropy (FA). Abdominal imaging was performed to quantify AATCs namely superficial subcutaneous adipose tissue (sSAT), deep subcutaneous adipose tissue (dSAT), and internal adipose tissue (IAT). Absolute and percentage adipose tissue of total abdominal volume (TAV) were calculated., Results: We showed that AATCs at birth were significantly associated with increased FA in bilateral ventral caudate heads which are part of the ventral striatum (sSAT: β left  = 0.56, p < 0.001; β right  = 0.65, p < 0.001, dSAT: β left  = 0.43, p < 0.001; β right  = 0.52, p < 0.001, IAT: β left  = 0.30, p = 0.005; β right  = 0.32, p = 0.002) in neonates with low birth weights adjusted for gestational age., Conclusions: Our study provides preliminary evidence of a potential relationship between neonatal adiposity and in-utero programming of the ventral striatum, a brain structure that governs feeding behavior., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The rodent caudate-putamen is a large heterogeneous neural structure with distinct anatomical connections that differ in their control of learning processes. Previous research suggests that the anterior and posterior dorsomedial caudate-putamen (a- and p-dmCPu) differentially regulate associative learning with a non-contingent nicotine stimulus. The current study used bilateral NMDA-induced excitotoxic lesions to the a-dmCPu and p-dmCPu to determine the functional involvement of a-dmCPu and p-dmCPu in appetitive learning with contingent nicotine stimulus. Rats with a-dmCPu, p-dmCPu, or sham lesions were trained to lever-press for intravenous nicotine (0.03 mg/kg/inf) followed by access to sucrose 30 s later. After 1, 3, 9, and 20 nicotine-sucrose training sessions, appetitive learning in the form of a goal-tracking response was assessed using a non-contingent nicotine-alone test. All rats acquired nicotine self-administration and learned to retrieve sucrose from a receptacle at equal rates. However, rats with lesions to p-dmCPu demonstrated blunted learning of the nicotine-sucrose association. Our primary findings show that rats with lesions to p-dmCPu had a blunted goal-tracking response to a non-contingent nicotine administration after 20 consecutive days of nicotine-sucrose pairing. Our findings extend previous reports to a contingent model of nicotine self-administration and show that p-dmCPu is involved in associative learning with nicotine stimulus using a paradigm where rats voluntarily self-administer nicotine infusions that are paired with access to sucrose-a paradigm that closely resembles learning processes observed in humans., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Apraxia is a core clinical feature of corticobasal syndrome (CBS). Among the subtypes of apraxia, ideomotor and imitation apraxia are frequently found in CBS. However, little is known about the brain networks that are characteristic of each apraxia subtype or their clinical implication. In this study, we used 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) to explore the specific patterns of glucose hypometabolism that are characteristic of apraxia subtypes by focusing on ideomotor and imitation apraxia., Methods: We compared the areas of glucose hypometabolism in the brains of 52 patients with CBS and 13 healthy controls, both as a whole and according to apraxia subtypes. In addition, we investigated the relationship between the apraxia subtypes and the clinical phenotype of CBS., Results: In patients with CBS, common hypometabolism was observed in the frontal gyrus, precentral gyrus and caudate regardless of apraxia subtypes. In particular, ideomotor apraxia was associated with hypometabolism in the angular gyrus, while imitation apraxia was associated with hypometabolism in the posterior part including the postcentral gyrus, precuneus, and posterior cingulate gyrus. Patients who showed both ideomotor and imitation apraxia were more likely to show the typical features of CBS and progressive supranuclear palsy compared with patients showing only one type of apraxia., Conclusion: Group comparison analysis using FDG-PET revealed distinct pathways of ideomotor and imitation apraxia in CBS. These findings add to our understanding of the brain networks underlying apraxia in association with the clinical features of CBS., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Complex regional pain syndrome (CRPS) is a common poststroke complication. However, the neural substrates associated with CRPS remain unclear. We investigated the neural correlates associated with poststroke CRPS using voxel-based lesion‒symptom mapping (VLSM) analysis. Among 145 patients with ischemic stroke, 35 were diagnosed with CRPS and categorized into the poststroke CRPS group, and the remaining 110 into the control group. We compared the clinical characteristics between the groups. VLSM analysis was performed to identify the brain region associated with the development of poststroke CRPS. The clinical findings suggested that the poststroke CRPS group had lower muscle strength; lower scores on Fugl‒Meyer assessment, Manual Function Test, Mini-Mental Status Examination; and higher incidence of absent somatosensory evoked potentials in the median nerve than the control group. The head of the caudate nucleus, putamen, and white matter complexes in the corona radiata were significantly associated with poststroke CRPS development in ischemic stroke patients. These results facilitate an understanding of poststroke CRPS pathophysiology. Monitoring patients with lesions in these structures may aid the prevention and early treatment of poststroke CRPS.

Background: While effective treatments for posttraumatic stress disorder (PTSD) exist, many individuals, including military personnel and veterans fail to respond to them. Equine-assisted therapy (EAT), a novel PTSD treatment, may complement existing PTSD interventions. This study employs longitudinal neuro-imaging, including structural magnetic resonance imaging (sMRI), resting state-fMRI (rs-fMRI), and diffusion tensor imaging (DTI), to determine mechanisms and predictors of EAT outcomes for PTSD., Method: Nineteen veterans with PTSD completed eight weekly group sessions of EAT undergoing multimodal MRI assessments before and after treatment. Clinical assessments were conducted at baseline, post-treatment and at 3-month follow-up., Results: At post-treatment patients showed a significant increase in caudate functional connectivity (FC) and reduction in the gray matter density of the thalamus and the caudate. The increase of caudate FC was positively associated with clinical improvement seen immediately at post-treatment and at 3-month follow-up. In addition, higher baseline caudate FC was associated with greater PTSD symptom reduction post-treatment., Conclusions: This exploratory study is the first to demonstrate that EAT can affect functional and structural changes in the brains of patients with PTSD. The findings suggest that EAT may target reward circuitry responsiveness and produce a caudate pruning effect from pre- to post-treatment., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: However, whether the whole-brain functional network hub changes occur in diabetic retinopathy patients remains unknown., Purpose: The purpose of the study was to investigate the function network centrality and connectivity changes in diabetic retinopathy patients using the voxel-wise degree centrality method., Materials and Methods: Thirty-four diabetic retinopathy patients (18 male and 16 female) and 38 healthy controls (18 male and 20 female) closely matched in age, sex, and education were enrolled in the study. Graph theory-based network analysis was performed to investigate the degree centrality between two groups., Results: Compared with healthy controls, diabetic retinopathy patients had significantly higher degree centrality values in the pons and bilateral caudate and had significantly lower degree centrality values in the left lingual and right lingual, and right angular/middle occipital gyrus (MOG). Moreover, diabetic retinopathy patients exhibited increased functional connectivity between the bilateral lingual and right cerebellum lobe and right fusiform/bilateral caudate and increased functional connectivity between the right angular/MOG and bilateral anterior cingulum and right cuneus/bilateral precuneus and increased functional connectivity between the bilateral caudate and right lingual and right superior occipital gyrus. In contrast, diabetic retinopathy patients showed decreased functional connectivity between bilateral lingual and left lingual and right lingual and left superior occipital gyrus and decreased functional connectivity between the angular/MOG and right inferior occipital gyrus/right fusiform and left MOG/inferior occipital gyrus and decreased functional connectivity between the bilateral caudate and bilateral cerebellum crus1., Conclusion: Our results highlight that reorganization of the hierarchy of the cortical connectivity network related to visual network., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The clinical presentation of binge eating disorder (BED) and data emerging from task-based functional neuroimaging research suggests that this disorder may be associated with alterations in reward processing. However, there is a dearth of research investigating the functional organization of brain networks that mediate reward in BED. To address this gap, 27 adults with BED and 21 weight-matched healthy controls (WMC) completed a multimodel assessment consisting of a resting functional magnetic resonance imaging scan, behavioral tasks measuring reward-based decision-making (i.e., delay discounting and reversal learning), and self-report assessing clinical symptoms. A seed-based approach was employed to examine the resting state functional connectivity (rsFC) of the striatum (nucleus accumbens [NAcc] and ventral and dorsal caudate), a collection of regions implicated in reward processing. Compared with WMC, the BED group exhibited lower rsFC of striatal seeds, with frontal regions mediating executive functioning (e.g., superior frontal gyrus [SFG]) and posterior, parietal, and temporal regions implicated in emotional processing. Lower NAcc-SFG rsFC was associated with more difficulties with reversal learning and binge eating frequency in the BED group. Results suggest that hypoconnectivity of striatal networks that integrate self-regulation and reward processing may promote the clinical phenomenology of BED. Interventions for BED may benefit from targeting these circuit-based disturbances., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

