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This study investigated the neural correlates of the so-called affect heuristic, which refers to the phenomenon whereby individuals tend to rely on affective states rather than rational deliberation of utility and probabilities during judgments of risk and utility of a given event or scenario. The study sought to explore whether there are shared regional activations during both judgments of relative risk and relative benefit of various scenarios, thus being a potential candidate of the affect heuristic. Using functional magnetic resonance imaging, we developed a novel risk perception task, based on a preexisting behavioral task assessing the affect heuristic. A whole-brain voxel-wise analysis of a sample of participants (n = 42) during the risk and benefit conditions revealed overlapping clusters in the left insula, left inferior frontal gyrus, and left medial frontal gyrus across conditions. Extraction of parameter estimates of these clusters revealed that activity of these regions during both tasks was inversely correlated with a behavioral measure assessing the inclination to use the affect heuristic. More activity in these areas during risk judgments reflect individuals' ability to disregard momentary affective impulses. The insula may be involved in integrating viscero-somatosensory information and forming a representation of the current emotional state of the body, whereas activity in the left inferior frontal gyrus and medial frontal gyrus indicates that executive processes may be involved in inhibiting the impulse of making judgments in favor of deliberate risk evaluations.

Background: Depersonalization/derealization disorder is a dissociative disorder characterized by feelings of unreality and detachment from the self and surroundings. Depersonalization/derealization disorder is classified as a primary disorder, but depersonalization symptoms are frequently observed in mood and anxiety disorders. In the context of major depressive disorder (MDD), depersonalization symptoms are associated with greater depressive severity as indexed by treatment resistance, inpatient visits, and duration of depressive episodes. In the current investigation, we tested four network-based, neural-functional hypotheses of depersonalization in MDD. These hypotheses were framed in terms of functional relationships between 1) extrastriate body area and default mode network (DMN); 2) hippocampus and DMN; 3) medial prefrontal cortex and ventral striatum; and 4) posterior and anterior insular cortex. Methods: We conducted functional magnetic resonance imaging during resting state on 28 female patients with MDD and 27 control subjects with no history of a psychiatric disorder. Functional connectivity between seed and target regions as specified by our network-level hypotheses was computed and correlated with scores on the Cambridge Depersonalization Scale. We used a conservative, unbiased bootstrapping procedure to test the significance of neural-behavioral correlations observed under each of the four models tested. Results: Of the four neural-functional models of depersonalization symptoms tested, only the model proposing that reduced connectivity between the extrastriate body area and DMN predicts higher levels of depersonalization symptoms in MDD was confirmed. Conclusions: Our results indicate that depersonalization/derealization disorder symptoms in patients with depression are related to reduced functional connectivity between brain regions that are proposed to support processing of body-related (extrastriate body area) and autobiographical (DMN) information.

Vasoactive intestinal polypeptide (VIP) is a neuroendocrine peptide distributed throughout the human body, including the CNS, where it is particularly abundant in brain regions associated with anxiety and depression. Based on earlier studies indicating that peripheral VIP may cross through the blood–brain barrier, we hypothesized plasma VIP levels to be associated with symptoms of anxiety and depression, as well as brain volume and resting-state functional connectivity in the amygdala, hippocampus, parahippocampus, and orbitofrontal cortex. Plasma VIP concentrations and anxiety/depression symptoms were measured in 37 healthy females. Functional and structural magnetic resonance imaging were used to evaluate functional connectivity and brain volume respectively, and their associations with VIP concentrations within brain regions associated with anxiety and depression. Negative correlations were found between VIP levels and symptoms of anxiety (r = − 0.44, p = 0.002) and depression (r = − 0.50, p = 0.001). Functional connectivity demonstrated significant VIP-dependent positive associations between the amygdala seed region with both the right parahippocampus (t(33) = 3.1, pFDR = 0.02) and right lateral orbitofrontal cortex (OFC; t(33) = 2.9, pFDR = 0.02). Moreover, VIP concentrations were significantly, positively correlated with brain volume in the left amygdala (r = 0.28, p = 0.007) and left lateral OFC (r = 0.29, p = 0.004). The present findings highlight a potential role for VIP in the neurobiology of affective symptoms.

BACKGROUND: Nonsuicidal self-injury (NSSI) is prevalent in adolescent populations worldwide. Emotion dysregulation is believed to contribute to NSSI, but underlying mechanisms are less known. We combined psychophysiological and neural data with subjective self-report in close temporal proximity to examine the mechanisms underlying emotion processing in adolescents with NSSI relative to control adolescents without a psychiatric diagnosis. METHODS: Thirty female adolescents with NSSI and 30 age-matched female control subjects were included in this case-control study. Participants were presented with negative affective pictures during a functional magnetic resonance imaging scan. In a separate facial electromyography session, the same participants were shown positive and negative affective images and also provided ratings of valence and arousal. RESULTS: Participants with NSSI responded to affective images with greater positive (e.g., zygomatic) and greater negative (e.g., corrugator) reactivity. We found no differences in self-reported affect in response to the images. Analyses of the negative picture-viewing functional magnetic resonance imaging data showed a significant positive correlation between anterior insula response and the averaged electromyography magnitude in NSSI, but not in control subjects. CONCLUSIONS: Adolescents with NSSI show enhanced emotional reactivity that is associated with anterior insula responding, but no abnormalities in self-reported affect. This discrepancy between self-report and objective measures of emotional reactivity potentially indicates a suppression of the emotional reaction in adolescents with NSSI. Moreover, the current data suggest potential targets for novel therapeutic approaches that can be combined with existing clinical treatment, such as real-time electromyography-based biofeedback focusing on emotional awareness, labeling, and expressing emotional experiences. Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission [538-2013-7434]; ALF Grants, Region Ostergotland [LIO-535931, LIO-520131]

Botvinik-Nezer, Rotem et al., Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses. The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset. Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed., European Union’s Horizon 2020 research and innovation programme (https://ec.europa.eu/programmes/horizon2020/en) under the Marie Skłodowska-Curie grant agreement no. 665501. A. Eed was supported by a predoctoral fellowship La Caixa-Severo Ochoa from Obra Social La Caixa. S.B.E. was supported by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement no. 785907 (HBP SGA2).

