Emma Thomas

The CREB1-BDNF-NTRK2 Pathway in Depression: Multiple Gene-Cognition-Environment Interactions.

BACKGROUND The neuroplastic pathway, which includes cyclic adenosine monophosphate response element-binding protein 1 (CREB1), brain-derived neurotrophic factor (BDNF), and its receptor (neurotrophic tyrosine kinase receptor, type 2 [NTRK2]), plays a crucial role in the adaptation of brain to stress, and thus variations of these genes are plausible risk factors for depression. METHODS A population-based sample was recruited, subsets of which were interviewed and underwent functional magnetic resonance imaging. We investigated the association of nine polymorphisms throughout the CREB1-BDNF-NTRK2 pathway with lifetime depression, rumination, current depression severity, negative life events, and sad face emotion processing in a three-level design. RESULTS In the population study, BDNF-rs6265 and CREB1-rs2253206 major alleles were significantly associated with rumination and through rumination with current depression severity. However, childhood adversity increased the risk of lifetime depression in the minor allele carriers of BDNF-rs6265 and CREB1-rs2253206 and in alleles of six other single nucleotide polymorphisms (SNPs). We validated our findings in the interviewed subjects using structural equation modeling. Finally, using functional magnetic resonance imaging, we found that viewing sad faces evoked greater activity in depression-related areas in healthy control subjects possessing the minor alleles of BDNF-rs6265 and CREB1-rs2253206. CONCLUSIONS Genetic variation associated with reduced function in the CREB1-BDNF-NTRK2 pathway has multiple, sometimes opposing, influences on risk mechanisms of depression, but almost all the SNPs studied amplified the effect of childhood adversity. The use of cognitive and neural intermediate phenotypes together with a molecular pathway approach may be critical to understanding how genes influence risk of depression.

Increased amygdala responses to sad but not fearful faces in major depression: relation to mood state and pharmacological treatment

OBJECTIVE Increased amygdala response to negative emotions seen in functional MRI (fMRI) has been proposed as a biomarker for negative emotion processing bias underlying depressive symptoms and vulnerability to depressive relapse that are normalized by antidepressant drug treatment. The purpose of this study was to determine whether abnormal amygdala responses to face emotions in depression are related to specific emotions or change in response to antidepressant treatment and whether they are present as a stable trait in medication-free patients in remission. METHOD Sixty-two medication-free unipolar depressed patients (38 were currently depressed, and 24 were in remission) and 54 healthy comparison subjects underwent an indirect face-emotion processing task during fMRI. Thirty-two currently depressed patients were treated with the antidepressant citalopram for 8 weeks. Adherence to treatment was evaluated by measuring citalopram plasma concentrations. RESULTS Patients with current depression had increased bilateral amygdala responses specific to sad faces relative to healthy comparison subjects and nonmedicated patients in stable remission. Treatment with citalopram abolished the abnormal amygdala responses to sad faces in currently depressed patients but did not alter responses to fearful faces. CONCLUSIONS Aberrant amygdala activation in response to sad facial emotions is specific to the depressed state and is a potential biomarker for a negative affective bias during a depressive episode.

State-dependent alteration in face emotion recognition in depression

BACKGROUND Negative biases in emotional processing are well recognised in people who are currently depressed but are less well described in those with a history of depression, where such biases may contribute to vulnerability to relapse. AIMS To compare accuracy, discrimination and bias in face emotion recognition in those with current and remitted depression. METHOD The sample comprised a control group (n = 101), a currently depressed group (n = 30) and a remitted depression group (n = 99). Participants provided valid data after receiving a computerised face emotion recognition task following standardised assessment of diagnosis and mood symptoms. RESULTS In the control group women were more accurate in recognising emotions than men owing to greater discrimination. Among participants with depression, those in remission correctly identified more emotions than controls owing to increased response bias, whereas those currently depressed recognised fewer emotions owing to decreased discrimination. These effects were most marked for anger, fear and sadness but there was no significant emotion × group interaction, and a similar pattern tended to be seen for happiness although not for surprise or disgust. These differences were confined to participants who were antidepressant-free, with those taking antidepressants having similar results to the control group. CONCLUSIONS Abnormalities in face emotion recognition differ between people with current depression and those in remission. Reduced discrimination in depressed participants may reflect withdrawal from the emotions of others, whereas the increased bias in those with a history of depression could contribute to vulnerability to relapse. The normal face emotion recognition seen in those taking medication may relate to the known effects of antidepressants on emotional processing and could contribute to their ability to protect against depressive relapse.

