Dopamine D3 receptor gene variation: impact on electroconvulsive therapy response and ventral striatum responsiveness in depression.

Dysfunction of dopamine D3 receptors, particularly in the mesocorticolimbic system, has been linked to the pathogenesis of major depression. Preclinical data show enhanced D3 receptor binding in the striatum upon antidepressant medication and electroconvulsive therapy (ECT). Thus, the potential impact of dopamine D3 receptor gene (DRD3) variation on ECT outcome in treatment-resistant major depression was evaluated by applying a combined molecular and imaging genetic approach. Altogether, 10 representative variants covering 95.4% of DRD3 gene variation were investigated for association with response to ECT in a sample of 104 (71 female, 33 male) Caucasian patients with pharmacorefractory major depression. Additionally, ventral striatum responsiveness to happy faces was assessed in two independent samples of depressed patients (total N=54) by means of functional magnetic resonance imaging at 3 T. Significant association of DRD3 rs3732790, rs3773679 and rs9817063 variants with response (uncorrected p=0.02-0.03) and remission (uncorrected p=0.01) after ECT was discerned. Logistic regression analyses revealed association of rs3732790 (uncorrected p=0.009; corrected p=0.045) and rs3773679 (uncorrected p=0.009; corrected p=0.045) with remission when applying a recessive model of inheritance. The rs3732790T allele conferring a more favourable treatment response was furthermore found to be associated with stronger striatal responsiveness to happy facial expressions (sample 1: cluster-corrected p=0.002; sample 2: p=0.023). In summary, the present study suggests some impact of DRD3 gene variation on ECT response, potentially mediated by alteration of striatal engagement during the processing of emotionally rewarding stimuli.

Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain.

BACKGROUND: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. METHODOLOGY: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e.g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs.Principal findings/resultsIn a whole-brain analysis, the polymorphism rs1800795 (-174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = -10, z = -15; F(2,286) = 8.54, p(uncorrected) = 0.0002; p(AlphaSim-corrected) = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. CONCLUSIONS/SIGNIFICANCE: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.

Emotion specific modulation of automatic amygdala responses by 5-HTTLPR genotype.

A functional polymorphism in the serotonin transporter gene (5-HTTLPR) has been reported to modulate amygdala responsiveness to negative environmental cues. However, it remains unclear whether 5-HTTLPR modulates amygdala responses specifically to negative stimuli or rather to emotionally salient stimuli in general. In 44 healthy subjects, amygdala responses to subliminally presented happy and sad facial expressions were assessed by means of fMRI at 3 Tesla. All subjects were genotyped for 5-HTTLPR and the recently discovered 5-HTT rs25531. We observed a robust emotion by genotype group interaction in the right amygdala. Risk allele carriers (S or L(G)) showed similar amygdala responses to happy faces compared to homozygous L(A)L(A) carriers but increased amygdala responses to sad faces. The right amygdala was the only anatomical region across the whole brain demonstrating this interaction at a reasonable threshold. It appears that whereas 5-HTT gene variation modulates automatic amygdala responsiveness to sad faces, no such association was found for happy faces. We conclude that 5-HTTLPR genotype predominantly impacts the central processing predominantly of negative environmental cues but not of emotionally salient stimuli in general.

Neuroimaging differences in spatial cognition between men and male-to-female transsexuals before and during hormone therapy.

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.

Working-memory fMRI reveals cingulate hyperactivation in euthymic major depression.

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.

Implicit and explicit procedural learning in patients recently remitted from severe major depression.

In acute depression a high prevalence of deficits in learning and memory performance has been reported. Still, it is unclear whether these cognitive deficits are present after remission of clinical symptoms of depression. The present study compared 20 inpatients recently remitted from severe major depressive disorder (MDD) with 20 healthy matched control participants on two sequence learning tasks: a modified serial reaction-time task (SRT) for implicit learning, which is sensitive to subcortical and frontal impairments, and a serial generation task (SGT) for explicit learning. As compared with performance in healthy controls, implicit and explicit learning were not impaired in recently remitted inpatients with depression. Intentional acquisition of new information was related to the severity of depressive symptoms as patients with higher scores on Beck's Depression Inventory (BDI) showed poorer explicit learning. In contrast to findings in acute depression, our results suggest a normal degree of learning in remitted depression; these findings are consistent with unimpaired fronto-striatal functioning. However, although not statistically significant, patients remitted from melancholic MDD revealed poorer implicit learning performance compared with patients remitted from non--melancholic MDD. Longitudinal studies in patients with melancholic vs. non-melancholic MDD are needed to investigate the course of cognitive functioning during the recovery from MDD.

Pre-attentive detection of syntactic and semantic errors.

