Structural integrity of frontostriatal connections predicts longitudinal changes in self-esteem

Diverse neurological and psychiatric conditions are marked by a diminished sense of positive self-regard, and reductions in self-esteem are associated with risk for these disorders. Recent evidence has shown that the connectivity of frontostriatal circuitry reflects individual differences in self-esteem. However, it remains an open question as to whether the integrity of these connections can predict self-esteem changes over larger timescales. Using diffusion magnetic resonance imaging and probabilistic tractography, we demonstrate that the integrity of white matter pathways linking the medial prefrontal cortex to the ventral striatum predicts changes in self-esteem 8 months after initial scanning in a sample of 30 young adults. Individuals with greater integrity of this pathway during the scanning session at Time 1 showed increased levels of self-esteem at follow-up, whereas individuals with lower integrity showed stifled or decreased levels of self-esteem. These results provide evidence that frontostriatal white matter integrity predicts the trajectory of self-esteem development in early adulthood, which may contribute to blunted levels of positive self-regard seen in multiple psychiatric conditions, including depression and anxiety.     

Multimodal Magnetic Resonance Imaging for Brain Disorders: Advances and Perspectives

Modern brain imaging technologies play essential roles in our understanding of brain information processing and the mechanisms of brain disorders. Magnetic Resonance Imaging (MRI) and Diffusion Tensor Imaging (DTI) can image the anatomy and structure of the brain. In addition, functional MRI (fMRI) can identify active regions, patterns of functional connectivities and functional networks during either tasks that are specifically related to various aspects of brain function or during the resting state. The merging of such structural and functional information obtained from brain imaging may be able to enhance our understanding of how the brain works and how its diseases can occur. In this paper, we will review advances in both methodologies and clinical applications of multimodal MRI technologies, including MRI, DTI, and fMRI. We will also give our perspectives for the future in these fields. The ultimate goal of our study is to find early biomarkers based on multimodal neuroimages and genome datasets for brain disorders. More importantly, future studies should focus on detecting exactly where and how these brain disorders affect the human brain. It would also be also very interesting to identify the genetic basis of the anatomical and functional abnormalities in the brains of people who have neurological and psychiatric disorders. We believe that we can use brain images to obtain effective biomarkers for various brain disorders with the aid of developing computational methods and models.     

Dynamic frontostriatal functional peak connectivity (in alcohol use disorder)

Alcohol use disorder (AUD) is associated with changes in frontostriatal connectivity, but functional magnetic resonance imaging (fMRI) functional connectivity (FC) approaches are usually not adapted to these circuits. We developed a circuit‐specific fMRI analysis approach to detect dynamic changes in frontostriatal FC inspired by medial‐ventral‐rostral to lateral‐dorsal‐caudal frontostriatal gradients originally identified in nonhuman primate tract‐tracing data. In our PeaCoG (“ pea k co nnectivity on a g radient”) approach we use information about the location of strongest FC on empirical frontostriatal connectivity gradients. We have recently described a basic PeaCoG version with conventional FC, and now developed a dynamic PeaCoG approach with sliding‐window FC. In resting state data of n = 66 AUD participants and n = 40 healthy controls we continue here the analyses that we began with the basic version. Our former result of an AUD‐associated ventral shift in right orbitofrontal cortex PeaCoG is consistently detected in the dynamic approach. Temporospatial variability of dynamic PeaCoG in the left dorsolateral prefrontal cortex is reduced in AUD and associated with self‐efficacy to abstain and days of abstinence. Our method has the potential to provide insight into the dynamics of frontostriatal circuits, which has so far been relatively unexplored, and into their role in mental disorders and normal cognition.     