The presence of white matter lesions in patients with cerebral small vessel disease (SVD) is among the main causes of cognitive decline. We investigated the relation between white matter hyperintensity (WMH) locations and executive and language abilities in 442 SVD patients without dementia with varying burden of WMH. We used Stroop Word Reading, Stroop Color Naming, Stroop Color-Word Naming, and Category Fluency as language measures with varying degrees of executive demands. The Symbol Digit Modalities Test (SDMT) was used as a control task, as it measures processing speed without requiring language use or verbal output. A voxel-based lesion-symptom mapping (VLSM) approach was used, corrected for age, sex, education, and lesion volume. VLSM analyses revealed statistically significant clusters for tests requiring language use, but not for SDMT. Worse scores on all tests were associated with WMH in forceps minor, thalamic radiations and caudate nuclei. In conclusion, an association was found between WMH in a core frontostriatal network and executive-verbal abilities in SVD, independent of lesion volume and processing speed. This circuitry underlying executive-language functioning might be of potential clinical importance for elderly with SVD. More detailed language testing is required in future research to elucidate the nature of language production difficulties in SVD., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Nicotine addiction is a severe public health problem. The aim of this study was to investigate the alterations in key neurotransmissions after 60 days of withdrawal from seven weeks of intermittent cigarette smoke, e-cigarette vapours, or an e-cigarette vehicle. In the nicotine withdrawal groups, increased depressive and anxiety/obsessive-compulsive-like behaviours were demonstrated in the tail suspension, sucrose preference and marble burying tests. Cognitive impairments were detected in the spatial object recognition test. A significant increase in Corticotropin-releasing factor (Crf) and Crf1 mRNA levels was observed, specifically after cigarette withdrawal in the caudate-putamen nucleus (CPu). The nociceptin precursor levels were reduced by cigarette (80%) and e-cigarette (50%) withdrawal in the CPu. The delta opioid receptor showed a significant reduction in the hippocampus driven by the exposure to an e-cigarette solubilisation vehicle, while the mRNA levels doubled in the CPu of mice that had been exposed to e-cigarettes. Withdrawal after exposure to e-cigarette vapour induced a 35% Bdnf mRNA decrease in the hippocampus, whereas Bdnf was augmented by 118% by cigarette withdrawal in the CPu. This study shows that long-term withdrawal-induced affective and cognitive symptoms associated to lasting molecular alterations in peptidergic signalling may determine the impaired neuroplasticity in the hippocampal and striatal circuitry.

Subjective emotional experience that is congruent with a given situation (i.e., target emotions) is critical for human survival (e.g., feeling disgusted in response to contaminated food motivates withdrawal behaviors). Neurodegenerative diseases including frontotemporal dementia and Alzheimer's disease affect brain regions critical for cognitive and emotional functioning, resulting in increased experience of emotions incongruent with the situation (i.e., non-target emotions, such as feeling happy when seeing someone grieving). We examined neuroanatomical correlates of subjective experience of non-target emotions in 147 patients with neurodegenerative diseases and 26 healthy individuals. Participants watched three films intended to elicit particular target emotions and rated their experience of negative and positive target and non-target emotions after watching each film. We found that smaller volume in left hemisphere regions (e.g., caudate, putamen, and dorsal anterior insula) was associated with greater experience of negative non-target emotions. Follow-up analyses confirmed that these effects were left-lateralized. No correlates emerged for positive non-target emotions. These findings suggest that volume loss in left-hemisphere regions produces a more diffuse, incongruent experience of non-target emotions. These findings provide a potential neuroanatomical basis for understanding how subjective emotional experience is constructed in the brain and how this can be disrupted in neurodegenerative disease., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Focal dystonias are the most common forms of isolated dystonia; however, the etiopathophysiological signatures of disorder penetrance and clinical manifestation remain unclear. Using an imaging genetics approach, we investigated functional and structural representations of neural endophenotypes underlying the penetrance and manifestation of laryngeal dystonia in families, including 21 probands and 21 unaffected relatives, compared to 32 unrelated healthy controls. We further used a supervised machine-learning algorithm to predict the risk for dystonia development in susceptible individuals based on neural features of identified endophenotypes. We found that abnormalities in prefrontal-parietal cortex, thalamus, and caudate nucleus were commonly shared between patients and their unaffected relatives, representing an intermediate endophenotype of laryngeal dystonia. Machine learning classified 95.2% of unaffected relatives as patients rather than healthy controls, substantiating that these neural alterations represent the endophenotypic marker of dystonia penetrance, independent of its symptomatology. Additional abnormalities in premotor-parietal-temporal cortical regions, caudate nucleus, and cerebellum were present only in patients but not their unaffected relatives, likely representing a secondary endophenotype of dystonia manifestation. Based on alterations in the parietal cortex and caudate nucleus, the machine learning categorized 28.6% of unaffected relative as patients, indicating their increased lifetime risk for developing clinical manifestation of dystonia. The identified endophenotypic neural markers may be implemented for screening of at-risk individuals for dystonia development, selection of families for genetic studies of novel variants based on their risk for disease penetrance, or stratification of patients who would respond differently to a particular treatment in clinical trials., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mild cognitive impairment (MCI) is common in Parkinson's disease patients. However, its underlying mechanism is not well understood, which has hindered new treatment discoveries specific to MCI. The aim of this study was to investigate functional connectivity changes of the caudate nucleus in cognitively impaired Parkinson's patients. We recruited 18 Parkinson's disease patients-10 PDNC [normal cognition Parkinson's disease; Montreal Cognitive Assessment (MoCA) ≥ 26], 8 PDLC (low cognition Parkinson's disease; MoCA < 26) -and 10 age-matched healthy controls. All subjects were scanned with resting-state functional magnetic resonance imaging (MRI) and perfusion MRI. We analyzed these data for graph theory metrics and Alzheimer's disease-like pattern score, respectively. A strong positive correlation was found between the functional connectivity of the right caudate nucleus and MoCA scores in Parkinson's patient groups, but not in healthy control subjects. Interestingly, PDNC's functional connectivity of the right caudate was significantly higher than both PDLC and healthy controls, while PDLC and healthy controls were not significantly different from each other. We found that Alzheimer's disease-like metabolic/perfusion pattern score correlated with MoCA scores in healthy controls, but not in Parkinson's disease. Increased caudate connectivity may be related to a compensatory mechanism found in cognitively normal patients with Parkinson's disease. Our findings support and complement the dual syndrome hypothesis.

