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Importance: More than half of all patients with major depressive disorder (MDD) experience a relapse within 2 years after recovery. It is unclear how relapse affects brain morphologic features during the course of MDD., Objective: To use structural magnetic resonance imaging to identify morphologic brain changes associated with relapse in MDD., Design, Setting, and Participants: In this longitudinal case-control study, patients with acute MDD at baseline and healthy controls were recruited from the University of Münster Department of Psychiatry from March 21, 2010, to November 14, 2014, and were reassessed from November 11, 2012, to October 28, 2016. Depending on patients' course of illness during follow-up, they were subdivided into groups of patients with and without relapse. Whole-brain gray matter volume and cortical thickness of the anterior cingulate cortex, orbitofrontal cortex, middle frontal gyrus, and insula were assessed via 3-T magnetic resonance imaging at baseline and 2 years later., Main Outcomes and Measures: Gray matter was analyzed via group (no relapse, relapse, and healthy controls) by time (baseline and follow-up) analysis of covariance, controlling for age and total intracranial volume. Confounding factors of medication and depression severity were assessed., Results: This study included 37 patients with MDD and a relapse (19 women and 18 men; mean [SD] age, 37.0 [12.7] years), 23 patients with MDD and without relapse (13 women and 10 men; mean [SD] age, 32.5 [10.5] years), and 54 age- and sex-matched healthy controls (24 women and 30 men; mean [SD] age, 37.5 [8.7] years). A significant group-by-time interaction controlling for age and total intracranial volume revealed that patients with relapse showed a significant decline of insular volume (difference, -0.032; 95% CI, -0.063 to -0.002; P = .04) and dorsolateral prefrontal volume (difference, -0.079; 95% CI, -0.113 to -0.045; P < .001) from baseline to follow-up. In patients without relapse, gray matter volume in these regions did not change significantly (insula: difference, 0.027; 95% CI, -0.012 to 0.066; P = .17; and dorsolateral prefrontal volume: difference, 0.023; 95% CI, -0.020 to 0.066; P = .30). Volume changes were not correlated with psychiatric medication or with severity of depression at follow-up. Additional analysis of cortical thickness showed an increase in the anterior cingulate cortex (difference, 0.073 mm; 95% CI, 0.023-0.123 mm; P = .005) and orbitofrontal cortex (difference, 0.089 mm; 95% CI, 0.032-0.147 mm; P = .003) from baseline to follow-up in patients without relapse., Conclusion and Relevance: A distinct association of relapse in MDD with brain morphologic features was revealed using a longitudinal design. Relapse is associated with brain structures that are crucial for regulation of emotions and thus needs to be prevented. This study might be a step to guide future prognosis and maintenance treatment in patients with recurrent MDD.

Objective: Structural and functional brain alterations in major depression disorder (MDD) are well studied in cross-sectional designs, but little is known about the causality between onset and course of depression on the one hand, and neurobiological changes over time on the other. To explore the direction of causality, longitudinal studies with a long time window (preferably years) are needed, but only few have been undertaken so far. This article reviews all prospective neuroimaging studies in MDD patients currently available and provides a critical discussion of methodological challenges involved in the investigation of the causal relationship between brain alterations and the course of MDD., Method: We conducted a systematic review of studies published before September 2015, to identify structural magnetic resonance imaging (MRI) studies that assess the relation between neuronal alterations and MDD in longitudinal (⩾1 year) designs., Results: Only 15 studies meeting minimal standards were identified. An analysis of these longitudinal data showed a large heterogeneity between studies regarding design, samples, imaging methods, spatial restrictions and, consequently, results. There was a strong relationship between brain-volume outcomes and the current mood state, whereas longitudinal studies failed to clarify the influence of pre-existing brain changes on depressive outcome., Conclusion: So far, available longitudinal studies cannot resolve the causality between the course of depression and neurobiological changes over time. Future studies should combine high methodological standards with large sample sizes. Cooperation in multi-center studies is indispensable to attain sufficient sample sizes, and should allow careful assessment of possible confounders.

