Correlation of striatal dopamine D2/3 receptor availability with GABA level in the anterior cingulate cortex in healthy controls but not in alcohol-dependent subjects and individuals at high risk: A multimodal magnetic resonance spectroscopy and positron emission tomography study.

BACKGROUND: The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced dopamine D2/3 receptors in the striatum of subjects with alcohol dependence (AD) compared to healthy controls have been found in previous studies. Furthermore, alterations of gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the anterior cingulate cortex (ACC) of AD subjects have been documented in several studies. However, the interaction between cortical Glu levels and striatal dopamine D2/3 receptors has not been investigated in AD thus far. METHODS: This study investigated dopamine D2/3 receptor availability via 18F-fallypride positron emission tomography (PET) and GABA as well as Glu levels via magnetic resonance spectroscopy (MRS) in 19 detoxified AD subjects, 18 healthy controls (low risk, LR) controls and 19 individuals at high risk (HR) for developing AD, carefully matched for sex, age and smoking status. RESULTS: We found a significant negative correlation between GABA levels in the ACC and dopamine D2/3 receptor availability in the associative striatum of LR but not in AD or HR individuals. Contrary to our expectations, we did not observe a correlation between Glu concentrations in the ACC and striatal D2/3 receptor availability. CONCLUSIONS: The results may reflect potential regulatory cortical mechanisms on mesolimbic dopamine receptors and their disruption in AD and individuals at high risk, mirroring complex neurotransmitter interactions associated with the pathogenesis of addiction. This is the first study combining 18F-fallypride PET and MRS in AD subjects and individuals at high risk.

Adolescents' neural reactivity to acute psychosocial stress: dysfunctional regulation habits are linked to temporal gyrus response.

Mid-adolescence is a critical time for the development of stress-related disorders and it is associated with significant social vulnerability. However, little is known about normative neural processes accompanying psychosocial stress at this time. Previous research found that emotion regulation strategies critically influence the relationship between stress and the development of psychiatric symptoms during adolescence. Using functional magnetic resonance imaging (fMRI), we examined neural responses to acute stress and analyzed whether the tendency to use adaptive or maladaptive emotion regulation strategies is related to neural and autonomic stress responses. Results show large linear activation increases from low to medium to high stress levels mainly in medial prefrontal, insulae and temporal areas. Caudate and subgenual anterior cingulate cortex, neural areas related to reward and affective valuations, showed linearly decreasing activation. In line with our hypothesis, the current adolescent neural stress profile resembled social rejection and was characterized by pronounced activation in insula, angular and temporal cortices. Moreover, results point to an intriguing role of the anterior temporal gyrus. Stress-related activity in the anterior temporal gyrus was positively related to maladaptive regulation strategies and stress-induced autonomic activity. Maladaptive coping might increase the social threat and reappraisal load of a stressor, relating to higher stress sensitivity of anterior temporal cortices.

Effects of baclofen on insular gain anticipation in alcohol-dependent patients - a randomized, placebo-controlled, pharmaco-fMRI pilot trial.

RATIONALE: One hallmark of addiction is an altered neuronal reward processing. In healthy individuals (HC), reduced activity in fronto-striatal regions including the insula has been observed when a reward anticipation task was performed repeatedly. This effect could indicate a desensitization of the neural reward system due to repetition. Here, we investigated this hypothesis in a cohort of patients with alcohol use disorder (AUD), who have been treated with baclofen or a placebo. The efficacy of baclofen in AUD patients has been shown to have positive clinical effects, possibly via indirectly affecting structures within the neuronal reward system. OBJECTIVES: Twenty-eight recently detoxified patients (13 receiving baclofen (BAC), 15 receiving placebo (PLA)) were investigated within a longitudinal, double-blind, and randomized pharmaco-fMRI design with an individually adjusted daily dosage of 30-270 mg. METHODS: Brain responses were captured by functional magnetic resonance imaging (fMRI) during reward anticipation while participating in a slot machine paradigm before (t1) and after 2 weeks of individual high-dose medication (t2). RESULTS: Abstinence rates were significantly higher in the BAC compared to the PLA group during the 12-week high-dose medication phase. At t1, all patients showed significant bilateral striatal activation. At t2, the BAC group showed a significant decrease in insular activation compared to the PLA group. CONCLUSIONS: By affecting insular information processing, baclofen might enable a more flexible neuronal adaptation during recurrent reward anticipation, which could resemble a desensitization as previously observed in HC. This result strengthens the modulation of the reward system as a potential mechanism of action of baclofen. TRIAL REGISTRATION: Identifier of the main trial (the BACLAD study) at clinical.gov: NCT0126665.