Caudate dopaminergic dysfunction is implied in the pathophysiology of patients with Parkinson's disease (PD). Still, connectivity specificities of the caudate nucleus (CN) subdivisions and the effect of dopamine are poorly understood. We collected MRI and neuropsychological data from 34 PD patients and 26 age- and sex-matched healthy elderly individuals (HEs) in this study. Resting-state functional connectivity analysis revealed that compared to the other CN subdivisions, the CN head was more strongly connected to the default mode network (DMN), the CN body to the frontoparietal network (FPN), and the CN tail to the visual network in HEs. PD patients off medication showed reduced connectivity within all these subdivision networks. In PD patients on medication, functional connectivity in the CN head network was significantly improved in the medial prefrontal cortex and in the body network it was improved in the dorsolateral prefrontal cortex. These improvements contributed to ameliorated motivation and cognitive function in PD patients. Our results highlighted the specific alterations and dopamine modulation in these CN subdivision networks in PD, which may provide insight into the pathophysiology and therapeutics of this disease.

Parkinson's disease (PD) is characterized by overlapping motor, neuropsychiatric, and cognitive symptoms. Worse performance in one domain is associated with worse performance in the other domains. Commonality analysis (CA) is a method of variance partitioning in multiple regression, used to separate the specific and common influence of collinear predictors. We apply, for the first time, CA to the functional connectome to investigate the unique and common neural connectivity underlying the interface of the symptom domains in 74 non-demented PD subjects. Edges were modeled as a function of global motor, cognitive, and neuropsychiatric scores. CA was performed, yielding measures of the unique and common contribution of the symptom domains. Bootstrap confidence intervals were used to determine the precision of the estimates and to directly compare each commonality coefficient. The overall model identified a network with the caudate nucleus as a hub. Neuropsychiatric impairment accounted for connectivity in the caudate-dorsal anterior cingulate and caudate-right dorsolateral prefrontal-right inferior parietal circuits, while caudate-medial prefrontal connectivity reflected a unique effect of both neuropsychiatric and cognitive impairment. Caudate-precuneus connectivity was explained by both unique and shared influence of neuropsychiatric and cognitive symptoms. Lastly, posterior cortical connectivity reflected an interplay of the unique and common effects of each symptom domain. We show that CA can determine the amount of variance in the connectome that is unique and shared amongst motor, neuropsychiatric, and cognitive symptoms in PD, thereby improving our ability to interpret the data while gaining novel insight into networks at the interface of these symptom domains., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Consistent findings postulate disturbed glutamatergic function (more specifically a hypofunction of the ionotropic NMDA receptors) as an important pathophysiologic mechanism in schizophrenia. However, the role of the metabotropic glutamatergic receptors type 5 (mGluR5) in this disease remains unclear. In this study, we investigated their significance (using [ 11 C]ABP688) for psychopathology and cognition in male patients with chronic schizophrenia and healthy controls. In the patient group, lower mGluR5 binding potential (BP ND ) values in the left temporal cortex and caudate were associated with higher general symptom levels (negative and depressive symptoms), lower levels of global functioning and worse cognitive performance. At the same time, in both groups, mGluR5 BP ND were significantly lower in smokers (F [27,1] = 15.500; p = .001), but without significant differences between the groups. Our findings provide support for the concept that the impaired function of mGluR5 underlies the symptoms of schizophrenia. They further supply a new perspective on the complex relationship between tobacco addiction and schizophrenia by identifying glutamatergic neurotransmission-in particularly mGluR5-as a possible connection to a shared vulnerability., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Objective: Anorexia nervosa has the highest mortality rate of any psychiatric condition, yet the pathophysiology of this disorder and its primary symptom, extreme dietary restriction, remains poorly understood. In states of hunger relative to satiety, the rewarding value of food stimuli normally increases to promote eating, yet individuals with anorexia nervosa avoid food despite emaciation. This study's aim was to examine potential neural insensitivity to these effects of hunger in anorexia nervosa., Methods: At two scanning sessions scheduled 24 hours apart, one after a 16-hour fast and one after a standardized meal, 26 women who were in remission from anorexia nervosa (to avoid the confounding effects of malnutrition) and 22 matched control women received tastes of sucrose solution or ionic water while functional MRI data were acquired. Within a network of interest responsible for food valuation and transforming taste signals into motivation to eat, the authors compared groups across conditions on blood-oxygen-level-dependent (BOLD) signal and task-based functional connectivity., Results: Participants in the two groups had similar BOLD responses to sucrose and water tastants. A group-by-condition interaction in the ventral caudal putamen indicated that hunger had opposite effects on tastant response in the control group and the remitted anorexia nervosa group, with an increase and a decrease, respectively, in BOLD response when hungry. Hunger had a similar opposite effect on insula-to-ventral caudal putamen functional connectivity in the remitted anorexia nervosa group compared with the control group. Exploratory analyses indicated that lower caudate response to tastants when hungry was associated with higher scores on harm avoidance among participants in the remitted anorexia nervosa group., Conclusions: Reduced recruitment of neural circuitry that translates taste stimulation to motivated eating behavior when hungry may facilitate food avoidance and prolonged periods of extremely restricted food intake in anorexia nervosa.