Our understanding of altered emotional processing in social anxiety disorder (SAD) is hampered by a heterogeneity of findings, which is probably due to the vastly different methods and materials used so far. This is why the present functional magnetic resonance imaging (fMRI) study investigated immediate disorder-related threat processing in 30 SAD patients and 30 healthy controls (HC) with a novel, standardized set of highly ecologically valid, disorder-related complex visual scenes. SAD patients rated disorder-related as compared with neutral scenes as more unpleasant, arousing and anxiety-inducing than HC. On the neural level, disorder-related as compared with neutral scenes evoked differential responses in SAD patients in a widespread emotion processing network including (para-)limbic structures (e.g. amygdala, insula, thalamus, globus pallidus) and cortical regions (e.g. dorsomedial prefrontal cortex (dmPFC), posterior cingulate cortex (PCC), and precuneus). Functional connectivity analysis yielded an altered interplay between PCC/precuneus and paralimbic (insula) as well as cortical regions (dmPFC, precuneus) in SAD patients, which emphasizes a central role for PCC/precuneus in disorder-related scene processing. Hyperconnectivity of globus pallidus with amygdala, anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) additionally underlines the relevance of this region in socially anxious threat processing. Our findings stress the importance of specific disorder-related stimuli for the investigation of altered emotion processing in SAD. Disorder-related threat processing in SAD reveals anomalies at multiple stages of emotion processing which may be linked to increased anxiety and to dysfunctionally elevated levels of self-referential processing reported in previous studies., (© 2016 Wiley Periodicals, Inc.)

Numerous studies have reported neurophysiological effects of semantic priming in electroencephalography (EEG) and in functional magnetic resonance imaging (fMRI). Because of differing methodological constraints, the comparability of the observed effects remains unclear. To directly compare EEG and fMRI effects and neural sources of semantic priming, we conducted a semantic word-picture priming experiment while measuring EEG and fMRI simultaneously. The visually presented primes were pseudowords, words unrelated to the target, semantically related words and the identical names of the target. Distributed source analysis of the event-related potentials (ERPs) successfully revealed a large effect of semantic prime-target relatedness (the N400 effect), which was driven by activations in a left-temporal source region. However, no significantly differing activations between priming conditions were found in the fMRI data. Our results support the notion that, for joint interpretations of existing EEG and fMRI studies of semantic priming, we need to fully appreciate the respective methodological limitations. Second, they show that simultaneous EEG-fMRI, including ERP source localization, is a feasible and promising methodological advancement for the investigation of higher-cognitive processes. Third, they substantiate the finding that, compared to fMRI, ERPs are often more sensitive to subtle cognitive effects.

Introduction: Neuropsychological abnormalities in transsexual patients have been reported in comparison with subjects without gender identity disorder (GID), suggesting differences in underlying neurobiological processes. However, these results have not consistently been confirmed. Furthermore, studies on cognitive effects of cross-sex hormone therapy also yield heterogeneous results., Aim: We hypothesized that untreated transsexual patients differ from men without GID in activation pattern associated with a mental rotation task and that these differences may further increase after commencing of hormonal treatment., Method: The present study investigated 11 male-to-female transsexual (MFTS) patients prior to cross-sex hormone therapy and 11 MFTS patients during hormone therapy in comparison with healthy men without GID. Using functional magnetic resonance imaging at 3-Tesla, a mental rotation paradigm with proven sexual dimorphism was applied to all subjects. Data were analyzed with SPM5., Main Outcome Measures: Patterns of brain activation associated with a mental rotation task., Results: The classical mental rotation network was activated in all three groups, but significant differences within this network were observed. Men without GID exhibited significantly greater activation of the left parietal cortex (BA 40), a key region for mental rotation processes. Both transsexual groups revealed stronger activation of temporo-occipital regions in comparison with men without GID., Conclusions: Our results confirmed previously reported deviances of brain activation patterns in transsexual men from men without GID and also corroborated these findings in a group of transsexual patients receiving cross-sex hormone therapy. The present study indicates that there are a priori differences between men and transsexual patients caused by different neurobiological processes or task-solving strategies and that these differences remain stable over the course of hormonal treatment.