BACKGROUND: Electroconvulsive therapy (ECT) is associated with volumetric enlargements of corticolimbic brain regions. However, the pattern of whole-brain structural alterations following ECT remains unresolved. Here, we examined the longitudinal effects of ECT on global and local variations in gray matter, white matter, and ventricle volumes in patients with major depressive disorder as well as predictors of ECT-related clinical response. METHODS: Longitudinal magnetic resonance imaging and clinical data from the Global ECT-MRI Research Collaboration (GEMRIC) were used to investigate changes in white matter, gray matter, and ventricle volumes before and after ECT in 328 patients experiencing a major depressive episode. In addition, 95 nondepressed control subjects were scanned twice. We performed a mega-analysis of single subject data from 14 independent GEMRIC sites. RESULTS: Volumetric increases occurred in 79 of 84 gray matter regions of interest. In total, the cortical volume increased by mean +/- SD of 1.04 +/- 1.03% (Cohens d = 1.01, p amp;lt; .001) and the subcortical gray matter volume increased by 1.47 +/- 1.05% (d = 1.40, p amp;lt; .001) in patients. The subcortical gray matter increase was negatively associated with total ventricle volume (Spearmans rank correlation rho = -.44, p amp;lt; .001), while total white matter volume remained unchanged (d = -0.05, p = .41). The changes were modulated by number of ECTs and mode of electrode placements. However, the gray matter volumetric enlargements were not associated with clinical outcome. CONCLUSIONS: The findings suggest that ECT induces gray matter volumetric increases that are broadly distributed. However, gross volumetric increases of specific anatomically defined regions may not serve as feasible biomarkers of clinical response. Funding Agencies|Western Norway Regional Health Authority [911986, 912238]; University of Bergen; Fulbright Program; National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [MH092301, MH110008, U01 MH11826]; Interdisciplinary Center for Clinical Research of the Medical Faculty of Munster [Dan 3/012/17]; Lundbeck FoundationLundbeckfonden; Carlos III Health InstituteInstituto de Salud Carlos III [CPII16/00048]; Innovative Medical Research [RE111604, RE111722, RO1 MH111359, U24 DA041123]; German Research FoundationGerman Research Foundation (DFG) [FOR2107 DA1151/5-1, DA1151/5-2, SFB-TRR58]

The interaction of the midbrain dopaminergic system and the striatum is implicated in reward processing; it is still unknown, however, how this interaction is altered in Major Depressive Disorder (MDD). In the current study, we related the dopamine release/binding inferred by [11C] Raclopride functional Positron Emission Tomography (fPET) to neural activity monitored by blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in adults diagnosed with MDD and healthy controls (CTL). Participants completed a monetary incentive delay (MID) task during simultaneous [11C] Raclopride fPET and fMRI. Instead of the usual kinetic modeling method for analyzing dynamic PET time activity curves (TACs), we used a simpler general linear model (GLM) approach, which includes introducing a fPET dopamine activation response function to model changes in the TAC associated with the MID task. In addition, using simulations, we show that the GLM approach has several advantages over kinetic modeling. This is achieved without invoking erroneous steady-state assumptions or selecting a suitable reference region. Our results include the observation of both decreased fMRI activation and dopamine release/binding in the striatum in the MDD cohort, implying a reduced reward processing capacity in MDD. Furthermore, in the MDD group, individuals with lower fMRI activations in the right middle putamen and ventral medial prefrontal cortex (vmPFC) had higher reflection rumination scores, and individuals with lower dopamine release/binding in the left putamen and the right nucleus accumbens (NAcc) also had higher reflection rumination scores. Significant cross-modal inter-subject and intra-subject correlations of dopamine release/binding and fMRI activation were observed in the CTL group, but not in the MDD group. The intra-subject correlation of the two modalities was negatively associated with reflection rumination scores in the CTL group, indicating that decoupling of the dopaminergic system and striatum may be important in the pathophysiology of MDD.

Major depressive disorder (MDD) is one of the most significant contributors to the global burden of illness. Diffusion tensor imaging (DTI) is a procedure that has been used in several studies to characterize abnormalities in white matter (WM) microstructural integrity in MDD. These studies, however, have provided divergent findings, potentially due to the large variety of methodological alternatives available in conducting DTI research. In order to determine the importance of different approaches to coregistration of DTI-derived metrics to a standard space, we compared results from two different skeletonized voxel-wise analysis approaches: the standard TBBS pipeline and the Advanced Normalization Tools (ANTs) approach incorporating a symmetric image normalization (SyN) algorithm and a group-wise template (ANTs TBSS). We also assessed effects of applying twelve different fitting procedures for the diffusion tensor. For our dataset, lower fractional anisotropy (FA) and axial diffusivity (AD) in depressed subjects compared with healthy controls were found for both methods and for all fitting procedures. No group differences were found for radial and mean diffusivity indices. Importantly, for the AD metric, the normalization methods and fitting procedures showed reliable differences, both in the volume and in the number of significant between-groups difference clusters detected. Additionally, a significant voxel-based correlation, in the left inferior fronto-occipital fasciculus, between AD and self-reported stress was found only for one of the normalization procedure (ANTs TBSS). In conclusion, the sensitivity to detect group-level effects on DTI metrics might depend on the DTI normalization and/or tensor fitting procedures used.