A few studies have reported aberrant functional connectivity in alcoholic patients, but the specific neural circuits involved remain unknown. Moreover, it is unclear whether these alterations can be reversed upon treatment. Here, we used functional MRI to study resting state connectivity in rats following chronic intermittent exposure to ethanol. Further, we evaluated the effects of SB-277011-a, a selective dopamine D3 receptor antagonist, known to decrease ethanol consumption. Alcohol-dependent and control rats (N = 13/14 per group), 3 weeks into abstinence, were administered SB-277011-a or vehicle before fMRI sessions. Resting state connectivity networks were extracted by independent component analysis. A dual-regression analysis was performed using independent component maps as spatial regressors, and the effects of alcohol history and treatment on connectivity were assessed. A history of alcohol dependence caused widespread reduction of the internal coherence of components. Weaker correlation was also found between the insula cortex (IC) and cingulate cortices, key constituents of the salience network. Similarly, reduced connectivity was observed between a component comprising the anterior insular cortex, together with the caudate putamen (CPu-AntIns), and the posterior part of the IC. On the other hand, postdependent rats showed strengthened connectivity between salience and reward networks. In particular, higher connectivity was observed between insula and nucleus accumbens, between the ventral tegmental area and the cingulate cortex and between the VTA and CPu-AntIns. Interestingly, aberrant connectivity in postdependent rats was partially restored by acute administration of SB-277011-a, which, conversely, had no significant effects in naïve rats., (© 2019 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Chronic use of methamphetamine impairs frontostriatal structure and function, which may result in increased incentive-motivational responses to drug cues and decreased regulation of drug-seeking behavior. However, less is known regarding how the drug affects these circuits after acute administration. The current study examined the effects of a single dose of methamphetamine on resting state frontostriatal functional connectivity in healthy volunteers. Participants (n = 22, 12 female) completed two sessions in which they received methamphetamine (20 mg) and placebo before a resting state scan during functional magnetic resonance imaging. Participants also provided self-report measures of euphoria and stimulation at regular intervals. We conducted seed-based voxelwise functional connectivity analyses using three bilateral striatal seed regions: nucleus accumbens (NAcc), caudate, and putamen and compared connectivity following methamphetamine versus placebo administration. Additionally, we conducted correlational analyses to assess if drug-induced changes in functional connectivity were related to changes in subjective response. Methamphetamine increased NAcc functional connectivity with medial frontal regions (ie, orbitofrontal cortex, medial frontal gyrus, and superior frontal gyrus) and decreased NAcc functional connectivity with subgenual anterior cingulate cortex (ACC). Methamphetamine also increased functional connectivity between putamen and left inferior frontal gyrus (IFG), and individuals who displayed greater drug-induced increase in connectivity reported less euphoria and stimulation. These findings provide important information regarding the effects of methamphetamine on brain function in nonaddicted individuals. Further studies will reveal whether such effects contribute to the abuse potential of the drug and whether they are related to the frontostriatal impairments observed after chronic methamphetamine use., (© 2019 Society for the Study of Addiction.)

Quitting smoking is challenging in part because environmental smoking cues can trigger the desire to smoke. Neurobiological responses to smoking cues are often observed in reward-related brain regions such as the caudate and nucleus accumbens (NAc). While reward plays a well-established role in the formation of cue reactivity, whether general reward responsiveness contributes to individual differences in cue-reactivity among chronic smokers is unclear; establishing such link could provide insight into the mechanisms maintaining cue reactivity. The current study explored this relationship by assessing smoking cue reactivity during functional magnetic imaging followed by an out-of-scanner probabilistic reward task (PRT) in 24 nicotine-dependent smokers (14 women). In addition, owing to sex differences in cue reactivity and reward function, this same relationship was examined as a function of sex. Following recent smoking, greater reward responsiveness on the PRT was associated with enhanced left caudate reactivity to smoking cues. No relationship was found in any other striatal subregion. The positive relationship between reward responsiveness and caudate smoking cue reactivity was significant only in male smokers, fitting with the idea that males and females respond to the reinforcing elements of smoking cues differently. These findings are clinically relevant as they show that, following recent smoking, nicotine-dependent individuals who are more cue reactive are also more likely to be responsive to non-drug rewards, which may be useful for making individualized treatment decisions that involve behavioral reward contingencies., Competing Interests: Declaration of Competing Interest Dr. Pizzagalli has received consulting fees from Blackthorn Therapeutics, Boehringer Ingelheim, Compass, Takeda and an honorarium from Alkermes for activities unrelated to the current research. Dr. Pizzagalli has a financial interest in BlackThorn Therapeutics, which has licensed the copyright to the Probabilistic Reward Task through Harvard University. Dr. Pizzagalli’s interests were reviewed and are managed by McLean Hospital and Partners HealthCare in accordance with their conflict of interest policies. All other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Recent resting-state functional connectivity studies have shown significant group differences in several networks between patients suffering from borderline personality disorder (BPD) and healthy controls. However, reliable and consistent findings have not been reported yet. Several methodological factors might be responsible for the discrepant findings, including the heterogeneity of patient samples in terms of symptom severity. In the current study, we combined investigations of the whole-brain resting-state functional connectivity patterns of BPD patients with seed-based connectivity measures and then computed the correlation of connectivity measures with borderline symptom severity. Correlation-based connectivity analysis was performed on resting-state functional magnetic resonance imaging (fMRI) data from 26 female BPD patients and 26 healthy controls. Increased intrinsic connectivity was found in clusters involving part of the caudate nucleus and the left insula in the patient group, indicating greater integration of each region. Further seed-based connectivity analyses revealed that with the caudate seed, the patient data exhibited an increased resting-state functional connectivity in the bilateral ventral striatum and the midline prefrontal regions extending to the ACC, a network associated with reward processing. The left insula seed showed significantly increased connectivity with the bilateral fronto-orbital/insula, the inferior parietal lobule and the mid-cingulate cortex, a network involved in attention and salience encoding, in the patient population. Moreover, symptom severity, as assessed with the BSL-95 outside the scanner, was negatively correlated with the coupling of the insula and the striatum in the BPD group. Overall, an increased functional connectivity within two large-scale circuitries underlying reward and salience processing was evident in patients, as compared to healthy participants. When correlated with borderline symptom severity, a reduced connectivity between key regions belonging to the reward system and salience network was observed in the patients. These findings may be helpful for facilitating further understanding of the potential mechanisms underlying the BPD pathophysiology and thereby delineate potential treatment targets.

One of the most prominent symptoms of schizophrenia is thought disorder, which manifests itself in language production difficulties. In patients with thought disorders the associations are loosened and sentence production is impaired. The determining behavioral and neural mechanisms of sentence production are still an important subject of recent research and have not yet been fully understood. The aim of the current study was to examine the influence of associative relations and distractor modalities on sentence production in healthy participants and participants with schizophrenia. Therefore, reaction times and neural activation of 12 healthy subjects and 13 subjects with schizophrenia were compared in an adapted picture word interference paradigm (PWI). No significant group differences were found, neither on the behavioral nor on the neural level. On the behavioral level, for the entire group incremental sentence processing was found, i.e. processing of the second noun only starts after the first noun was processed. At the neural level, activation was discovered in the bilateral caudate nuclei and the cerebellum. Those activations could be related to response enhancement and suppression as well as to the modulation of cognitive processes.