While cognitive impairments are well documented for the acute episode of major depressive disorder (MDD), less is known about cognitive functioning in the euthymic state. For working memory, dysfunctional activation of lateral prefrontal and cingulate cortex has been reported in the acute episode. This study investigates working-memory function and its neurobiological correlate in euthymic MDD patients, particularly whether dysfunctional activation persists when depressive symptoms improve. We investigated 56 subjects with functional magnetic resonance imaging (fMRI) at 3 Tesla. To challenge working-memory function, a classical verbal n-back task (0-, 1-, and 2-back) was used in 28 well-characterized, euthymic, unipolar MDD patients and 28 healthy control subjects matched according to age, sex, and educational level. Data were analyzed using SPM5. In the absence of significant behavioral differences, we observed comparable overall patterns of brain activation in both groups. As expected, both groups showed stronger activation of the typical working-memory network with increasing memory load. However, significant hyperactivation of the cingulate cortex was observed in euthymic patients, while lateral prefrontal activation was comparable between patients and controls. Working-memory challenge in the euthymic state of MDD revealed a dissociation of lateral prefrontal and cingulate brain function. Cingulate function, which is important for both emotional and cognitive processing and their integration, is still abnormal when mood is restored. This could reflect a different speed of normalization in prefrontal and limbic cortices, persistent systematic changes in neuronal networks after an episode of MDD, or a compensatory mechanism to maintain working-memory performance., (2008 Wiley-Liss, Inc.)

Fear conditioning and extinction are basic forms of associative learning that have gained considerable clinical relevance in enhancing our understanding of anxiety disorders and facilitating their treatment. Modern neuroimaging techniques have significantly aided the identification of anatomical structures and networks involved in fear conditioning. On closer inspection, there is considerable variation in methodology and results between studies. This systematic review provides an overview of the current neuroimaging literature on fear conditioning and extinction on healthy subjects, taking into account methodological issues such as the conditioning paradigm. A Pubmed search, as of December 2008, was performed and supplemented by manual searches of bibliographies of key articles. Two independent reviewers made the final study selection and data extraction. A total of 46 studies on cued fear conditioning and/or extinction on healthy volunteers using positron emission tomography or functional magnetic resonance imaging were reviewed. The influence of specific experimental factors, such as contingency and timing parameters, assessment of conditioned responses, and characteristics of conditioned and unconditioned stimuli, on cerebral activation patterns was examined. Results were summarized descriptively. A network consisting of fear-related brain areas, such as amygdala, insula, and anterior cingulate cortex, is activated independently of design parameters. However, some neuroimaging studies do not report these findings in the presence of methodological heterogeneities. Furthermore, other brain areas are differentially activated, depending on specific design parameters. These include stronger hippocampal activation in trace conditioning and tactile stimulation. Furthermore, tactile unconditioned stimuli enhance activation of pain related, motor, and somatosensory areas. Differences concerning experimental factors may partly explain the variance between neuroimaging investigations on human fear conditioning and extinction and should, therefore, be taken into serious consideration in the planning and the interpretation of research projects.