GABAergic signaling is involved in modulating the reinforcing properties of alcohol, and GABAB receptors have been proposed as a potential target for clinical treatment of alcoholism. The orthosteric GABAB receptor agonist baclofen has been shown to suppress operant self-administration of alcohol in animals and alcohol use in alcohol-dependent patients, but its utility is limited by a narrow therapeutic index. We tested the effects of ADX71441, a novel GABAB receptor positive allosteric modulator, on alcohol-related behaviors in rats. We first assessed the effects of ADX71441 (1, 3, 10 and 30 mg/kg, I.P.) on both non-dependent and dependent male Wistar rats trained to self-administer 20% alcohol. We then determined the effects of ADX71441 on stress-induced as well as cue-induced relapse-like behavior. Finally, we sought to identify the brain regions through which ADX71441 may act to prevent relapse-like behavior by mapping the neuronal activation induced by stress-induced reinstatement of alcohol-seeking using c-Fos immunohistochemistry. ADX71441 dose-dependently decreased alcohol self-administration of both dependent and non-dependent animals, but its potency was higher in alcohol-dependent rats. Furthermore, both cue- and stress-induced alcohol seeking were blocked by the GABAB receptor positive allosteric modulator. Finally, pretreatment with 3 mg/kg of ADX71441 before stress-induced reinstatement significantly decreased c-Fos expression in a network of brain regions implicated in stress-induced relapse, comprising the nucleus accumbens shell, the dorsal raphe nucleus and the medial prefrontal cortex. Our findings support a causal role of GABAB receptors in alcohol reinforcement and relapse to alcohol seeking. These effects are observed in the absence of significant sedative side effects. Jointly, these observations indicate that GABAB receptor positive allosteric modulators merit being tested clinically for the treatment of alcoholism. Our data also point to a potential biomarker of target engagement for early clinical studies.

Neural models of major depressive disorder (MDD) posit that over-response of components of the brain’s salience network (SN) to negative stimuli plays a crucial role in the pathophysiology of MDD. In the present proof-of-concept study, we tested this formulation directly by examining the affective consequences of training depressed persons to down-regulate response of SN nodes to negative material. Ten participants in the real neurofeedback group saw, and attempted to learn to down-regulate, activity from an empirically identified node of the SN. Ten other participants engaged in an equivalent procedure with the exception that they saw SN-node neurofeedback indices from participants in the real neurofeedback group. Before and after scanning, all participants completed tasks assessing emotional responses to negative scenes and to negative and positive self-descriptive adjectives. Compared to participants in the sham-neurofeedback group, from pre- to post-training, participants in the real-neurofeedback group showed a greater decrease in SN-node response to negative stimuli, a greater decrease in self-reported emotional response to negative scenes, and a greater decrease in self-reported emotional response to negative self-descriptive adjectives. Our findings provide support for a neural formulation in which the SN plays a primary role in contributing to negative cognitive biases in MDD.

Diffusion tensor imaging (DTI) holds promise for developing our understanding of white-matter pathology in major depressive disorder (MDD). Variable findings in DTI-based investigations of MDD, however, have thwarted development of this literature. Effects of extra-cellular free-water on the sensitivity of DTI metrics could account for some of this inconsistency. Here we investigated whether applying a free-water correction algorithm to DTI data could improve the sensitivity to detect clinical effects using DTI metrics. Only after applying this correction, we found: a) significantly decreased fractional anisotropy and axial diffusivity (AD) in the left inferior fronto-occipital fasciculus (IFOF) in MDD; and b) increased self-reported stress that significantly correlated with decreased IFOF AD in depression. We estimated and confirmed the robustness of differences observed between free-water corrected and uncorrected approaches using bootstrapping. We conclude that applying a free-water correction to DTI data increases the sensitivity of DTI-based metrics to detect clinical effects in MDD., Highlights • DTI suffers from partial volume effects that limit the estimation of white-matter integrity in major depressive disorder. • Applying a free-water correction to DTI data improves the sensitivity of DTI metrics to identify effects in depression. • Reductions in free-water DTI metrics in depression were associated with increased stress.

Objective Behavioral inhibition (BI) is an early developing trait associated with cautiousness and development of clinical depression and anxiety. Little is known about the neural basis of BI and its predictive importance concerning risk for internalizing disorders. We looked at functional connectivity of the default-mode network (DMN) and salience network (SN), given their respective roles in self-relational and threat processing, in the risk for internalizing disorders, with an emphasis on determining the functional significance of these networks for BI. Method We used functional magnetic resonance imaging to scan, during the resting state, children and adolescents 8 to 17 years of age who were either at high familial risk (HR; n = 16) or low familial risk (LR; n = 18) for developing clinical depression and/or anxiety. Whole-brain DMN and SN functional connectivity were estimated for each participant and compared across groups. We also compared the LR and HR groups on levels of BI and anxiety, and incorporated these data into follow-up neurobehavioral correlation analyses. Results The HR group, relative to the LR group, showed significantly decreased DMN connectivity with the ventral striatum and bilateral sensorimotor cortices. Within the HR group, trait BI increased as DMN connectivity with the ventral striatum and sensorimotor cortex decreased. The HR and LR groups did not differ with respect to SN connectivity. Conclusion Our findings show, in the risk for internalizing disorders, a negative functional relation between brain regions supporting self-relational processes and reward prediction. These findings represent a potential neural substrate for behavioral inhibition in the risk for clinical depression and anxiety.

Negative biases in cognition have been documented consistently in major depressive disorder (MDD), including difficulties in the ability to control the processing of negative material. Although negative information-processing biases have been studied using both behavioral and neuroimaging paradigms, relatively little research has been conducted examining the difficulties of depressed persons with inhibiting the retrieval of negative information from long-term memory. In this study, we used the think/no-think paradigm and functional magnetic resonance imaging to assess the cognitive and neural consequences of memory suppression in individuals diagnosed with depression and in healthy controls. The participants showed typical behavioral forgetting effects, but contrary to our hypotheses, there were no differences between the depressed and nondepressed participants or between neutral and negative memories. Relative to controls, depressed individuals exhibited greater activity in right middle frontal gyrus during memory suppression, regardless of the valence of the suppressed stimuli, and differential activity in the amygdala and hippocampus during memory suppression involving negatively valenced stimuli. These findings indicate that depressed individuals are characterized by neural anomalies during the suppression of long-term memories, increasing our understanding of the brain bases of negative cognitive biases in MDD. Electronic supplementary material The online version of this article (doi:10.3758/s13415-016-0464-x) contains supplementary material, which is available to authorized users.