This magnetoencephalographic study tested whether magnetic fields evoked by syntactic and semantic errors differ in their time course and magnitude from fields evoked by phonemic differences. An oddball design, using German sentences with embedded critical words was applied: The error condition (with the standard word RASEN, lawn, in 70% of the trials, and the syntactic and semantic errors ROSEN, roses and RIESEN, giant as deviants) was compared with a neutral, correct phonemic condition. Mismatch responses were significantly larger for syntactic and semantic errors as compared to mere phonemic deviations. The semantic error elicited higher mismatch responses than the syntactic error. This error-sensitive component is interpreted as a very early detector for semantic and syntactic errors.

Insular and hippocampal gray matter volume reductions in patients with major depressive disorder.

BACKGROUND: Major depressive disorder is a serious psychiatric illness with a highly variable and heterogeneous clinical course. Due to the lack of consistent data from previous studies, the study of morphometric changes in major depressive disorder is still a major point of research requiring additional studies. The aim of the study presented here was to characterize and quantify regional gray matter abnormalities in a large sample of clinically well-characterized patients with major depressive disorder. METHODS: For this study one-hundred thirty two patients with major depressive disorder and 132 age- and gender-matched healthy control participants were included, 35 with their first episode and 97 with recurrent depression. To analyse gray matter abnormalities, voxel-based morphometry (VBM8) was employed on T1 weighted MRI data. We performed whole-brain analyses as well as a region-of-interest approach on the hippocampal formation, anterior cingulate cortex and amygdala, correlating the number of depressive episodes. RESULTS: Compared to healthy control persons, patients showed a strong gray-matter reduction in the right anterior insula. In addition, region-of-interest analyses revealed significant gray-matter reductions in the hippocampal formation. The observed alterations were more severe in patients with recurrent depressive episodes than in patients with a first episode. The number of depressive episodes was negatively correlated with gray-matter volume in the right hippocampus and right amygdala. CONCLUSIONS: The anterior insula gray matter structure appears to be strongly affected in major depressive disorder and might play an important role in the neurobiology of depression. The hippocampal and amygdala volume loss cumulating with the number of episodes might be explained either by repeated neurotoxic stress or alternatively by higher relapse rates in patients showing hippocampal atrophy.

Tumor necrosis factor gene variation predicts hippocampus volume in healthy individuals.

BACKGROUND: Cytokines such as tumor necrosis factor (TNF) α have been implicated in neurodegeneration relevant to various neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative properties of cytokine genes on brain function and on hippocampus (HC) function in particular. In this study we investigate the neurodegenerative role of TNF polymorphisms on brain morphology in healthy individuals. METHODS: Voxel-based morphometry was used in a large sample of healthy individuals (n = 303) to analyze the associations between genetic variants of TNF (rs1800629; rs361525) and brain morphology (gray matter concentration). RESULTS: In a region of interest analysis of the HC, for rs1800629, we observed a strong genotype effect on bilateral HC gray matter concentration. Carriers of one or two A-alleles had significantly smaller volumes compared with GG-homozygotes. For rs361525, a similar effect was observed at almost the same location, with the A-allele resulting in smaller HC volumes compared with GG homozygotes. CONCLUSIONS: The findings suggest a neurodegenerative role of the A-alleles of the TNF single nucleotide polymorphisms rs1800629 (-308G/A) and rs361525 (-238G/A) on hippocampal volumes in healthy individuals. Future imaging studies on the role of these single nucleotide polymorphisms in psychiatric populations of diseases with neurodegenerative components are warranted.

Persistent non-verbal memory impairment in remitted major depression - caused by encoding deficits?

BACKGROUND: While neuropsychological impairments are well described in acute phases of major depressive disorders (MDD), little is known about the neuropsychological profile in remission. There is evidence for episodic memory impairments in both acute depressed and remitted patients with MDD. Learning and memory depend on individuals' ability to organize information during learning. This study investigates non-verbal memory functions in remitted MDD and whether nonverbal memory performance is mediated by organizational strategies whilst learning. METHODS: 30 well-characterized fully remitted individuals with unipolar MDD and 30 healthy controls matching in age, sex and education were investigated. Non-verbal learning and memory were measured by the Rey-Osterrieth-Complex-Figure-Test (RCFT). The RCFT provides measures of planning, organizational skills, perceptual and non-verbal memory functions. For assessing the mediating effects of organizational strategies, we used the Savage Organizational Score. RESULTS: Compared to healthy controls, participants with remitted MDD showed more deficits in their non-verbal memory function. Moreover, participants with remitted MDD demonstrated difficulties in organizing non-verbal information appropriately during learning. In contrast, no impairments regarding visual-spatial functions in remitted MDD were observed. LIMITATIONS: Except for one patient, all the others were taking psychopharmacological medication. The neuropsychological function was solely investigated in the remitted phase of MDD. CONCLUSIONS: Individuals with MDD in remission showed persistent non-verbal memory impairments, modulated by a deficient use of organizational strategies during encoding. Therefore, our results strongly argue for additional therapeutic interventions in order to improve these remaining deficits in cognitive function.