Association between DRD2/ANKK1 TaqIA Allele Status and Striatal Dopamine D2/3 Receptor Availability in Alcohol Use Disorder.

BACKGROUND: The association between blunted dopaminergic neurotransmission and alcohol use disorder (AUD) is well-known. In particular, the impairment of postsynaptic dopamine 2 and 3 receptors (DRD2/3) in the ventral and dorsal striatum during the development and maintenance of alcohol addiction has been investigated in several positron emission tomography (PET) studies. However, it is unclear whether these changes are the result of adaptation or genetic predisposition. METHODS: Here we investigated the association between DRD2/ankyrin repeat and kinase domain-containing 1 (ANKK1) TaqIA allele (rs1800497) status and striatal DRD2/3 availability measured by 18F-fallypride PET in 12 AUD patients and 17 sex-matched healthy controls. Age and smoking status were included as covariates. RESULTS: Contrary to our expectations, TaqIA allele status was not associated with striatal DRD2/3 availability in either group and there was no significant difference between groups, possibly due to the relatively small sample size (N = 29). CONCLUSIONS: Nonetheless, this is the first in vivo study investigating the relationship between dopamine receptor availability and genetic factors in AUD. The pitfalls of assessing such relationships in a relatively small sample are discussed. CLINICAL TRIAL REGISTRATION: The published analysis is an additional, post hoc analysis to the preregistered trial with clinical trial number NCT01679145 available on https://clinical-trials.gov/ct2/show/NCT01679145.

Extrastriatal Dopamine D2/3 Receptor Availability in Alcohol Use Disorder and Individuals at High Risk.

INTRODUCTION: Reduced striatal dopamine D2/3 receptor availability in alcohol use disorder (AUD) has been demonstrated in recent clinical studies and meta-analyses. However, only a limited number of studies investigated extrastriatal D2/3 availability in AUD or in at-risk populations. In line with a dimensional understanding of addiction, extrastriatal dopaminergic neuroadaptations have been suggested to be relevant from a pathobiological perspective. METHODS: We investigated D2/3 receptor availability via 18F-fallypride positron emission tomography applying a region of interest (ROI) approach. We selected ROIs for the prefrontal cortex (PFC) and the anterior cingulate cortex (ACC). Our sample included 19 healthy controls (low risk [LR]), 19 individuals at high risk (HR) to develop addiction, and 20 recently detoxified AUD patients. RESULTS: We found significantly higher D2/3 receptor availability of HR compared to AUD in the left and right rostral ACC (rACC), as well as in the left ventrolateral PFC (vlPFC). We did not observe a significant difference between AUD and LR. After corrections for multiple comparisons none of the ROIs reached significance throughout the group comparison. The D2/3 receptor availability in the left rACC was inversely correlated with symptom severity assessed with the Alcohol Dependency Scale. DISCUSSION: To our knowledge, the present work is the first study investigating extrastriatal D2/3 receptor availabilities in individuals at HR and patients with AUD. The observation that D2/3 receptor availabilities are highest in HR might suggest that their pathobiology differs from subjects with AUD. Future studies are necessary to clarify the intraindividual course of this biomarker over different disease stages and its possible role as a risk or protective factor.

Do Belonging and Social Exclusion at School Affect Structural Brain Development During Adolescence?