Assessing neural commonalities and differences among depression, anxiety and their comorbidity is critical in developing a more integrative clinical neuroscience and in evaluating currently debated categorical vs dimensional approaches to psychiatric classification. Therefore, in this study, we sought to identify patterns of anomalous neural responding to criticism and praise that are specific to and common among major depressive disorder (MDD), social anxiety disorder (SAD) and comorbid MDD-SAD. Adult females who met formal diagnostic criteria for MDD, SAD or MDD-SAD and psychiatrically healthy participants underwent functional magnetic resonance imaging as they listened to statements directing praise or criticism at them or at another person. MDD groups showed reduced responding to praise across a distributed cortical network, an effect potentially mediated by thalamic nuclei undergirding arousal-mediated attention. SAD groups showed heightened anterior insula and decreased default-mode network response to criticism. The MDD-SAD group uniquely showed reduced responding to praise in the dorsal anterior cingulate cortex. Finally, all groups with psychopathology showed heightened response to criticism in a region of the superior frontal gyrus implicated in attentional gating. The present results suggest novel neural models of anhedonia in MDD, vigilance-withdrawal behaviors in SAD, and poorer outcome in MDD-SAD. Importantly, in identifying unique and common neural substrates of MDD and SAD, these results support a formulation in which common neural components represent general risk factors for psychopathology that, due to factors that are present at illness onset, lead to distinct forms of psychopathology with unique neural signatures.

Background Functional neuroimaging studies have examined the neural substrates of treatments for major depressive disorder (MDD). Low sample size and methodological heterogeneity, however, undermine the generalizability of findings from individual studies. We conducted a meta-analysis to identify reliable neural changes resulting from different modes of treatment for MDD and compared them with each other and with reliable neural functional abnormalities observed in depressed versus control samples. Methods We conducted a meta-analysis of studies reporting changes in brain activity (e.g., as indexed by positron emission tomography) following treatments with selective serotonin reuptake inhibitors (SSRIs), electroconvulsive therapy (ECT), or transcranial magnetic stimulation. Additionally, we examined the statistical reliability of overlap among thresholded meta-analytic SSRI, ECT, and transcranial magnetic stimulation maps as well as a map of abnormal neural function in MDD. Results Our meta-analysis revealed that 1) SSRIs decrease activity in the anterior insula, 2) ECT decreases activity in central nodes of the default mode network, 3) transcranial magnetic stimulation does not result in reliable neural changes, and 4) regional effects of these modes of treatment do not significantly overlap with each other or with regions showing reliable functional abnormality in MDD. Conclusions SSRIs and ECT produce neurally distinct effects relative to each other and to the functional abnormalities implicated in depression. These treatments therefore may exert antidepressant effects by diminishing neural functions not implicated in depression but that nonetheless impact mood. We discuss how the distinct neural changes resulting from SSRIs and ECT can account for both treatment effects and side effects from these therapies as well as how to individualize these treatments.

Recent research detailing the intrinsic functional organization of the brain provides a unique and useful framework to gain a better understanding of the neural bases of Major Depressive Disorder (MDD). In this review, we first present a brief history of neuroimaging research that has increased our understanding of the functional macro-architecture of the brain. From this macro-architectural perspective, we examine the extant body of functional neuroimaging research assessing MDD with a specific emphasis on the contributions of default-mode, executive, and salience networks in this debilitating disorder. Next, we describe recent investigations conducted in our laboratory in which we explicitly adopt a neural-systems perspective in examining the relations among these networks in MDD. Finally, we offer directions for future research that we believe will facilitate the development of more detailed and integrative models of neural dysfunction in depression.

Background: Responses to stress vary greatly in young adolescents, and little is known about neural correlates of the stress response in youth. The purpose of this study was to examine whether variability in cortisol responsivity following a social stress test in young adolescents is associated with altered neural functional connectivity (FC) of the salience network (SN) measured during resting-state functional magnetic resonance imaging (rs-fMRI). Methods: Forty-nine typically developing young adolescents participated in a social stress test during which they contributed salivary cortisol samples. Following this, they underwent rs-fMRI scanning. We examined the association of FC of the SN [composed of anterior cingulate cortex and bilateral anterior insula regions] with cortisol responsivity. Results: Greater cortisol responsivity was significantly positively correlated with higher FC between subgenual anterior cingulate cortex (Cg25) and the SN, controlling for participant age. There were no regions of the brain that showed an inverse relation. Conclusions: Brain systems that have been implicated in autonomic arousal and that influence subjective feeling states show altered FC associated with stress responsivity in early life. Keywords: Resting-state, adolescents, HPA axis, stress, subgenual cingulate, fMRI, salience network, connectivity.

The advent of real-time neurofeedback techniques has allowed us to begin to map the controllability of sensory and cognitive and, more recently, affective centers in the brain. The subgenual anterior cingulate cortex (sACC) is thought to be involved in generation of affective states and has been implicated in psychopathology. In this study, we examined whether individuals could use real-time fMRI neurofeedback to modulate sACC activity. Following a localizer task used to identify an sACC region of interest, an experimental group of eight women participated in four scans: (1) a pretraining scan in which they were asked to decrease activity in the sACC without neurofeedback; (2) two training scans in which sACC neurofeedback was presented along with instructions to decrease sACC activity; and (3) a neurofeedback-free post-training scan. An additional nine women in a yoked feedback control group saw sACC activity from the participants in the experimental group. Activity in the sACC was significantly reduced during neurofeedback training in the experimental group, but not in the control group. This training effect in the experimental group, however, did not generalize to the neurofeedback-free post-training scan. A psychophysiological interaction analysis showed decreased correlation in the experimental group relative to the sham control group between activity in the sACC and the posterior cingulate cortex during neurofeedback training relative to neurofeedback-free scans. The finding that individuals can down-modulate the sACC shows that a primary emotion center in which functional abnormality has been strongly implicated in affective disorders can be controlled with the aid of neurofeedback.

A functional variant of the serotonin transporter gene (5-HTTLPR) has been associated with increased risk for major depression in the context of stress. In attempting to understand the mechanisms underlying this relation, we tested the hypothesis that 5-HTTLPR genotype affects the speed with which amygdala is recruited during emotional processing in young girls with no history of psychiatric disorder. We used functional magnetic resonance imaging to compare the rise time to peak amygdala activation in 5-HTTLPR short-allele carriers and long-allele homozygotes during enhancement of sad mood. Relative to long-allele homozygotes, participants with at least one copy of the 5-HTTLPR short allele showed both stronger and earlier activation in left amygdala as they increased a sad mood state. Individuals carrying the short allele appear to exhibit a neural ‘readiness’ to engage and enhance negative affect. Future research should examine how exposure to negative life events and more chronic sadness modify the time course of amygdala activity during the experience of negative emotion.