Major depressive disorder (MDD), characterized by low mood or anhedonia, is commonly associated with a greater suicidal susceptibility. There are numerous suicide-related findings pertaining to the dorsolateral prefrontal cortex (DLPFC), caudate nucleus and thalamus, which form a cortico-striato-thalamo-cortical (CSTC) circuit responsible for executive function and working memory. An aberrant CSTC circuitry is hypothesized to be implicated in depressed patients with a high suicidal risk. 27 MDD patients were assessed with the Nurses Global Assessment of Suicide Risk (NGASR), following which 14 patients were classified into a high suicide risk group (NGASR ≥ 12) and 13 patients were assigned to a low suicide risk group (NGASR < 6). All 27 patients were enrolled with 25 healthy controls for resting-state magnetoencephalography (MEG). Cross-frequency coupling (CFC) measured the phase of alpha-band (8-13 Hz) as it modulated to cortical gamma-band (30-48 Hz). There was a significantly lower alpha-to-gamma phase-amplitude coupling (PAC) between the right caudate and left thalamus in high-risk suicide group compared to both the low-risk suicide group and healthy controls. The presence of a weaker coupling between the right caudate and left thalamus is indicative of a caudothalamic abnormality in suicidally depressed patients. This implies that a disruption of CSTC loop could result in executive dysfunction and working memory impairment, leading to an increased suicidal risk in MDD patients. In the future, this preliminary study has the possibility of being replicated on a larger scale, and hence validates caudothalamic dysfunction as a reliable neuroimaging biomarker for suicide in depression.

There is growing evidence suggesting that abnormalities in cortical-basal ganglia circuitry may play a significant role in determining outcomes in schizophrenia. The globus pallidus (GP), a critical structure within this circuitry, unique in its role as a mediator of competing inputs through the striatum, has not been well characterized in schizophrenia. The following study examined functional interactions of the GP in individuals with first-episode schizophrenia (FES). To probe the large-scale intrinsic connectivity of the GP, resting-state fMRI scans were obtained from patients with FES and sex and age-matched healthy controls. Participants with FES were also evaluated after 6 months via the Strauss-Carpenter Outcomes Scale to assess overall functional trajectory. The GP was parcellated to generate seeds within its substructures, and connectivity maps were generated. Our FES cohort showed significantly lower functional connectivity between the left GP interna and a network of regions including the dorsolateral prefrontal cortex, caudate, and cerebellum at baseline. In addition, FES participants with lower overall scores of functioning at 6 months showed significantly decreased connectivity between the GP interna and the dorsal anterior cingulate and bilateral insula, all regions important for motivational salience. These results provide novel evidence for unique abnormalities in functional interactions of the GP with key prefrontal cortical regions in FES. Our findings also suggest that reduced prefrontal-pallidal connectivity may serve as a predictor of early functional outcome., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Fatigue is one of the most disabling symptoms of multiple sclerosis (MS). While progressive resistance training (PRT) has been shown to reduce fatigue in persons with MS, it is not clear why these reductions occur. One hypothesis is that PRT may induce functional changes to the caudate, a region highly implicated in MS fatigue. The aim of the current study was to study the effects of PRT on overall fatigue impact and resting-state functional connectivity of the caudate in persons with MS reporting severe fatigue. Participants were semi-randomly assigned to either a 16-week home-based PRT ( n  = 5) or stretching control ( n  = 5) condition. Both groups demonstrated reductions in overall fatigue impact (main effect of time: F  = .84, d  = .65). Significant group × time interactions were found, with the PRT group demonstrating post-training increases in functional connectivity between the caudate and left inferior parietal ( F  = 66.0, p  < .001), bilateral frontal (both p  < .001), and right insula ( F  = 21.8, p  = .002) regions compared to the stretching group. Furthermore, greater post-training increases in functional connectivity between the caudate and left inferior parietal region were associated with greater decreases in cognitive fatigue ( r  = -.52) specifically. This study provides initial evidence for the caudate as a potential neural substrate for the beneficial effects of PRT on fatigue in persons with MS.

Objective : Frequent falls are common in Parkinson's disease (PD). Resting-state fMRI (rs-fMRI) studies have found differences in functional connectivity between PD patients and healthy controls. However, whether functional connectivity in PD patients with frequent falls (PD-fallers) differs from those without falls (PD-non fallers) is unknown. Therefore, to elucidate the underlying mechanisms leading to postural instability in PD patients with frequent falls, we compared changes in functional connectivity between PD-fallers, PD-non fallers and healthy controls. Methods : Thirteen healthy controls (70.7 ± 7.2 years) were compared to thirteen PD-fallers (70.6 ± 5.9 years) and 19 PD-non fallers (71.61 ± 5.8 years) without cognitive impairment. We performed 1.5T rs-fMRI scans and evaluated gait and balance, motor symptoms and cognitive functions. Results : Cerebellar seed regions showed increased functional connectivity in PD-fallers compared to controls in two connections between the cerebellar cortex and vermis ( p -value = 0.02). Conversely, in comparison to controls, functional connectivity between the precuneus and caudate nucleus was decreased in PD-non fallers ( p -value = 0.015). A similar trend was also observed between controls and PD-fallers, although this difference did not reach statistical significance. Discussion : We found increased functional connectivity among cerebellar structures in PD, which may reflect an adaptive (compensatory) mechanism through activation of additional brain structures to restore gait function. In contrast, a relative disconnection between the precuneus and caudate nucleus in PD patients might indicate an impaired brain network unrelated to the risk of falls. Cerebellar areas might thus be considered as future therapeutic targets for neuromodulatory treatment of postural instability in PD. Abbreviations : DMN: default mode network; FC: functional connectivity; IPL: inferior parietal lobule; MMSE: Minimal Mental Status Examination; PD: Parkinson's disease; rs-fMRI: resting-state functional Magnetic Resonance Imaging; UPDRS III : Unified Parkinson's disease ranking scale.