Automatic mood-congruent amygdala responses to masked facial expressions in major depression.

BACKGROUND: Cognitive theories of depression predict mood-congruent negative biases already at automatic stages of processing, although several behavioral studies seem to contradict this notion. That is, depression should potentiate emotional reactivity to negative emotional cues, whereas it should reduce reactivity in response to positive emotional stimuli. Assessing neurobiological substrates of automatic emotion processing might be a more sensitive challenge for automatic negative bias in depression than behavioral measures. METHODS: In 30 acutely depressed inpatients and 26 healthy control subjects, automatic amygdala responses to happy and sad facial expressions were assessed by means of functional magnetic resonance imaging (fMRI) at 3 Tesla. To examine automatic responses, a presentation paradigm using subliminal, backward-masked stimuli was employed. A detection task was administered to assess participants' awareness of the masked emotional faces presented in the fMRI experiment. RESULTS: Detection performance was at chance level for both patients and healthy control subjects, suggesting that the neurobiological reactions took place in absence of conscious awareness of the emotional stimuli. A robust emotion by group interaction was observed in the right amygdala. Whereas healthy control subjects demonstrated stronger responses to happy faces, depressed patients showed the opposite. Furthermore, amygdala responsiveness to happy facial expression was negatively correlated with current depression severity. CONCLUSIONS: Depressed patients exhibit potentiated amygdala reactivity to masked negative stimuli along with a reduced responsiveness to masked positive stimuli compared with healthy individuals. Thus, depression is characterized by mood-congruent processing of emotional stimuli in the amygdala already at an automatic level of processing.

Human fear conditioning and extinction in neuroimaging: a systematic review.

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.

Impact of working memory load on FMRI resting state pattern in subsequent resting phases.

BACKGROUND: The default-mode network (DMN) is a functional network with increasing relevance for psychiatric research, characterized by increased activation at rest and decreased activation during task performance. The degree of DMN deactivation during a cognitively demanding task depends on its difficulty. However, the relation of hemodynamic responses in the resting phase after a preceding cognitive challenge remains relatively unexplored. We test the hypothesis that the degree of activation of the DMN following cognitive challenge is influenced by the cognitive load of a preceding working-memory task. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-five healthy subjects were investigated with functional MRI at 3 Tesla while performing a working-memory task with embedded short resting phases. Data were decomposed into statistically independent spatio-temporal components using Tensor Independent Component Analysis (TICA). The DMN was selected using a template-matching procedure. The spatial map contained rest-related activations in the medial frontal cortex, ventral anterior and posterior cingulate cortex. The time course of the DMN revealed increased activation at rest after 1-back and 2-back blocks compared to the activation after a 0-back block. CONCLUSION/SIGNIFICANCE: We present evidence that a cognitively challenging working-memory task is followed by greater activation of the DMN than a simple letter-matching task. This might be interpreted as a functional correlate of self-evaluation and reflection of the preceding task or as relocation of cerebral resources representing recovery from high cognitive demands. This finding is highly relevant for neuroimaging studies which include resting phases in cognitive tasks as stable baseline conditions. Further studies investigating the DMN should take possible interactions of tasks and subsequent resting phases into account.

Reduced amygdala-prefrontal coupling in major depression: association with MAOA genotype and illness severity.

The amygdala plays a pivotal role in a cortico-limbic circuitry implicated in emotion processing and regulation. In the present study, functional connectivity of the amygdala with prefrontal areas involved in emotion regulation was investigated during a facial expression processing task in a sample of 34 depressed inpatients and 31 healthy controls. All patients were genotyped for a common functional variable number tandem repeat (VNTR) polymorphism in the promoter region of the monoamine oxidase A gene (MAOA u-VNTR) which has been previously associated with major depression as well as reduced cortico-limbic connectivity in healthy subjects. In our control group, we observed tight coupling of the amygdala and dorsal prefrontal areas comprising the dorsolateral prefrontal cortex (DLPFC), dorsal parts of the anterior cingulate cortex (dACC), and lateral orbitofrontal cortex. Amygdala-prefrontal connectivity was significantly reduced in depressed patients and carriers of the higher active MAOA risk alleles (MAOA-H). Hence, depressed MAOA-H carriers showed the weakest amygdala-prefrontal coupling of the investigated subgroups. Furthermore, reduced coupling of this circuitry predicted more than 40% variance of clinical variables characterizing a longer and more severe course of disease. We conclude that genetic variation in the MAOA gene may affect the course of major depression by disrupting cortico-limbic connectivity.