Despite the fact that emotions involve multiple time-varying components, little is known about the underlying neural basis of these temporal dynamics. In this paper, we assess these temporal dynamics by using time-varying hemodynamic response functions (HRF) to model BOLD responses to emotional stimuli. We show that these time-varying HRFs lead to a better fit to the BOLD data and yield larger areas of significant activation than do conventional gamma-based canonical HRFs. We also report for the first time that intensity of emotional experience is associated with both magnitude and duration of brain activation. Specifically, greater negative emotional intensity was associated with greater magnitude of activation in the occipital cortex and with longer duration of activation in regions along the cortical midline associated with self-referent processing: the anterior medial prefrontal cortex and the posterior cingulate cortex. These data significantly advance our understanding of how the brain processes emotion and suggest that the intensity of a negative emotional experience is due in part to elaborative self-referent processing that is captured by the duration of neural activity in cortical midline structures. These data also underscore the importance of using modeling techniques that will help elucidate the chronometry of both normal and psychopathological emotional processes.

Background Although memory biases for negatively valenced stimuli have been reliably associated with depression and have been postulated to play a critical role in the maintenance of this disorder, the neural bases of these biases have received little attention. In this study, we tested a model of heightened memory sensitivity for negative information in depression in which neural mechanisms that normally facilitate memory for affective material are over-recruited during encoding of negative material in depression. Methods We used functional magnetic resonance imaging to examine amygdala activity and functional connectivity with the hippocampus and caudate-putamen during successful encoding—as assessed by a recognition memory probe 1 week after scanning—of negative, neutral, and positive pictures by 14 depressed and 12 nondepressed individuals. Results Depressed individuals demonstrated greater memory sensitivity than nondepressed participants to negative but not to neutral or positive stimuli. The right amygdala was more active and showed greater functional connectivity with the hippocampus and caudate-putamen in depressed than in control participants during encoding of subsequently remembered negative but not neutral or positive stimuli. The degree of memory-related right amygdala responsivity in the depressed participants was significantly correlated with depressive severity. Conclusions These findings support the formulation that, in remembering negative information better than nondepressed persons, depressed individuals over-recruit a neural network involved more generally in enhancing memory for affective stimuli and that the degree to which they over-recruit this system is related to the severity of clinical symptomatology.

Major depression is among the most debilitating, prevalent, and recurrent of all psychiatric disorders. Over the past decade, investigators have examined the neural mechanisms associated with this disorder. In this article we present an overview of neuroimaging research that has assessed the structure and functioning of the amygdala, subgenual anterior cingulate cortex, and dorsolateral prefrontal cortex in major depression. We then describe results of studies that have attempted to elucidate the nature of the relations among these brain structures. The picture that emerges from these investigations is one in which heightened activity in limbic structures that underlie the experience and expression of emotion dampens activation in dorsal cortical structures that are involved in affect regulation, reducing their ability to influence limbic activation. We conclude by highlighting unresolved issues concerning the roles of these structures in depression and their relation to specific symptoms of this disorder.

Despite its high prevalence and morbidity, the underlying neural basis of major depressive disorder (MDD) in youth is not well understood.To identify in youth diagnosed as having MDD the most reliable neural abnormalities reported in existing functional neuroimaging studies and characterize their relations with specific psychological dysfunctions.Searches were conducted in PubMed and Web of Science to identify relevant studies published from November 2006 through February 2015. The current analysis took place from August 21, 2014, to March 28, 2015.We retained articles that conducted a comparison of youth aged 4 to 24 years diagnosed as having MDD and age-matched healthy controls using task-based functional magnetic resonance imaging and a voxelwise whole-brain approach.We extracted coordinates of brain regions exhibiting differential activity in youth with MDD compared with healthy control participants. Multilevel kernel density analysis was used to examine voxelwise between-group differences throughout the whole brain. Correction for multiple comparisons was performed by computing null hypothesis distributions from 10 000 Monte Carlo simulations and calculating the cluster size necessary to obtain the familywise error rate control at P .05.Abnormal levels of activation in youth diagnosed as having MDD compared with control participants during a variety of affective processing and executive functioning tasks.Compared with age-matched healthy control participants (n = 274), youth with MDD (n = 246) showed reliable patterns of abnormal activation, including the following task-general and task-specific effects: hyperactivation in subgenual anterior cingulate cortex (P .05) and ventrolateral prefrontal cortex (P .05) and hypoactivation in caudate (P .01) across aggregated tasks; hyperactivation in thalamus (P .03) and parahippocampal gyrus (P .003) during affective processing tasks; hypoactivation in cuneus (P .001), dorsal cingulate cortex (P .05), and dorsal anterior insula (P .05) during executive functioning tasks; hypoactivity in posterior insula (P .005) during positive valence tasks; and hyperactivity in dorsolateral prefrontal cortex (P .001) and superior temporal cortex (P .003) during negative valence tasks.Altered activations in several distributed brain networks may help explain the following seemingly disparate symptoms of MDD in youth: hypervigilance toward emotional stimuli from the overactivation of central hubs in the subgenual anterior cingulate cortex and thalamus that lead to a cascade of other symptoms; ineffective emotion regulation despite increased activation of the dorsolateral prefrontal cortex and ventrolateral prefrontal cortex during affective processing, which may reverse across development or the clinical course; maladaptive rumination and poor executive control from difficulties shifting from default mode network activity to task-positive network activity during cognitively demanding tasks; and anhedonia from hypoactivation of the cuneus and posterior insula during reward processing.