Objective: There is increasing evidence of cognitive impairment (CI) frequently occurring in patients with multiple system atrophy (MSA); however, the neurobiological mechanisms underlying CI in patients with MSA remain unclear., Methods: We enrolled 61 patients with probable MSA and 33 healthy controls (HC). We used degree centrality (DC) analysis to assess changes in the centrality level of MSA-CI related brain nodes. We conducted a secondary seed-based functional connectivity (FC) analysis to investigate dysfunctions in cognitive networks related to MSA. Further, we analysed the correlation between clinical symptoms and acquired connectivity measures., Results: Compared with HC, patients with MSA-CI and those with MSA with normal cognition (MSA-NCI) exhibited lower DC values in the left calcarine and right postcentral regions and higher DC values in the bilateral caudate and left precuneus. There were significant differences in the DC values in the right middle prefrontal gyrus between the MSA-CI and MSA-NCI groups. The mean DC values in the right middle prefrontal gyrus (RMPFG) were correlated with clinical cognitive severity. Consequently, we used this brain region as a seed in secondary seed-based FC analysis and observed FC changes within the right precuneus, inferior parietal lobe, and right insula., Conclusions: Decreased middle prefrontal cortex activity and its altered functional connectivity with the precuneus, inferior parietal lobe, and insula are possible biomarkers of cognitive dysfunction in patients with MSA-CI., Significance: Cognitive impairment in MSA is associated with alterations in the dorsolateral prefrontal cortex network., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Binge Drinking (BD) is a pattern of excessive alcohol consumption highly prevalent among college students, and has been associated with structural and functional alterations of brain networks. Recent advances in the resting-state connectivity analysis have boosted the research of the network-level connectivity disturbances associated with many psychiatric and neurological disorders, including addiction. Accordingly, atypical functional connectivity patterns in resting-state networks such as the Executive Control Network (ECN) have been found in substance users and alcohol-dependent individuals. In this study, we assessed for the first time the ECN functional and structural connectivity in a group of 34 college students, 20 (10 women) binge drinkers (BDs) in comparison with a group of 14 (8 women) alcohol abstinent controls (AACs). Overall, our findings documented increased resting-state functional connectivity (rsFC) in the BDs left middle frontal cortex of the left ECN in comparison to the AACs, while no structural connectivity differences were observed between groups. Pearson correlations revealed a positive association between the left middle frontal gyrus rsFC and the frequency of BD episodes per month, in the BD group. These findings suggest that maintaining a pattern of acute and intermittent alcohol consumption during important stages of brain development, as the transition from adolescence to adulthood, is associated with impaired ECN rsFC despite no group differences being yet noticed in the ECN structural connectivity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Youth with elevated psychopathic traits exhibit a number of comparable neurocognitive deficits as adult psychopathic offenders, including error-related processing deficits. Subregions of the basal ganglia play an important, though indirect, role in error-related processing through connections with cortical areas including the anterior cingulate cortex. A number of recent structural and functional magnetic resonance imaging (s/fMRI) studies have associated basal ganglia dysfunction in youth with elevated psychopathic traits, but these studies have not examined whether dysfunction occurring within subregions of the basal ganglia help contribute to error-related processing deficits previously observed in such at-risk youth. Here, we investigated error-related processing using a response inhibition Go/NoGo fMRI experimental paradigm in a large sample of incarcerated male adolescent offenders (n = 182). In the current report, psychopathy scores (measured via the Psychopathy Checklist: Youth Version (PCL:YV)) were negatively related to hemodynamic activity within input nuclei of the basal ganglia (i.e., the caudate and nucleus accumbens), as well as intrinsic/output nuclei (i.e., the globus pallidus and substantia nigra) and related nuclei (i.e., the subthalamic nucleus) during error-related processing. This is the first evidence to suggest that error-related dysfunction previously observed in youth with elevated psychopathic traits may be related to underlying abnormalities occurring within subregions of the basal ganglia.

Abnormalities of SNAP25 (synaptosome-associated protein 25) amount and protein-protein interactions occur in schizophrenia, and may contribute to abnormalities of neurotransmitter release in patients. However, presynaptic terminal function depends on multiple subcellular mechanisms, including energy provided by mitochondria. To explore the SNAP25 interactome in schizophrenia, we immunoprecipitated SNAP25 along with interacting proteins from the ventromedial caudate of 15 cases of schizophrenia and 13 controls. Proteins were identified with mass spectrometry-based proteomics. As well as 15 SNARE- (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) associated proteins, we identified 17 mitochondria-associated and four other proteins. The mitochondrial small GTPase ARF1 (ADP-ribosylation factor 1) was identified in eight schizophrenia SNAP25 immunoprecipitates and none from controls (P = 0.004). Although the ARF1-SNAP25 interaction may be increased, immunoblotting demonstrated 21% lower ARF1-21 (21 kiloDaltons) in schizophrenia samples (P = 0.04). In contrast, the mitochondrial protein UQCRC1 (ubiquinol-cytochrome c reductase core protein 1) did not differ. Lower ARF1-21 levels were associated with the previously reported increased SNAP25-syntaxin interaction in schizophrenia (r = -0.39, P = 0.04). Additional immunoprecipitation studies confirmed the ARF1-21-SNAP25 interaction, independent of UQCRC1. Both ARF1 and SNAP25 were localized to synaptosomes. Confocal microscopy demonstrated co-localization of ARF1 and SNAP25, and further suggested fivefold enrichment of ARF1 in synaptosomes containing an excitatory marker (vesicular glutamate transporter) compared with synaptosomes containing an inhibitory marker (vesicular GABA transporter). The present findings suggest an association between abnormalities of SNARE proteins involved with vesicular neurotransmission and the mitochondrial protein ARF1 that may contribute to the pathophysiology of schizophrenia., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Frontostriatal circuits are centrally involved in the selection of behavioral programs and play a prominent role in alcohol use disorder (AUD) as well as other mental disorders. However, how frontal regions change their striatal connectivity to implement adaptive cognitive control is still not fully understood. Here, we developed an approach for functional magnetic resonance imaging (fMRI) connectivity analysis in which we change the focus from connectivity to individual voxels towards spatial information about the location of strongest functional connectivity. In resting state data of n = 66 participants with AUD and n = 40 healthy controls (HC) we used the approach to estimate frontostriatal connectivity gradients consistent with nonhuman primate tract-tracing studies, characterized for each frontal voxel the striatal peak connectivity location on this gradient (PeaCoG), and tested for group differences and associations with clinical variables. We identified a cluster in the right orbitofrontal cortex (rOFC) with a peak connectivity shift towards ventral striatal regions in AUD. Reduced variability of rOFC striatal peak connectivity in the AUD group suggests a "clamping" to the ventral striatum as the underlying effect. Within the AUD group striatal peak connectivity in the superior frontal gyrus was associated with self-efficacy to abstain from alcohol, in the medial frontal and dorsolateral prefrontal cortex with alcohol dependency, and in the right inferior frontal gyrus with the urge to consume alcohol. Our results demonstrate that the functional topography of frontostriatal circuits exhibits interindividual variability, which provides insight into frontostriatal network adaptations in AUD and potentially other mental disorders., (© 2018 Society for the Study of Addiction.)