Students' sense of belonging presents an essential resource for academic and health outcomes, whereas social exclusion at school negatively impacts students' well-being and academic performance. Aiming to understand how feelings of school-related belonging and exclusion shape the structural brain development, this study applied longitudinal questionnaire-based data and MRI data from 71 adolescent students (37 females, Mage at t1 = 15.0; t2 = 16.1 years). All were white participants from Germany. Voxel-based morphometry revealed only an association of social exclusion (and not of belonging) and gray matter volume in the left anterior insula: From t1 to t2, there was less gray matter decrease, the more social exclusion students perceived. School-related social exclusion and disturbed neurodevelopment are thus significantly associated.

Dopamine D2/3 receptor availability in alcohol use disorder and individuals at high risk: Towards a dimensional approach.

Alcohol use disorder (AUD) is the most common substance use disorder worldwide. Although dopamine-related findings were often observed in AUD, associated neurobiological mechanisms are still poorly understood. Therefore, in the present study, we investigate D2/3 receptor availability in healthy participants, participants at high risk (HR) to develop addiction (not diagnosed with AUD), and AUD patients in a detoxified stage, applying 18 F-fallypride positron emission tomography (18 F-PET). Specifically, D2/3 receptor availability was investigated in (1) 19 low-risk (LR) controls, (2) 19 HR participants, and (3) 20 AUD patients after alcohol detoxification. Quality and severity of addiction were assessed with clinical questionnaires and (neuro)psychological tests. PET data were corrected for age of participants and smoking status. In the dorsal striatum, we observed significant reductions of D2/3 receptor availability in AUD patients compared with LR participants. Further, receptor availability in HR participants was observed to be intermediate between LR and AUD groups (linearly decreasing). Still, in direct comparison, no group difference was observed between LR and HR groups or between HR and AUD groups. Further, the score of the Alcohol Dependence Scale (ADS) was inversely correlated with D2/3 receptor availability in the combined sample. Thus, in line with a dimensional approach, striatal D2/3 receptor availability showed a linear decrease from LR participants to HR participants to AUD patients, which was paralleled by clinical measures. Our study shows that a core neurobiological feature in AUD seems to be detectable in an early, subclinical state, allowing more individualized alcohol prevention programs in the future.

Adolescents' Personality Development - A Question of Psychosocial Stress.

Following the relational-developmental systems approach, this three-wave study examines whether acute stress (T2) mediates the relationship between the development of personality traits from the beginning of 8th grade (T1, M age = 15.63, SD = 0.59; 22 girls) to the end of 9th grade (T3). Using the Montréal Imaging Stress Task, which is a task that provokes acute social stress by negative social feedback, this study combined the functional magnetic resonance imaging (fMRI), heart rate, and longitudinal survey data of 41 adolescents. Mediation analysis revealed that stress-induced left insula activation partially mediates the longitudinal stability of conscientiousness. These results highlight the impact of negative social feedback during stress on students' personality development.

Association of Cortical Glutamate and Working Memory Activation in Patients With Schizophrenia: A Multimodal Proton Magnetic Resonance Spectroscopy and Functional Magnetic Resonance Imaging Study.

BACKGROUND: Cognitive deficits such as working memory (WM) impairment are core features of schizophrenia. One candidate marker for the integrity of synaptic neurotransmission necessary for cognitive processes is glutamate. It is frequently postulated that antipsychotic medication possibly alters functional mechanisms in the living brain. We tested in vivo for group differences in activation of the dorsolateral prefrontal cortex (DLPFC) during WM performance and the association with glutamate concentration in DLPFC depending on medication status. METHODS: A total of 90 subjects (35 control subjects, 36 medicated patients, and 19 unmedicated patients) contributed magnetic resonance spectroscopy data. We estimated glutamate in left DLPFC. Subjects performed an n-back WM task (2-back vs. 0-back) during functional magnetic resonance imaging, and local activation in left DLPFC was measured. For analysis of association with medication status, we calculated linear regression models including an interaction effect with group. RESULTS: Medicated and unmedicated patients with schizophrenia showed impaired performance. We found significantly reduced WM activation in left DLPFC in medicated patients and a trendwise reduction in unmedicated patients as compared with control subjects. We found no group difference in local glutamate concentration. However, we found differential effects of medication status on the association between local glutamate concentration and WM activation in left DLPFC, with a positive association in unmedicated patients but not in medicated patients. CONCLUSIONS: We provide evidence that WM-dependent activation is associated with glutamate concentration in unmedicated patients with schizophrenia. Our finding points to putative allostatic changes that affect the functioning of the brain and might be altered through medication.