Urbanization has many benefits, but it also is associated with increased levels of mental illness, including depression. It has been suggested that decreased nature experience may help to explain the link between urbanization and mental illness. This suggestion is supported by a growing body of correlational and experimental evidence, which raises a further question: what mechanism(s) link decreased nature experience to the development of mental illness? One such mechanism might be the impact of nature exposure on rumination, a maladaptive pattern of self-referential thought that is associated with heightened risk for depression and other mental illnesses. We show in healthy participants that a brief nature experience, a 90-min walk in a natural setting, decreases both self-reported rumination and neural activity in the subgenual prefrontal cortex (sgPFC), whereas a 90-min walk in an urban setting has no such effects on self-reported rumination or neural activity. In other studies, the sgPFC has been associated with a self-focused behavioral withdrawal linked to rumination in both depressed and healthy individuals. This study reveals a pathway by which nature experience may improve mental well-being and suggests that accessible natural areas within urban contexts may be a critical resource for mental health in our rapidly urbanizing world.

The intuitive association between self-focused rumination in major depressive disorder (MDD) and the self-referential operations performed by the brain's default-mode network (DMN) has prompted interest in examining the role of the DMN in MDD. In this article, we present meta-analytic findings showing reliably increased functional connectivity between the DMN and subgenual prefrontal cortex (sgPFC)-connectivity that often predicts levels of depressive rumination. We also present meta-analytic findings that, while there is reliably increased regional cerebral blood flow in sgPFC in MDD, no such abnormality has been reliably observed in nodes of the DMN. We then detail a model that integrates the body of research presented. In this model, we propose that increased functional connectivity between sgPFC and the DMN in MDD represents an integration of the self-referential processes supported by the DMN with the affectively laden, behavioral withdrawal processes associated with sgPFC-an integration that produces a functional neural ensemble well suited for depressive rumination and that, in MDD, abnormally taxes only sgPFC and not the DMN. This synthesis explains a broad array of existing data concerning the neural substrates of depressive rumination and provides an explicit account of functional abnormalities in sgPFC in MDD.

Adolescence is characterized by an increase in risk-taking and reward-seeking behaviors. In other populations, increased risk taking has been associated with tighter coupling between cortisol production and ventral striatum (VS) activation during reward anticipation; this relation has not yet been examined, however, as a function of adolescent development. This study examined the influence of pubertal development on the association between diurnal cortisol production and VS activity during reward anticipation. Pre- and post-menarcheal girls collected diurnal cortisol and completed an functional magnetic resonance imaging-based monetary incentive delay task, from which we extracted estimates of VS activity during the anticipation of reward, anticipation of loss and anticipation of non-incentive neutral trials. Post-menarcheal girls showed greater coupling between the cortisol awakening response and VS activation during anticipation of reward and loss than did their pre-menarcheal counterparts. Post-menarcheal girls did not differ from pre-menarcheal girls in their cortisol-VS coupling during anticipation of neutral trials, suggesting that puberty-related changes in cortisol-VS coupling are specific to affective stimuli. Interestingly, behavioral responses during the task indicate that post-menarcheal girls are faster to engage with affective stimuli than are pre-menarcheal girls. Thus, post-menarcheal girls exhibit neurobiological and behavioral patterns that have been associated with risk taking and that may underlie the dramatic increase in risk-taking behavior documented during adolescence.

Diffusion-weighted imaging allows for in vivo assessment of white matter structure, which can be used to assess aberrations associated with disease. Several new methods permit the automated assessment of important white matter characteristics. In the current study we used Automated Fiber Quantification (AFQ) to assess differences between depressed and nondepressed individuals in 18 major white matter tracts. We then used the Maximum Density Path (MDP) method to further characterize group differences identified with AFQ. The results of the AFQ analyses indicated that fractional anisotropy (FA; an index of white matter integrity) along bilateral corticospinal tracts (CST) was higher in depressed than in nondepressed individuals. MDP analyses revealed that white matter anomalies were restricted to four subregions that included the corona radiata and the internal and external capsules. These results provide further evidence that MDD is associated with abnormalities in cortical-to-subcortical connectivity.

Abnormally high response of the amygdala to negative affective challenge has been observed reliably in major depressivedisorder (1, 2), but little is knownabout the trajectory of this abnormality over the broad longitudinal arc of depression, particularly as premorbid risk factors emerge and potentially compound during critical periods of emotional development. Is higher amygdala responsivity present in children at risk for major depression, before the first onset of depression? Do children at high risk for depression show typical patterns of attenuation of amygdala response over the course of development (3)? How might distinct risk factors and their co-occurrence affect this developmental trajectory? In this issue, Swartz andcolleagues (4)address thesequestions in the context of a study examining developmental changes in amygdala reactivity in groups of adolescents at high and low familial risk for major depression. The authors measured amygdala reactivity at initial assessment and again at 2-year follow-up in never-depressed adolescents at high risk for developing major depression—by virtue of having both afirstand a second-degree relativewith ahistoryofdepression(5)—andinlow-risk adolescentswithno firstor second-degree familial history of major depression. The investigators used functional MRI (fMRI) to estimate amygdala reactivity with an emotion-face comparison task that has been successful in eliciting amygdala response in individual scanning participants (6). For each trial of this task, participants viewed three faces and selected, from two faces presented at the bottom of the display, the one that had the same emotional facial expression as the target face at the top; for a given trial, all faces showed either fear or anger. In addition to measuring amygdala reactivity, the authors assessed thenumber and severity of stressful life events encounteredby participants in the year preceding each scan (7). Notably, this study incorporated large samples relative to typical functional neuroimaging investigations, with 157 participants (85 high risk and 72 low risk) completing both stages of data collection with viable neuroimaging data. This large sample size allowed the investigators to obtain reliable estimates of developmental changes in amygdala response associatedwith the interactions of two factors: familial risk status (low or high) and the occurrence of stressful life events (low or high). Consistent with previous data (3), Swartz et al. found decreasing amygdala response from initial assessment to 2-year follow-up in adolescents who had a low familial risk for depression and comparatively fewer stressful life events. Having an increased familial risk or having experienced a relatively greater number of stressful life events, however, was associated with (roughly equivalent) developmental increases in amygdala response to emotional challenge. Finally, having both an increased familial risk for depression and experiencing a greater numberofstressfuleventswasassociatedwithanevensharper increase in amygdala response from initial assessment to 2year follow-up. These findings remained when participants with an anxiety disorder were excluded from the analysis. The pattern of amygdala reactivity findings presented in this reportwaspresentonly for fearful andnot for angry facial expressions. This is not surprising, given that comparisons of response to fearful versus angry facial expressions have shown fearful expressions to be better elicitors of amygdala reactivity (8). Furthermore, the localization of emotionface reactivity to limbic and paralimbic regions as well as the differential effects observed for fearful and angry expressions suggests that thepatternof data reporteddidnot result from stimulus-correlated motion. This study is emblematic of a maturing clinical neuroscience of depression and reflects the growing realization that the pathophysiology of major depression manifests itself more over thecourseofdecades thanmonths.Moreover, thisworkassumes the lesson learned from the failings of first-generation neuroimaging studies of the risk for major depression that the most informative and ultimately useful investigations will be conceived with an appreciation of the many trajectories toward depressive illness. Indeed, as accumulation continues in these and other large data sets (9, 10)—which are necessary for approaching inquiries of the risk for major depression with the requisitecomplexity inmind—weare likely toachieveevenmore meaningful theoretical and clinical advances. In addition to the sensitivity conferred by the use of large samples to detect multivariate effects, the authors’ experimental design had other notable strengths. For example, using both firstand seconddegree family histories in defining highand low-risk groups increased the likelihood of capturing familial risk. Furthermore, This study is emblematic of a maturing clinical neuroscience of depression and reflects the growing realization that the pathophysiology of major depression manifests itself more over the course of decades than months.