Cognitive behavioral therapy for depression changes medial prefrontal and ventral anterior cingulate cortex activity associated with self-referential processing

Cognitive behavioral therapy (CBT), an effective treatment for depression, targets self-referential processing of emotional stimuli. We examined the effects of CBT on brain functioning during self-referential processing in depressive patients using functional magnetic resonance imaging (fMRI). Depressive patients (n = 23) and healthy participants (n = 15) underwent fMRI scans during a self-referential task using emotional trait words. The depressive patients had fMRI scans before and after completing a total of 12 weekly sessions of group CBT for depression, whereas the healthy participants underwent fMRI scans 12 weeks apart with no intervention. Before undergoing CBT, the depressive patients showed hyperactivity in the medial prefrontal cortex (MPFC) during self-referential processing of negative words. Following CBT, MPFC and ventral anterior cingulate cortex (vACC) activity during self-referential processing among depressive patients was increased for positive stimuli, whereas it was decreased for negative stimuli. Improvements in depressive symptoms were negatively correlated with vACC activity during self-referential processing of negative stimuli. These results suggest that CBT-related improvements in depressive symptoms are associated with changes in MPFC and vACC activation during self-referential processing of emotional stimuli.     

Enhanced brain responsiveness during active emotional face processing in obsessive compulsive disorder

Abstract

Objectives. The abnormal processing of emotional stimuli is common to a variety of psychiatric disorders. Specifically, patients with prominent anxiety symptoms generally overreact to emotional cues, which has been linked to increased amygdala activation. However, in OCD, enhanced responses are predominantly obtained using disease-specific stimuli and preferentially involve frontostriatal systems. Methods. We assessed 21 OCD patients and 21 healthy controls with fMRI during an emotional face-processing paradigm involving active response generation to test for alterations in both brain activation and task-induced functional connectivity of the frontal cortex, the amygdala and the fusiform face area. Results. OCD patients showed significantly greater activation of “face-processing” regions including the amygdala, fusiform gyrus and dorsolateral prefrontal cortex. The reciprocal connectivity between face-processing regions was enhanced in OCD. Importantly, we detected significant correlations between patients’ clinical symptom severity and both task-related region activation and network functional connectivity. Conclusions. The results suggest that OCD patients may show enhanced brain responsiveness during emotional face-processing when tasks involve active response generation. Our findings diverge from previously described alterations in anxiety disorders, as patients showed enhanced amygdala-prefrontal connectivity as opposed to negative reciprocal interaction. This pattern would appear to be disorder-specific and was significantly related to obsessive-compulsive symptom severity.     

In search of the emotional self: an fMRI study using positive and negative emotional words

OBJECTIVE: The authors used functional magnetic resonance imaging (fMRI) to define the neural regions mediating self-referential processing of emotional stimuli and to explore how these regions are influenced by the emotional valence of the stimulus. METHOD: Ten healthy subjects were presented with words describing positive and negative personality traits during fMRI scanning in three different conditions. In the self-referential processing condition, subjects judged whether they thought each trait described them. In the other-referential processing condition, subjects judged whether the stimulus described a generally desirable trait. In the letter-recognition control condition, subjects indicated whether the word contained a specific target letter. RESULTS: The self-referential condition induced bilateral activation in the dorsomedial prefrontal cortex, whereas the other-referential condition induced activation in lateral prefrontal areas. Activation in the right dorsomedial prefrontal cortex was unique to the self-referential condition regardless of the valence of the words, although positive words produced a more robust activation than did negative words. In the self-referential condition, differences between the processing of positive and negative words were seen in regions outside the medial frontal cortex, with reductions in the insula, temporal and occipital regions, and inferior parietal regions associated with negative words. CONCLUSIONS: A widely distributed network of brain areas contributes to emotional processing. Among these regions, the right dorsomedial prefrontal cortex is one main area mediating self-reference. By providing a personal perspective in the evaluation of emotional stimuli, the right dorsomedial prefrontal cortex may mediate cognitive processes, such as those involved in psychotherapy, that guide self-regulation of emotional experience.     

Toward dysfunctional connectivity: a review of neuroimaging findings in pediatric major depressive disorder

Child and adolescent psychiatric neuroimaging research typically lags behind similar advances in adult disorders. While the pediatric depression imaging literature is less developed, a recent surge in interest has created the need for a synthetic review of this work. Major findings from pediatric volumetric and functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI) and resting state functional connectivity studies converge to implicate a corticolimbic network of key areas that work together to mediate the task of emotion regulation. Imaging the brain of children and adolescents with unipolar depression began with volumetric studies of isolated brain regions that served to identify key prefrontal, cingulate and limbic nodes of depression-related circuitry elucidated from more recent advances in DTI and functional connectivity imaging. Systematic review of these studies preliminarily suggests developmental differences between findings in youth and adults, including prodromal neurobiological features, along with some continuity across development.     