Loneliness and Adolescents' Neural Processing of Self, Friends, and Teachers: Consequences for the School Self-Concept.

The present interdisciplinary study explored whether perceived loneliness is associated with ventromedial prefrontal cortex (vMPFC) activation during self- and social judgments (friends and teachers) in adolescents. Moreover, we examined how vMPFC activity is related to the academic self-concept (ASC). Results of manifest path analysis indicated that high perceived loneliness was related to lower neural response to self-judgments. In turn, high neural response to self-judgments was positively associated with the ASC, whereas there was a trendwise negative association between high neural response to teacher-related judgments and ASC. This study reveals associations between perceived loneliness and neural processing of the self, underlining the idea that feeling isolated from others may hinder self-insight and, by extension, the formation of a stable academic self-concept.

Hippocampal gray matter increases following multimodal psychological treatment for combat-related post-traumatic stress disorder.

Introduction: Smaller hippocampal volumes are one of the most consistent findings in neuroimaging studies of post-traumatic stress disorder (PTSD). However, very few prospective studies have assessed changes in hippocampal gray matter prior to and following therapy for PTSD, and no neuroimaging studies to date have longitudinally assessed military populations. Methods: A pilot study was conducted, assessing patients with combat-related PTSD with structural MRI. Participants were then assigned either to a treatment group or waiting-list control group. After the treatment group received multimodal psychological therapy for approximately 6 weeks, both groups completed a second neuroimaging assessment. Results: Region-of-interest analysis was used to measure gray matter volume in the hippocampus and amygdala. There was a group by time interaction; the therapy group (n = 6) showed a significant increase in hippocampal volume and a nonsignificant trend toward an increase in amygdala volume following therapy, while no change was observed in the waiting-list group (n = 9). Conclusions: This study provides initial evidence for increases in gray matter volume in the hippocampus in response to therapy for combat-related PTSD.

Functional changes in the reward circuit in response to gaming-related cues after training with a commercial video game.

In the present longitudinal study, we aimed to investigate video game training associated neuronal changes in reward processing using functional magnetic resonance imaging (fMRI). We recruited 48 healthy young participants which were assigned to one of 2 groups: A group in which participants were instructed to play a commercial video game ("Super Mario 64 DS") on a portable Nintendo DS handheld console at least 30minutes a day over a period of two months (video gaming group; VG) or to a matched passive control group (CG). Before and after the training phase, in both groups, fMRI imaging was conducted during passively viewing reward and punishment-related videos sequences recorded from the trained video game. The results show that video game training may lead to reward related decrease in neuronal activation in the dorsolateral prefrontal cortex (DLPFC) and increase in the hippocampus. Additionally, the decrease in DLPFC activation was associated with gaming related parameters experienced during playing. Specifically, we found that in the VG, gaming related parameters like performance, experienced fun and frustration (assessed during the training period) were correlated to decrease in reward related DLPFC activity. Thus, neuronal changes in terms of video game training seem to be highly related to the appetitive character and reinforcement schedule of the game. Those neuronal changes may also be related to the often reported video game associated improvements in cognitive functions.

Internal and external attention and the default mode network.