Background Major depressive disorder (MDD) has been associated reliably with ruminative responding; this kind of responding is composed of both maladaptive and adaptive components. Levels of activity in the default-mode network (DMN) relative to the task-positive network (TPN), as well as activity in structures that influence DMN and TPN functioning, may represent important neural substrates of maladaptive and adaptive rumination in MDD. Methods We used a unique metric to estimate DMN dominance over TPN from blood oxygenation level-dependent data collected during eyes-closed rest in 17 currently depressed and 17 never-disordered adults. We calculated correlations between this metric of DMN dominance over TPN and the depressive, brooding, and reflective subscales of the Ruminative Responses Scale, correcting for associations between these measures both with one another and with severity of depression. Finally, we estimated and compared across groups right fronto-insular cortex (RFIC) response during initiations of ascent in DMN and in TPN activity. Results In the MDD participants, increasing levels of DMN dominance were associated with higher levels of maladaptive, depressive rumination and lower levels of adaptive, reflective rumination. Moreover, our RFIC state-change analysis showed increased RFIC activation in the MDD participants at the onset of increases in TPN activity; conversely, healthy control participants exhibited increased RFIC response at the onset of increases in DMN activity. Conclusions These findings support a formulation in which the DMN undergirds representation of negative, self-referential information in depression, and the RFIC, when prompted by increased levels of DMN activity, initiates an adaptive engagement of the TPN.

Previous brain imaging studies have reported that Major Depressive Disorder (MDD) is characterized by decreased volumes of several cortical and subcortical structures, including the hippocampus, amygdala, anterior cingulate cortex, and caudate nucleus. The purpose of the present study was to identify structural volumetric differences between MDD and healthy participants using a method that allows a comparison of gray and white matter volume across the whole brain. In addition, we explored the relation between symptom severity and brain regions with decreased volumes in MDD participants. Twenty-two women diagnosed with MDD and 25 healthy women with no history of major psychiatric disorders participated in this study. Magnetic resonance brain images were analyzed using optimized voxel-based morphometry to examine group differences in regional gray and white matter volume. Compared with healthy controls, MDD participants were found to have decreased gray matter volume in the bilateral caudate nucleus and the thalamus. No group differences were found for white matter volume, nor were there significant correlations between gray matter volumes and symptom severity within the MDD group. The present results suggest that smaller volume of caudate nucleus may be related to the pathophysiology of MDD and may account for abnormalities of the cortico-striatal-pallido-thalamic loop in MDD.

t T he concept of endophenotypes, introduced almost 4 decades ago, has become increasingly important in the study of complex neuropsychiatric diseases. Endophenotypes are easurable, but not overtly observable, constructs in the pathway rom genetic variation to psychiatric disorder. As originally concepualized, endophenotypes must: 1) be associated with illness in the opulation; 2) be heritable; 3) be state independent, although they ay need to be elicited by a challenge; 4) cosegregate with illness ithin families; and 5) be found in unaffected relatives of probands t a higher rate than in the general population (1). Initially, scientists ad hoped that investigating endophenotypes would hasten the dentification of the genetic origins of various disorders, but this has ot proven to be the case. This difficulty in identifying the genetic oundations of psychiatric disorders is due, in part, to the restrictive ature of the definitions included in the International Classification f Diseases, 10th revision, and the Diagnostic and Statistical Manual f Mental Disorders-IV, which are not based on etiology or pathohysiology (2). But it is also due to the fact that investigators have eparted from the original criteria for endophenotypes noted bove and have considered as a possible endophenotype virtually ny neural, cognitive, or affective abnormality associated with a ental illness, regardless of its genetic links. This overgeneralizaion has impeded the study of endophenotypes in promoting the iscovery of genes underlying psychopathology. In this issue of Biological Psychiatry, Glahn et al. (3) present work hat both returns to the original conceptualization of endophenoypes (with, arguably, one notable exception described below) and rovides a formal, mathematical procedure for identifying endohenotypes that may promote gene discovery in psychiatry. In the ontext of major depressive disorder (MDD), these researchers dene and test the usefulness of the endophenotype ranking value ERV), an index for measuring the strength of association with geetics of endophenotypes implicated in psychiatric illness. The ERV s a straightforward index that increases with increasing values of hree constructs: 1) the heritability of the psychiatric illness; 2) the eritability of the endophenotype; and 3) the genetic correlation etween the illness and the endophenotype. In this formulation, a utative endophenotype that is associated with a heritable disorer and that is itself heritable will receive a high ERV, provided that t has high genetic correlation with the disorder; thus, the ERV eturns genetic linkage to the conception of the endophenotypes nd also maintains the requisite links between the endophenotype nd the illness. Glahn et al. (3) calculated ERVs for a large set (more than 11,000) f behavioral, neural, and transcriptomic factors that were assessed n a sample of 1122 Mexican-American persons. They then perormed quality tests on the ERV index by conducting univariate and ivariate linkage analyses of the endophenotypes from each of hese three categories that have the highest ERVs: the Beck Depresion Inventory (BDI) scores, the bilateral diencephalon volume, and he RNF123 transcriptional endophenotype, as well as the inci