Trait anhedonia is associated with reduced reactivity and connectivity of mesolimbic and paralimbic reward pathways

Anhedonia is the inability to experience pleasure from normally pleasant stimuli. Although anhedonia is a prominent feature of many psychiatric disorders, trait anhedonia is also observed dimensionally in healthy individuals. Currently, the neurobiological basis of anhedonia is poorly understood because it has been mainly investigated in patients with psychiatric disorders. Thus, previous studies have not been able to adequately disentangle the neural correlates of anhedonia from other clinical symptoms. In this study, trait anhedonia was assessed in well-characterized healthy participants with no history of Axis I psychiatric illness. Functional magnetic resonance imaging with musical stimuli was used to examine brain responses and effective connectivity in relation to individual differences in anhedonia. We found that trait anhedonia was negatively correlated with pleasantness ratings of music stimuli and with activation of key brain structures involved in reward processing, including nucleus accumbens (NAc), basal forebrain and hypothalamus which are linked by the medial forebrain bundle to the ventral tegmental area (VTA). Brain regions important for processing salient emotional stimuli, including anterior insula and orbitofrontal cortex were also negatively correlated with trait anhedonia. Furthermore, effective connectivity between NAc, VTA and paralimbic areas, that regulate emotional reactivity to hedonic stimuli, was negatively correlated with trait anhedonia. Our results indicate that trait anhedonia is associated with reduced reactivity and connectivity of mesolimbic and related limbic and paralimbic systems involved in reward processing. Critically, this association can be detected even in individuals without psychiatric illness. Our findings have important implications both for understanding the neurobiological basis of anhedonia and for the treatment of anhedonia in psychiatric disorders.     

A network of amygdala connections predict individual differences in trait anxiety

In this study we demonstrate that the pattern of an amygdala‐centric network contributes to individual differences in trait anxiety. Individual differences in trait anxiety were predicted using maximum likelihood estimates of amygdala structural connectivity to multiple brain targets derived from diffusion‐tensor imaging (DTI) and probabilistic tractography on 72 participants. The prediction was performed using a stratified sixfold cross validation procedure using a regularized least square regression model. The analysis revealed a reliable network of regions predicting individual differences in trait anxiety. Higher trait anxiety was associated with stronger connections between the amygdala and dorsal anterior cingulate cortex, an area implicated in the generation of emotional reactions, and inferior temporal gyrus and paracentral lobule, areas associated with perceptual and sensory processing. In contrast, higher trait anxiety was associated with weaker connections between amygdala and regions implicated in extinction learning such as medial orbitofrontal cortex, and memory encoding and environmental context recognition, including posterior cingulate cortex and parahippocampal gyrus. Thus, trait anxiety is not only associated with reduced amygdala connectivity with prefrontal areas associated with emotion modulation, but also enhanced connectivity with sensory areas. This work provides novel anatomical insight into potential mechanisms behind information processing biases observed in disorders of emotion. Hum Brain Mapp 36:4819–4830, 2015. © 2015 Wiley Periodicals, Inc.     

Diffusions-Tensor-Bildgebung (DTI) und funktionelle Magnetresonanztomographie (fMRI) erweitern das Methodenspektrum in der psychiatrischen Forschung

In psychiatric research, there is a growing interest in the microstructural and functional characteristics of brain networks, which often form the basis of current etiological concepts. As a result of novel magnetic resonance imaging techniques, the pathogenic characteristics of neuronal activity and connectivity can be examined in a noninvasive, safe, and repeatable manner. Functional magnetic resonance imaging (fMRI) uses blood oxygenation level-dependent (BOLD) measures for identifying the gray matter contribution to cognition. Diffusion tensor imaging (DTI) reveals the course and structural integrity of white matter projections. Because DTI does not require special motivation and performance, group differences in psychiatry are more easily interpreted in terms of underlying pathology. To date few studies have tried to investigate both, i.e. dynamic and microstructural data in the sense of a modern multi-dimensional investigation approach. The combination of both techniques, however, seems to offer a promising vehicle to further extent our current understanding of mental disorders and to identify populations at risk. In addition to addressing findings in psychiatric research, the present article presents a technical overview of DTI and examines the limitations and potential applications of both techniques.     