Objective: Although not typical of Parkinson's disease (PD), caudate dopaminergic dysfunction can occur in early stages of the disease. However, its frequency and longitudinal implications in large cohorts of recently diagnosed patients remain to be established. We investigated the occurrence of caudate dopaminergic dysfunction in the very early phases of PD (<2 years from diagnosis) using 123 I-FP-CIT single photon emission CT and determined whether it was associated with the presence or subsequent development of cognitive impairment, depression, sleep and gait problems., Methods: Patients with PD and healthy controls were identified from the Parkinson's Progression Markers Initiative (PPMI) database. We defined a clinically significant caudate dysfunction as 123 I-FP-CIT binding <-2 SDs compared with the controls' mean and categorised three groups accordingly (no reduction, unilateral reduction, bilateral reduction). All statistical analyses were adjusted for mean putamen binding., Results: At baseline, 51.6% of 397 patients had normal caudate dopamine transporter binding, 26.0% had unilateral caudate involvement, 22.4% had bilaterally impaired caudate.Compared with those with a baseline normal caudate function, at the4-year follow-up patients with a baseline bilateral caudate involvement showed a higher frequency of cognitive impairment (p<0.001) and depression (p<0.001), and worse cognitive (p<0.001), depression (<0.05) and gait (<0.001) ratings. Significant caudate involvement was observed in 83.9% of the population after 4 years (unilateral 22.5%, bilateral 61.4%)., Conclusions: Early significant caudate dopaminergic denervation was found in half of the cases in the PPMI series. Baseline bilateral caudate involvement was associated with increased risk of developing cognitive impairment, depression and gait problems over the next 4 years., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Test whether a dissonance-based transdiagnostic eating disorder treatment reduces valuation of the thin beauty ideal and high-calorie binge foods, the intervention targets, and eating pathology relative to waitlist controls., Method: Women with Diagnostic and Statistical Manual of Mental Disorders-5 eating disorders (N = 100) were randomized to an 8-week group-implemented Body Project Treatment (BPT) redesigned to encourage rapid symptom reduction or a waitlist control condition, completing functional MRI paradigms assessing neural response to thin models and binge foods, questionnaires, and diagnostic interviews at pretest and posttest., Results: Compared to controls, BPT participants showed greater reductions in responsivity of regions involved in reward valuation (ventromedial prefrontal cortex, dorsolateral prefrontal cortex, caudate) to thin models but not binge foods, pursuit of the thin ideal (d = .72), palatability ratings of binge foods (d = .78), and greater increases in attractiveness ratings of average-weight models (d = .44), the intervention targets. BPT participants also showed significantly greater reductions in body dissatisfaction (d = .83), negative affect (d = .76), and eating disorder symptoms (d = .59), and marginally greater abstinence from binge eating and compensatory behaviors (39% vs. 21%) than controls., Conclusions: Results provide novel evidence that BPT affected the hypothesized intervention targets and reduced variables that are putatively secondary to pursuit of the thin ideal, including body dissatisfaction, negative affect, and eating disorder symptoms. Symptom reductions were smaller than in past trials, suggesting that it may be optimal to reduce valuation of the thin ideal before asking participants to reduce disordered eating behaviors that are used to pursue this ideal. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Background: Emotion dysfunction is a key symptom in patients with borderline personality disorder (BPD) and is considered a consequence of dysfunctional emotion regulation (e.g., reduced emotion acceptance). In the present functional MRI (fMRI) study, we investigated the neural correlates of habitual emotion acceptance in individuals with BPD., Methods: Female patients with BPD and female healthy controls passively viewed negative and neutral movie clips of faces during fMRI. We assessed emotion acceptance using the Emotion Acceptance Questionnaire (EAQ). To examine brain activation associated with habitual emotional acceptance of negative stimuli, the EAQ score was included as a regressor of interest in brain data analyses of activation intensity during negative compared with neutral movies., Results: We included 20 women with BPD and 20 heatlhy controls in our analysis. Compared with healthy controls, patients with BPD showed significantly more activation in frontostriatal brain regions (i.e., left superior frontal gyrus, right caudate) as well as in the left precuneus, left precentral gyrus, left posterior cingulate cortex and left hippocampus when confronted with negative (v. neutral) stimuli. Patients with BPD reported decreased emotion acceptance compared with healthy controls, and habitual emotion acceptance was inversely associated with activation of striatal areas (i.e., left putamen, left caudate) in patients with BPD., Limitations: Causal conclusions are not possible. Comorbid diagnoses were not excluded, and only female participants were investigated. Stimuli were not rated immediately and may not be generalizable to all negative emotions. We cannot make any statements about other emotion-regulation strategies that may have been applied here., Conclusion: Data indicate that striatal hyperactivation during the processing of negative stimuli in women with BPD is related to their decreased disposition to accept unpleasant emotional states. Thus, individuals with BPD may benefit from therapy approaches that focus on emotion acceptance in order to normalize emotional reactions., (© 2019 Joule Inc. or its licensors)

Mood disorders/psychosis have been associated with dysfunctions in the default mode network (DMN). However, the relative contributions of DMN regions to state and trait disturbances in pediatric bipolar disorder (PBD) remain unclear. The aim of this study was to investigate the possible mechanisms of PBD through brain imaging and explore the influence of psychotic symptoms on functional alterations in PBD patients. Twenty-nine psychotic and 26 non-psychotic PBD patients, as well as 19 age- and sex-matched healthy controls underwent a resting-state functional MRI scan and the data were analyzed by independent component analysis. The DMN component from the fMRI data was extracted for each participant. Spearman's rank correlation analysis was performed between aberrant connectivity and clinical measurements. The results demonstrated that psychotic PBD was characterized by aberrant DMN connectivity in the anterior cingulate cortex/medial prefrontal cortex, bilateral caudate nucleus, bilateral angular gyri, and left middle temporal gyrus, while non-psychotic PBD was not, suggesting further impairment with the development of psychosis. In summary, we demonstrated unique impairment in DMN functional connectivity in the psychotic PBD group. These specific neuroanatomical abnormalities may shed light on the underlying pathophysiology and presentation of PBD.