Brain imaging correlates of cognitive impairment in depression

This review briefly summarises recent research on the neural basis of cognition in depression. Two broad areas are covered: emotional and non-emotional processing. We consider how research findings support models of depression based on disrupted cortico-limbic circuitry, and how modern connectivity analysis techniques can be used to test such models explicitly. Finally we discuss clinical implications of cognitive imaging in depression, and specifically the possible role for these techniques in diagnosis and treatment planning.

The effect of acute citalopram on face emotion processing in remitted depression: A pharmacoMRI study

Both reduced serotonergic (5-HT) function and negative emotional biases have been associated with vulnerability to depression. In order to investigate whether these might be related we examined 5-HT modulation of affective processing in 14 remitted depressed subjects compared with 12 never depressed controls matched for age and sex. Participants underwent function magnetic resonance imaging (fMRI) during a covert face emotion task with and without intravenous citalopram (7.5mg) pretreatment. Compared with viewing neutral faces, and irrespective of group, citalopram enhanced left anterior cingulate blood oxygen level dependent (BOLD) response to happy faces, right posterior insula and right lateral orbitofrontal responses to sad faces, and reduced amygdala responses bilaterally to fearful faces. In controls, relative to remitted depressed subjects, citalopram increased bilateral hippocampal responses to happy faces and increased right anterior insula response to sad faces. These findings were not accounted for by changes in BOLD responses to viewing neutral faces. These results are consistent with previous findings showing 5-HT modulation of affective processing; differences found in previously depressed participants compared with controls may contribute to emotional processing biases underlying vulnerability to depressive relapse.

Interaction between a history of depression and rumination on neural response to emotional faces

BACKGROUND Both past depressive episodes and the personality trait of depressive rumination are strong risk factors for future depression. Depression is associated with abnormal emotional processing, which may be a neurobiological marker for vulnerability to depression. A consistent picture has yet to emerge as to how a history of depression and the tendency to ruminate influence emotional processing. The aim of this study was to investigate the relationship between rumination, past depression and neural responses when processing face emotions. METHOD The Ruminative Responses Scale (RRS) was completed by 30 remitted depressives and 37 controls who underwent functional magnetic resonance imaging (fMRI) scanning while viewing happy, sad, fearful and neutral faces. RESULTS The remitted depressives showed overall reductions in neural responses to negative emotions relative to the controls. However, in the remitted depressives, but not the controls, RRS scores were correlated with increased neural responses to negative emotions and decreased responses to happiness in limbic regions. CONCLUSIONS Automatic emotion processing biases and rumination seem to be correlated to aspects of vulnerability to depression. However, remission from depression may be maintained by a general suppression of limbic responsiveness to negative emotion.

Risk-taking behavior in a gambling task associated with variations in the tryptophan hydroxylase 2 gene: relevance to psychiatric disorders

Decision making, choosing the best option from the possible outcomes, is impaired in many psychiatric conditions including affective disorders. We tested the hypothesis that variations in serotonergic genes (TPH2, TPH1, SLC6A4, HTR1A), which influence serotonin availability, affect choice behavior in a probabilistic gambling task. A population cohort (N=1035) completed a paper-and-pencil gambling task, filled out personality and symptom questionnaires and gave consent for the use of their DNA in a genetic association study. A subgroup of subjects (N=69) also completed a computer version of the task. The gambling task was designed to estimate an individuals tendency to take a risk when choosing between a smaller but more certain ‘win’ and a larger, less probable one. We genotyped seven haplotype tagging SNPs in the TPH2 gene, and previously reported functional polymorphisms from the other genes (rs1800532, 5HTTLPR, and rs6295). Carriers of the more prevalent TPH2 haplotype, which was previously associated with less active enzyme variant, showed reduced risk taking on both tasks compared with subjects not carrying the common haplotype. The effect of TPH2 haplotypes on risk-taking was independent of current depression and anxiety symptoms, neuroticism and impulsiveness scores. We did not find an association between functional polymorphisms in the TPH1, SLC6A4, HTR1A genes and risk-taking behavior. In conclusion, our study demonstrates the role of the TPH2 gene and the serotonin system in risk taking and suggests that TPH2 gene may contribute to the expression of psychiatric phenotypes through altered decision making.