Impact of meditation training on the default mode network during a restful state

Mindfulness meditation has been shown to promote emotional stability. Moreover, during the processing of aversive and self-referential stimuli, mindful awareness is associated with reduced medial prefrontal cortex (MPFC) activity, a central default mode network (DMN) component. However, it remains unclear whether mindfulness practice influences functional connectivity between DMN regions and, if so, whether such impact persists beyond a state of meditation. Consequently, this study examined the effect of extensive mindfulness training on functional connectivity within the DMN during a restful state. Resting-state data were collected from 13 experienced meditators (with over 1000 h of training) and 11 beginner meditators (with no prior experience, trained for 1 week before the study) using functional magnetic resonance imaging (fMRI). Pairwise correlations and partial correlations were computed between DMN seed regions’ time courses and were compared between groups utilizing a Bayesian sampling scheme. Relative to beginners, experienced meditators had weaker functional connectivity between DMN regions involved in self-referential processing and emotional appraisal. In addition, experienced meditators had increased connectivity between certain DMN regions (e.g. dorso-medial PFC and right inferior parietal lobule), compared to beginner meditators. These findings suggest that meditation training leads to functional connectivity changes between core DMN regions possibly reflecting strengthened present-moment awareness.     

Identifying dynamic functional connectivity biomarkers using GIG‐ICA: Application to schizophrenia,schizoaffective disorder,and psychotic bipolar disorder

Functional magnetic resonance imaging (fMRI) studies have shown altered brain dynamic functional connectivity (DFC) in mental disorders. Here, we aim to explore DFC across a spectrum of symptomatically‐related disorders including bipolar disorder with psychosis (BPP), schizoaffective disorder (SAD), and schizophrenia (SZ). We introduce a group information guided independent component analysis procedure to estimate both group‐level and subject‐specific connectivity states from DFC. Using resting‐state fMRI data of 238 healthy controls (HCs), 140 BPP, 132 SAD, and 113 SZ patients, we identified measures differentiating groups from the whole‐brain DFC and traditional static functional connectivity (SFC), separately. Results show that DFC provided more informative measures than SFC. Diagnosis‐related connectivity states were evident using DFC analysis. For the dominant state consistent across groups, we found 22 instances of hypoconnectivity (with decreasing trends from HC to BPP to SAD to SZ) mainly involving post‐central, frontal, and cerebellar cortices as well as 34 examples of hyperconnectivity (with increasing trends HC through SZ) primarily involving thalamus and temporal cortices. Hypoconnectivities/hyperconnectivities also showed negative/positive correlations, respectively, with clinical symptom scores. Specifically, hypoconnectivities linking postcentral and frontal gyri were significantly negatively correlated with the PANSS positive/negative scores. For frontal connectivities, BPP resembled HC while SAD and SZ were more similar. Three connectivities involving the left cerebellar crus differentiated SZ from other groups and one connection linking frontal and fusiform cortices showed a SAD‐unique change. In summary, our method is promising for assessing DFC and may yield imaging biomarkers for quantifying the dimension of psychosis. Hum Brain Mapp 38:2683–2708, 2017. © 2017 Wiley Periodicals, Inc.     