Background: Animal models of addiction suggest that the transition from incentive-driven drug use to habitual and ultimately compulsive drug use is mediated by a shift from ventral to dorsal striatal cue control over drug seeking. Previous studies in human cannabis users reported elevated trait impulsivity and neural cue reactivity in striatal circuits; however, these studies were not able to separate addiction-related from exposure-related adaptations., Methods: To differentiate the adaptive changes, the current functional magnetic resonance imaging study examined behavioral and neural cue reactivity in dependent (n = 18) and nondependent (n = 20) heavy cannabis users and a nonusing reference group (n = 44)., Results: Irrespective of dependence status, cannabis users demonstrated elevated trait impulsivity as well as increased ventral striatal reactivity and striatal frontal coupling in response to drug cues. Dependent users selectively exhibited dorsal striatal reactivity and decreased striatal limbic coupling during cue exposure. An exploratory analysis revealed that higher ventral caudate neural cue reactivity was associated with stronger cue-induced arousal and craving in dependent users, whereas this pattern was reversed in nondependent users., Conclusions: Taken together, the current findings suggest that exaggerated responses of the ventral striatal reward system may promote excessive drug use in humans, whereas adaptations in dorsal striatal systems engaged in habit formation may promote the transition to addictive use., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Intense anger and anger-related aggression are frequently reported by patients with borderline personality disorders (BPD). Recent results suggest that anger-related aggression and its control is associated with a complex interplay of different neural systems in BPD. To further investigate this, we complement standard activation and seed-based connectivity analyses by examining whole-brain changes in functional connectivity during anger and reactive aggression in BPD., Methods: We reanalyzed functional MRI data from 33 women with BPD, all of them fulfilling BPD criterion 8, "anger proneness", according to DSM-IV, and 30 healthy women. Subjects performed a script-driven imagery task consisting of four phases: baseline, anger-induction by a narrative of interpersonal rejection, a narrative of directing physical aggression towards others, and relaxation. We used a data-driven, spatially constrained spectral clustering approach to parcellate the brain into 200 regions. For each script-phase and subject, we computed the full connectivity matrix using wavelet coefficient correlations in the 0.05-0.10 Hz range. We calculated the individual increase in connectivity from baseline to the anger-induction and physical aggression phases by subtracting the corresponding connectivity matrices per subject, as well as the increase and decrease from the anger-induction to the aggression phase. We then applied permutation-based sampling to determine a combined threshold on the strength of individual connections and the size of the discovered networks for these difference matrices., Results: We discovered a single, large network showing a significantly stronger increase in connectivity from baseline to the aggression phase in female patients with BPD compared to healthy women. This network consisted of regions in the anterior and posterior cingulate cortex, precuneus, dorsomedial prefrontal cortex, superior and middle temporal gyrus, hippocampus, insula, ventrolateral and dorsolateral prefrontal cortex, superior parietal lobe, thalamus, precentral and postcentral gyrus, caudate, pallidum, cerebellum, middle occipital lobe, lingual gyrus, calcarine sulcus, and fusiform gyrus. Hub regions with highest node centrality were found in the right caudate and left thalamus. We found no significant differences for the increase of connectivity from baseline to anger-induction, as well as for the increase or decrease from the anger-induction to the aggression phase., Conclusions: We identified a large network showing a significantly stronger increase in connectivity from baseline to the aggression phase in female patients with BPD compared to healthy women. The regions constituting this network belong to four previously described functional networks: The frontoparietal cognitive control network, the extended default mode network, the visual system, and the motor system. This stronger increase in connectivity between regions of different functional brain systems associated with cognitive control of behavior, socio-affective and self-referential thinking, as well as salience processing and emotion regulation, visual perception, and action is mediated via hubs in the thalamus and caudate, i.e., core components of the thalamocorticostriatal motor loop essential for action selection and initiation. These findings suggest increased interaction of prefrontal cognitive control processes with thalamocorticostriatal action-selection processes in female patients with BPD during the processing of aggressive action impulses, which are facilitated by states of high emotional salience and associated processes of self-referential and social processing, and ineffective emotion regulation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Adolescence is a common time for initiation of alcohol use and development of alcohol use disorders. The present study investigates neuroanatomical predictors for trajectories of future alcohol use based on a novel voxel-wise whole-brain structural equation modeling framework. In 1814 healthy adolescents of the IMAGEN sample, the Alcohol Use Disorder Identification Test (AUDIT) was acquired at three measurement occasions across five years. Based on a two-part latent growth curve model, we conducted whole-brain analyses on structural MRI data at age 14, predicting change in alcohol use score over time. Higher grey-matter volumes in the caudate nucleus and the left cerebellum at age 14 years were predictive of stronger increase in alcohol use score over 5 years. The study is the first to demonstrate the feasibility of running separate voxel-wise structural equation models thereby opening new avenues for data analysis in brain imaging., Competing Interests: SK, AM, AB, UB, EQ, SD, HF, AG, HG, PG, AH, BI, JM, FN, DP, TP, LP, SM, JF, MS, HW, RW, GS, UL, JG No competing interests declared, TB Has served as an advisor or consultant to Bristol-Myers Squibb, Desitin Arzneimittel, Eli Lilly, Medice, Novartis, Pfizer, Shire, UCB, and Vifor Pharma; he has received conference attendance support, conference support, or speaking fees from Eli Lilly, Janssen McNeil, Medice, Novartis, Shire, and UCB; and he is involved in clinical trials conducted by Eli Lilly, Novartis, and Shire; the present work is unrelated to these relationships. CB Reviewing editor, eLife, (© 2019, Kühn et al.)

Epigenetic agents, such as neonatal isolation during neurodevelopmental period of life, can change various regions of the brain. It may further induce psychological disorders such as autistic-like phenomena. This study indicated the role of chronic increased anterior cingulate cortex (ACC) output on alteration of caudate putamen (CPu) as a main behavior regulator region of the brain in adult maternal deprived (MD) rats. For making an animal model, neonates were isolated from their mothers in postnatal days (PND 1-10, 3 h/day). Subsequently, they bilaterally received pLenti-CaMKIIa-hChR2 (H134R)-mCherry-WPRE virus in ACC area via stereotaxic surgery in PND50. After 22 days, these regions were exposed to blue laser (473 nm) for six consecutive days (15 min/day). Then, behavioral deficits were tested and were compared with control group in the following day. Animals were immediately killed and their brains were prepared for tissue processing. Results showed that neonatal isolation induces autistic-like behaviors and leads to overexpression of NMDAR1 and Nox2-gp91 phox proteins and elevation of catalase activity in the CPu regions of the adult offspring compared with control group. Chronic optogenetic stimulation of ACC neurons containing (ChR2+) led to significant reduction in the appearance of stereotypical behavior and alien-phobia in MD rats. The amount of NMDAR1 and Nox2-gp91 phox expression and the catalase activity in CPu were reduced after this treatment. Therefore, autistic-like behavior seems to be related with elevation of NMDAR1 and Nox2-gp91 phox protein levels that enhance the effect of glutamatergic projection on CPu regions. Optogenetic treatment also could ameliorate behavioral deficits by modulating these protein densities.

The nociceptive and autonomic nervous systems (ANS) are significantly intertwined. Decoupling of these systems may occur in pathological pain conditions, including irritable bowel syndrome (IBS). We investigated ANS activity and its association with visceral perception and brain activity during rectal distention in 27 patients with non-constipated IBS and 33 controls by assessing heart rate variability (HRV) using electrocardiography at rest, before, and during colorectal distention. Brain responses to colorectal distention were measured using functional magnetic resonance imaging and correlated with individual ANS function parameters. The IBS group displayed blunted sympathovagal balance [low/high-frequency ratio (LF:HF) of HRV] in response to colorectal distention compared with controls (P = 0.003). In controls, basal parasympathetic tone (HF component of HRV) was significantly negatively correlated with toleration threshold to the rectal distention, but not in patients with IBS (group comparison P = 0.04). Further, a positive correlation between baseline HF values and neural responses to rectal distension was found in the right caudate, bilateral dorsolateral anterior cingulate cortex, and pregenual anterior cingulate cortex in the control group but not in the IBS group. The results indicate abnormal interactions between ANS activity and the brain mechanisms underlying visceral perception in patients with IBS.