The HTR1A and HTR1B receptor genes influence stress-related information processing

The serotonergic system has been widely implicated in stress related psychiatric disorders such as depression and anxiety. We investigated the possible association between depression and anxiety scores and SNPs within the HTR1A and HTR1B genes in a population sample (n=1387). There was no direct SNP-phenotype association, but in interaction with recent stressful life events rs6295 G, rs878567 T alleles and rs6296 C alleles were associated with significantly higher symptom scores. A subset of control subjects (n=101) took part in a computerised face emotion processing task. Healthy rs6295 GG carriers did not show an affective bias to perceive more negative emotions but reacted more quickly to fearful faces. Thus we conclude that the serotonin-1A receptor conveys vulnerability to these psychiatric disorders by modulating threat-related information processing. Our results extend previous findings of an interaction between stressful life events and the serotonin transporter gene to two other genes in the serotonergic pathway and emphasise the possible role of increased threat-related information processing as an intermediate phenotype.

Reversed Frontotemporal Connectivity During Emotional Face Processing in Remitted Depression

Background Vulnerability to relapse persists after remission of an acute episode of major depressive disorder. This has been attributed to abnormal biases in the processing of emotional stimuli in limbic circuits. However, neuroimaging studies have not so far revealed consistent evidence of abnormal responses to emotional stimuli in limbic structures, such as the amygdala, in remitted depression. This suggests the problem might lie in the integrated functioning of emotion processing circuits. Methods We recruited 22 unmedicated patients in remission from major depressive disorder (rMDD) and 21 age-matched healthy control subjects. Functional magnetic resonance imaging was performed during a face emotion processing task. Dynamic causal modeling was used with Bayesian model selection to determine the most likely brain networks and valence-specific modulation of connectivity in healthy control subjects and rMDD. Results In healthy volunteers, sad faces modulated bi-directional connections between amygdala and orbitofrontal cortex and between fusiform gyrus and orbitofrontal cortex. Happy faces modulated unidirectional connections from fusiform gyrus to orbitofrontal cortex. In rMDD, the opposite pattern was observed, with evidence of happy faces modulating bidirectional frontotemporal connections and sad faces modulating unidirectional fusiform–orbitofrontal connections. Conclusions Participants with rMDD have abnormal modulation of frontotemporal effective connectivity in response to happy and sad face emotions, despite normal activations within each region. Specifically, processing of mood incongruent happy information was associated with a more richly modulated frontotemporal brain network, whereas mood congruent sad information was associated with less network modulation. This supports a hypothesis of dysfunction within cortico–limbic connections in individuals vulnerable to depression.

Reduced medial prefrontal responses to social interaction images in remitted depression.

CONTEXT Major depressive disorder is associated with impairments in processing emotional stimuli, and residual impairments are observed during remission, possibly indicating trait vulnerability. Stimuli with social context represent a distinct class of emotional stimuli, which in healthy volunteers are associated with specific neural substrates but have not previously been studied relative to vulnerability to depression. OBJECTIVE To explore whether individuals with remitted major depressive disorder had altered neuronal processing of social emotional stimuli. DESIGN Cross-sectional design using functional magnetic resonance imaging, combined with a cognitive activation task. SETTING General community of greater Manchester, England. PARTICIPANTS Twenty-five unmedicated participants fully remitted from major depressive disorder and 29 age-matched control subjects. MAIN OUTCOME MEASURES Neuronal responses to positive and negative social interaction images vs valence-matched images with less overt social context. RESULTS Participants with remitted depression showed attenuated frontopolar response relative to controls for positive and negative images depicting social interactions. For negative social images, participants with remitted depression also showed reduced latero-orbitofrontal response relative to controls. CONCLUSIONS In the absence of current symptoms, individuals with remitted major depressive disorder showed reduced frontopolar processing of stimuli showing social interactions, a reduction not seen for stimuli showing individual successes and failures and, therefore, not simply an effect of emotional valence. These results suggest a specific trait abnormality in social emotional processing associated with vulnerability to depression, which may have implications for understanding social cognition mechanisms and for developing effective psychological therapies.