A transcallosal fibre system between homotopic inferior frontal regions supports complex linguistic processing

Inferior frontal regions in the left and right hemisphere support different aspects of language processing. In the canonical model, left inferior frontal regions are mostly involved in processing based on phonological, syntactic and semantic features of language, whereas the right inferior frontal regions process paralinguistic aspects like affective prosody. Using diffusion tensor imaging (DTI)‐based probabilistic fibre tracking in 20 healthy volunteers, we identify a callosal fibre system connecting left and right inferior frontal regions that are involved in linguistic processing of varying complexity. Anatomically, we show that the interhemispheric fibres are highly aligned and distributed along a rostral to caudal gradient in the body and genu of the corpus callosum to connect homotopic inferior frontal regions. In the light of converging data, taking previous DTI‐based tracking studies and clinical case studies into account, our findings suggest that the right inferior frontal cortex not only processes paralinguistic aspects of language (such as affective prosody), as purported by the canonical model, but also supports the computation of linguistic aspects of varying complexity in the human brain. Our model may explain patterns of right‐hemispheric contribution to stroke recovery as well as disorders of prosodic processing. Beyond language‐related brain function, we discuss how inter‐species differences in interhemispheric connectivity and fibre density, including the system we described here may also explain differences in transcallosal information transfer and cognitive abilities across different mammalian species.     

Challenges in measuring individual differences in functional connectivity using fMRI: The case of healthy aging

Many studies report individual differences in functional connectivity, such as those related to age. However, estimates of connectivity from fMRI are confounded by other factors, such as vascular health, head motion and changes in the location of functional regions. Here, we investigate the impact of these confounds, and pre‐processing strategies that can mitigate them, using data from the Cambridge Centre for Ageing & Neuroscience ( www.cam-can.com ). This dataset contained two sessions of resting‐state fMRI from 214 adults aged 18–88. Functional connectivity between all regions was strongly related to vascular health, most likely reflecting respiratory and cardiac signals. These variations in mean connectivity limit the validity of between‐participant comparisons of connectivity estimates, and were best mitigated by regression of mean connectivity over participants. We also showed that high‐pass filtering, instead of band‐pass filtering, produced stronger and more reliable age‐effects. Head motion was correlated with gray‐matter volume in selected brain regions, and with various cognitive measures, suggesting that it has a biological (trait) component, and warning against regressing out motion over participants. Finally, we showed that the location of functional regions was more variable in older adults, which was alleviated by smoothing the data, or using a multivariate measure of connectivity. These results demonstrate that analysis choices have a dramatic impact on connectivity differences between individuals, ultimately affecting the associations found between connectivity and cognition. It is important that fMRI connectivity studies address these issues, and we suggest a number of ways to optimize analysis choices. Hum Brain Mapp 38:4125–4156, 2017. © 2017 Wiley Periodicals, Inc.     

Altered resting state connectivity of the default mode network in alexithymia

Alexithymia is a trait characterized by a diminished capacity to describe and distinguish emotions and to fantasize; it is associated with reduced introspection and problems in emotion processing. The default mode network (DMN) is a network of brain areas that is normally active during rest and involved in emotion processing and self-referential mental activity, including introspection. We hypothesized that connectivity of the DMN might be altered in alexithymia. Twenty alexithymic and 18 non-alexithymic healthy volunteers underwent a resting state fMRI scan. Independent component analysis was used to identify the DMN. Differences in connectivity strength were compared between groups. Within the DMN, alexithymic participants showed lower connectivity within areas of the DMN (medial frontal and temporal areas) as compared to non-alexithymic participants. In contrast, connectivity in the high-alexithymic participants was higher for the sensorimotor cortex, occipital areas and right lateral frontal cortex than in the low-alexithymic participants. These results suggest a diminished connectivity within the DMN of alexithymic participants, in brain areas that may also be involved in emotional awareness and self-referential processing. On the other hand, alexithymia was associated with stronger functional connections of the DMN with brain areas involved in sensory input and control of emotion.     

Cognitive function in eating disorders and therapeutic approach

We examined brain activation in the presence of eating disorders while processing unpleasant words concerning body images using functional magnetic resonance imaging (fMRI). Anorexia nervosa restricting type (AN-R) and anorexia nervosa binge-eating/ purging type (AN-BP) patients showed significant amygdala activation. Farther, AN-BP and bulimia nervosa (BN) patients showed significant medial prefrontal cortex activation. Next, we conducted short-term integrated group therapy for eating disorders. After treatment, depressive scores of POMS and emotional-oriented coping scores of CISS were significantly decreased, and EAT scores and self-esteem scores of RSES were significantly increased.     