Focused attention meditations have been shown to improve psychological health and wellbeing and are nowadays an integral part of many psychotherapies. While research on the neural correlates of focused attention meditation is increasing, findings vary on whether meditations are associated with high or low activity in the default mode network (DMN). To clarify the relationship between focused attention meditation and the activity in DMN regions, it may be helpful to distinguish internal and external attention as well as different phases within one meditation: During focused attention meditation, the practitioner switches between mindful attention, mind-wandering and refocusing. Here, we employed a thought-probe paradigm to study the neural correlates of these different phases. Twenty healthy, meditation naïve participants were introduced to external (mindfulness of sound) and internal (mindfulness of breathing) attention meditation and then practiced the meditation at home for four consecutive days. They then performed the same focused attention meditations during fMRI scanning, in four runs alternating between internal and external attention. At pseudorandom intervals, participants were asked whether they had just been focused on the task (mindful attention) or had been distracted (mind-wandering). During mindful attention, brain regions typically associated with the DMN, such as the medial prefrontal cortex, posterior cingulate cortex and left temporoparietal junction showed significantly less neural activation compared to mind-wandering phases. Reduced activity of the DMN was found during both external and internal attention, with stronger deactivation in the posterior cingulate cortex during internal attention compared to external attention. Moreover, refocusing after mind-wandering was associated with activity in the left inferior frontal gyrus. Our results support the theory that mindful attention is associated with reduced DMN activity compared to mind-wandering, independent of the practitioner's attention focus (i.e., internal vs. external).

Reversal learning strategy in adolescence is associated with prefrontal cortex activation.

Adolescence is a critical maturation period for human cognitive control and executive function. In this study, a large sample of adolescents (n = 85) performed a reversal learning task during functional magnetic resonance imaging. We analyzed behavioral data using a reinforcement learning model to provide individually fitted parameters and imaging data with regard to reward prediction errors (PE). Following a model-based approach, we formed two groups depending on whether individuals tended to update expectations predominantly for the chosen stimulus or also for the unchosen one. These groups significantly differed in their problem behavior score obtained using the child behavior checklist (CBCL) and in a measure of their developmental stage. Imaging results showed that dorsolateral striatal areas covaried with PE. Participants who relied less on learning based on task structure showed less prefrontal activation compared with participants who relied more on task structure. An exploratory analysis revealed that PE-related activity was associated with pubertal development in prefrontal areas, insula and anterior cingulate. These findings support the hypothesis that the prefrontal cortex is implicated in mediating flexible goal-directed behavioral control.

Neural correlates of the self-concept in adolescence-A focus on the significance of friends.

The formation of a coherent and unified self-concept represents a key developmental stage during adolescence. Imaging studies on self-referential processing in adolescents are rare, and it is not clear whether neural structures involved in self-reflection are also involved in reflections of familiar others. In the current study, 41 adolescents were asked to make judgments about trait adjectives during functional magnetic resonance imaging (fMRI): they had to indicate whether the word describes themselves, their friends, their teachers or politicians. Findings indicate a greater overlap in neural networks for responses to self- and friend-related judgments compared to teachers and politicians. In particular, classic self-reference structures such as the ventromedial prefrontal cortex and medial posterior parietal cortex also exhibited higher activation to judgments about friends. In contrast, brain responses towards judgments of teachers (familiar others) compared to politicians (unfamiliar others) did not significantly differ. Results support behavioral findings of a greater relevance of friends for the development of a self-concept during adolescence and indicate underlying functional brain processes. Hum Brain Mapp 38:987-996, 2017. © 2016 Wiley Periodicals, Inc.

Maternal parenting behavior and emotion processing in adolescents-An fMRI study.