Background Scientists are beginning to document abnormalities in white matter connectivity in major depressive disorder (MDD). Recent developments in diffusion-weighted image analyses, including tractography clustering methods, may yield improved characterization of these white matter abnormalities in MDD. In this study, we acquired diffusion-weighted imaging data from MDD participants and matched healthy controls. We analyzed these data using two tractography clustering methods: automated fiber quantification (AFQ) and the maximum density path (MDP) procedure. We used AFQ to compare fractional anisotropy (FA; an index of water diffusion) in these two groups across major white matter tracts. Subsequently, we used the MDP procedure to compare FA differences in fiber paths related to the abnormalities in major fiber tracts that were identified using AFQ. Results FA was higher in the bilateral corticospinal tracts (CSTs) in MDD (p’s

Context Deficits in reward processing and their neural correlates have been associated with major depression. However, it is unclear if these deficits precede the onset of depression or are a consequence of this disorder. Objective To determine whether anomalous neural processing of reward characterizes children at familial risk for depression in the absence of a personal history of diagnosable disorder. Design Comparison of neural activity among children at low and high risk for depression as they process reward and loss. Setting University functional magnetic resonance imaging facility. Participants Thirteen 10- to 14-year-old never-disordered daughters of mothers with recurrent depression (“high risk”) and 13 age-matched never-disordered daughters with no family history of depression (“low risk”). Main Outcome Measure Neural activity, as measured using functional magnetic resonance imaging, in key reward and attention neural circuitry during anticipation and receipt of reward and loss. Results While anticipating gains, high-risk participants showed less activation than did their low-risk counterparts in the putamen and left insula but showed greater activation in the right insula. When receiving punishment, high-risk participants showed greater activation in the dorsal anterior cingulate gyrus than did low-risk participants, who showed greater activation in the caudate and putamen. Conclusions Familial risk for depression affects neural mechanisms underlying the processing of reward and loss; young girls at risk for depression exhibit anomalies in the processing of reward and loss before the onset of depressive symptoms. Longitudinal studies are needed to examine whether these characteristics predict the subsequent onset of depression.

Researchers have documented that the hippocampus is smaller in individuals with depression than in those without. The temporal or causal association of this reduction in hippocampal volume in depression, however, is not known.To test the hypothesis that reduced hippocampal volume precedes and therefore may be implicated in the onset of depression.We used magnetic resonance imaging to examine brain structure volume in individuals at high and low familial risk of depression. Anatomic images from magnetic resonance imaging were analyzed using both whole-brain voxel-based morphometry and manual tracing of the bilateral hippocampus.A research university.Fifty-five girls aged between 9 and 15 years: 23 daughters of mothers with recurrent episodes of depression in the daughter's lifetime (high risk) and 32 age-matched daughters of mothers with no history of psychopathology (low risk). None of the girls had any past or current Axis I psychopathology.Group differences in voxel-based morphometry brain matter density estimates and traced hippocampal volume.Voxel-based morphometry analyses indicated that individuals at high risk of depression had significantly less gray matter density in clusters in the bilateral hippocampus (P.001) than low-risk participants. Tracing yielded a volumetric reduction in the left hippocampus in the high-risk participants (P.05).Compared with individuals at low familial risk of the development of depression, high-risk individuals have reduced hippocampal volume, indicating that neuroanatomic anomalies associated with depression may precede the onset of a depressive episode and influence the development and course of this disorder.

Background Despite advances in neurobiological research on Major Depressive Disorder and Social Anxiety Disorder, little is known about the neural functioning of individuals with comorbid depression/social anxiety. We examined the timing of neural responses to social stress in individuals with major depression and/or social anxiety. We hypothesized that having social anxiety would be associated with earlier responses to stress, having major depression would be associated with sustained responses to stress, and that comorbid participants would exhibit both of these response patterns. Methods Participants were females diagnosed with pure depression (n = 12), pure social anxiety (n = 16), comorbid depression/social anxiety (n = 17), or as never having had any Axis-I disorder (control; n = 17). Blood oxygenation-level dependent activity (BOLD) was assessed with functional magnetic resonance imaging (fMRI). To induce social stress, participants prepared a speech that was ostensibly to be evaluated by a third party. Results Whereas being diagnosed with depression was associated with a resurgence of activation in the medial frontal cortex late in the stressor, having social anxiety was associated with a vigilance-avoidance activation pattern in the occipital cortex and insula. Comorbid participants exhibited activation patterns that generally overlapped with the non-comorbid groups, with the exception of an intermediate level of activation, between the level of activation of the pure depression and social anxiety groups, in the middle and posterior cingulate cortex. Conclusions These findings advance our understanding of the neural underpinnings of major depression and social anxiety, and of their comorbidity. Future research should elucidate more precisely the behavioral correlates of these patterns of brain activation.

Background Abnormalities of the striatum and frontal cortex have been reported consistently in studies of neural structure and function in major depressive disorder (MDD). Despite speculation that compromised connectivity between these regions may underlie symptoms of MDD, little work has investigated the integrity of frontostriatal circuits in this disorder. Methods Functional magnetic resonance images were acquired from 21 currently depressed and 19 never-disordered women during wakeful rest. Using four predefined striatal regions-of-interest, seed-to-whole brain correlations were computed and compared between groups. Results Compared to controls, depressed participants exhibited attenuated functional connectivity between the ventral striatum and both ventromedial prefrontal cortex and subgenual anterior cingulate cortex. Depressed participants also exhibited stronger connectivity between the dorsal caudate and dorsal prefrontal cortex, which was positively correlated with severity of the disorder. Conclusions Depressed individuals are characterized by aberrant connectivity in frontostriatal circuits that are posited to support affective and cognitive processing. Further research is required to examine more explicitly the link between patterns of disrupted connectivity and specific symptoms of depression, and the extent to which these patterns precede the onset of depression and normalize with recovery from depressive illness.