Aberrant connectivity of lateral prefrontal networks in presymptomatic Huntington's disease

In clinically presymptomatic individuals with the Huntington's disease (HD) gene mutation, functional neuroimaging data have suggested a dysfunction of multiple cortical and subcortical regions including the prefrontal and parietal cortex, as well as the striatum. Although it has been hypothesized that these activation differences most likely reflect aberrant corticostriatal circuits, the functional coupling of neural networks associated with cognitive performance has not been investigated so far. In this study, we used functional magnetic resonance imaging (fMRI) and multivariate analytic techniques to investigate memory-related patterns of functional connectivity in healthy controls (n = 16) and pre-HD individuals (n = 16). Independent component analyses (ICA) revealed distinct bilateral frontostriatal and frontoparietal networks that were activated during a verbal working memory paradigm in both healthy controls and pre-HD subjects. Compared with healthy controls, pre-HD individuals exhibited lower functional connectivity in left lateral prefrontal and parietal regions as well as in the bilateral putamen. Functional connectivity indices in the left putamen were negatively correlated with the CAG repeat size and the UHDRS behavioral score, and positively correlated with the predicted years to manifest symptom onset. The connectivity of the right putamen was negatively correlated with the UHDRS motor score. In pre-HD individuals, these results suggest an early frontostriatal and frontoparietal deficit of dissociable functional networks associated with executive processing.     

Disrupted default mode network connectivity in male adolescents with conduct disorder

Conduct disorder (CD) is a serious behavioral disorder of childhood and adolescence. The default mode network (DMN) is a brain network which supports self-referential cognitive processes and is typically deactivated during task performance. The aim of this study was to investigate DMN connectivity in male adolescents with pure CD compared to typically-developing controls. Eighteen male adolescents with CD and 18 sex-, age- and education-matched typically-developing (TD) participants were recruited. Current and lifetime psychiatric disorders were assessed using the Chinese version of the Schedule for Affective Disorder and Schizophrenia for School-Age Children-Present and Lifetime Version. Resting state functional magnetic resonance imaging (fMRI) data were obtained using a 3.0 T scanner. Independent components analysis (ICA) was used to investigate functional connectivity between the DMN and related brain regions. DMN activity was observed in medial prefrontal, posterior cingulate, and lateral parietal cortices, and extended to the brainstem. Adolescents with CD showed significantly reduced functional connectivity within the bilateral posterior cingulate cortex (PCC), bilateral precuneus and right superior temporal gyrus relative to TD controls. CD is associated with reduced functional connectivity within the DMN and between the DMN and other regions. These preliminary results suggest that deficits in DMN functional connectivity may serve as a biomarker of CD.     

Prefrontal transcranial direct current stimulation changes connectivity of resting-state networks during fMRI

Transcranial direct current stimulation (tDCS) has been proposed for experimental and therapeutic modulation of regional brain function. Specifically, anodal tDCS of the dorsolateral prefrontal cortex (DLPFC) together with cathodal tDCS of the supraorbital region have been associated with improvement of cognition and mood, and have been suggested for the treatment of several neurological and psychiatric disorders. Although modeled mathematically, the distribution, direction, and extent of tDCS-mediated effects on brain physiology are not well understood. The current study investigates whether tDCS of the human prefrontal cortex modulates resting-state network (RSN) connectivity measured by functional magnetic resonance imaging (fMRI). Thirteen healthy subjects underwent real and sham tDCS in random order on separate days. tDCS was applied for 20 min at 2 mA with the anode positioned over the left DLPFC and the cathode over the right supraorbital region. Patterns of resting-state brain connectivity were assessed before and after tDCS with 3 T fMRI, and changes were analyzed for relevant networks related to the stimulation-electrode localizations. At baseline, four RSNs were detected, corresponding to the default mode network (DMN), the left and right frontal-parietal networks (FPNs) and the self-referential network. After real tDCS and compared with sham tDCS, significant changes of regional brain connectivity were found for the DMN and the FPNs both close to the primary stimulation site and in connected brain regions. These findings show that prefrontal tDCS modulates resting-state functional connectivity in distinct functional networks of the human brain.