Parenting is an essential factor within a child's development, yet the impact of normative variations of parenting on neural emotion processing has not been studied to date. The present study investigated 83 healthy adolescents using functional magnetic resonance imaging and an emotional face-matching paradigm. The faces paradigm elicited an increased amygdala response towards negative facial expressions (fearful and angry each compared to neutral faces) and a significant activation of fusiform gyrus to all emotions separately (fearful, happy, angry faces) compared to neutral faces. Moreover, we investigated associations between neural responses towards emotional faces and mother's parenting behavior (maternal warmth and support, psychological pressure and control behavior). High maternal warmth and support correlated with lower activation to fearful faces in the amygdala. Maternal supportive rather than control behavior seems to have an impact on neural emotion processing, which could also be the key factor for brain functional abnormalities in maltreated children. These results expand existent findings in maltreated children to healthy populations.

Does Feedback-Related Brain Response during Reinforcement Learning Predict Socio-motivational (In-)dependence in Adolescence?

This multi-methodological study applied functional magnetic resonance imaging to investigate neural activation in a group of adolescent students (N = 88) during a probabilistic reinforcement learning task. We related patterns of emerging brain activity and individual learning rates to socio-motivational (in-)dependence manifested in four different motivation types (MTs): (1) peer-dependent MT, (2) teacher-dependent MT, (3) peer-and-teacher-dependent MT, (4) peer-and-teacher-independent MT. A multinomial regression analysis revealed that the individual learning rate predicts students' membership to the independent MT, or the peer-and-teacher-dependent MT. Additionally, the striatum, a brain region associated with behavioral adaptation and flexibility, showed increased learning-related activation in students with motivational independence. Moreover, the prefrontal cortex, which is involved in behavioral control, was more active in students of the peer-and-teacher-dependent MT. Overall, this study offers new insights into the interplay of motivation and learning with (1) a focus on inter-individual differences in the role of peers and teachers as source of students' individual motivation and (2) its potential neurobiological basis.

Keratoacanthoma: a distinct entity?

Keratoacanthoma (KA) are common but exceptional benign tumors, often appearing on sun-exposed areas of light skinned people and showing spontaneous resolution. The goal of this study was to review existing literature, to point out the etiological complexity of KA biology and to answer the controversial debate if or not KA is a distinct entity or a variant of squamous cell carcinoma (SCC). Relying on recent results, we highlight that KA is an individual lesion with a unique molecular signature caused by alterations in the TGFß signalling pathway. These recent findings will help to understand the nature of KA and to develop new reliable diagnostic tools, simplifying the discrimination of the histologically similar KA and SCC.

Aberrant Salience Is Related to Dysfunctional Self-Referential Processing in Psychosis.

BACKGROUND: A dysfunctional differentiation between self-relevant and irrelevant information may affect the perception of environmental stimuli as abnormally salient. The aberrant salience hypothesis assumes that positive symptoms arise from an attribution of salience to irrelevant stimuli accompanied by the feeling of self-relevance. Self-referential processing relies on the activation of cortical midline structures which was demonstrated to be impaired in psychosis. We investigated the neural correlates of self-referential processing, aberrant salience attribution, and the relationship between these 2 measures across the psychosis continuum. METHODS: Twenty-nine schizophrenia patients, 24 healthy individuals with subclinical delusional ideation, and 50 healthy individuals participated in this study. Aberrant salience was assessed behaviorally in terms of reaction times to task irrelevant cues. Participants performed a self-reference task during fMRI in which they had to apply neutral trait words to them or to a public figure. The correlation between self-referential processing and aberrant salience attribution was tested. RESULTS: Schizophrenia patients displayed increased aberrant salience attribution compared with healthy controls and individuals with subclinical delusional ideation, while the latter exhibited intermediate aberrant salience scores. In the self-reference task, schizophrenia patients showed reduced activation in the ventromedial prefrontal cortex (vmPFC), but individuals with subclinical delusional ideation did not differ from healthy controls. In schizophrenia patients, vmPFC activation correlated negatively with implicit aberrant salience attribution. CONCLUSIONS: Higher aberrant salience attribution in schizophrenia patients is related to reduced vmPFC activation during self-referential judgments suggesting that aberrant relevance coding is reflected in decreased neural self-referential processing as well as in aberrant salience attribution.