Objectives: The medial temporal lobe (MTL) is essential for declarative memory formation, but also a frequent source of seizures. To decrease the risk of amnestic impairments after temporal lobectomy, functional magnetic resonance imaging (fMRI) is increasingly used to establish pre-operative measures for a prognosis of postoperative memory performance. The present study addresses one of the major challenges in clinical fMRI, the interpretation of activation pattern in single subjects. Before investigating patients however, it must be first assessed to which extent the verbal memory paradigm can be used to determine the lateralization and the functional neuroanatomy of MTL-activity. Therefore, this study took a "step backwards" by first examining healthy subjects without known MTL pathology., Patients and Methods: An implicit verbal encoding task was applied to a group of ten healthy volunteers using fMRI., Results: At the group level the MTL activation was strongly left-lateralized and separated into three distinct clusters. At the individual level, the lateralization of MTL-activity could be determined in 9 of 10 subjects. In contrast, its localization was inter-individually highly variable. In each case, only one of the three group activation clusters was detected., Conclusions: The present study shows that fMRI can be used to assess the lateralization of brain activity related to verbal encoding even in individual subjects. For the routine use in a clinical setting however, the results of verbal memory paradigms must at present be treated with care if they are used to support decisions as to how far the resection of one MTL can be extended.

Background: Increased automatic processing of threat-related stimuli has been proposed as a key element in panic disorder. Little is known about the neural basis of automatic processing, in particular to task-irrelevant, panic-related, ecologically valid stimuli, or about the association between brain activation and symptomatology in patients with panic disorder. Methods: The present event-related functional MRI (fMRI) study compared brain responses to task-irrelevant, panic-related and neutral visual stimuli in medication-free patients with panic disorder and healthy controls. Panic-related and neutral scenes were presented while participants performed a spatially nonoverlapping bar orientation task. Correlation analyses investigated the association between brain responses and panic-related aspects of symptomatology, measured using the Anxiety Sensitivity Index (ASI). Results: We included 26 patients with panic disorder and 26 heatlhy controls in our analysis. Compared with controls, patients with panic disorder showed elevated activation in the amygdala, brainstem, thalamus, insula, anterior cingulate cortex and midcingulate cortex in response to panic-related versus neutral task-irrelevant stimuli. Furthermore, fear of cardiovascular symptoms (a subcomponent of the ASI) was associated with insula activation, whereas fear of respiratory symptoms was associated with brainstem hyperactivation in patients with panic disorder. Limitations: The additional implementation of measures of autonomic activation, such as pupil diameter, heart rate, or electrodermal activity, would have been informative during the fMRI scan as well as during the rating procedure. Conclusion: Results reveal a neural network involved in the processing of panic-related distractor stimuli in patients with panic disorder and suggest an automatic weighting of panic-related information depending on the magnitude of cardiovascular and respiratory symptoms. Insula and brainstem activations show function-related associations with specific components of panic symptomatology. [ABSTRACT FROM AUTHOR]

Background: Anhedonia has long been recognized as a key feature of major depressive disorders, but little is known about the association between hedonic symptoms and neurobiological processes in depressed patients. We investigated whether amygdala mood congruent responses to emotional stimuli in depressed patients are correlated with anhedonic symptoms at automatic levels of processing. Methods: We measured amygdala responsiveness to subliminally presented sad and happy facial expressions in depressed patients and matched healthy controls using functional magnetic resonance imaging. Amygdala responsiveness was compared between patients and healthy controls within a 2 (group) × 2 (emotion) design. In addition, we correlated patients' amygdala responsiveness to sad and happy facial stimuli with self-report questionnaire measures of anhedonia. Results: We included 35 patients and 35 controls in our study. As in previous studies, we observed a strong emotion × group interaction in the bilateral amygdala: depressed patients showed greater amygdala responses to sad than happy faces, whereas healthy controls responded more strongly to happy than sad faces. The lack of automatic right amygdala responsiveness to happy faces in depressed patients was associated with higher physical anhedonia scores. Limitations: Almost all depressed patients were taking antidepressant medications. Conclusion: We replicated our previous finding of depressed patients showing automatic amygdala mood-congruent biases in terms of enhanced reactivity to negative emotional stimuli and reduced activity to positive emotional stimuli. The altered amygdala processing of positive stimuli in patients was associated with anhedonia scores. The results indicate that reduced amygdala responsiveness to positive stimuli may contribute to anhedonic symptoms due to reduced/inappropriate salience attribution to positive information at very early processing levels. [ABSTRACT FROM AUTHOR]