Vocal brain development in infants of mothers with serious mental illness (CAPRI-Voc): study protocol.

INTRODUCTION: Improving the lives of children and adolescents with parental mental illness (CAPRI) remains an urgent political and public health concern for the UK and European Union. Recurrent parental mental illness is believed to lead to fractures in the family, academic and social lives of these children, yet interventions are poorly targeted and non-specific. Part of an interdisciplinary programme of work (the CAPRI Programme; grant number: 682741), CAPRI-Voc aims to achieve two goals: first, to test the feasibility of our longitudinal imaging paradigm in mother-infant pairs where the mother has a diagnosis of severe mental illness. Second, to compare development of vocal processing in these infants with infants in the general population. METHODS AND ANALYSIS: Recruitment of 100 infants of mothers with mental illness, alongside 50 infants of healthy mothers. Both cohorts of infants will undergo functional near infrared spectroscopy (fNIRS) brain imaging at three time points: 9, 12 and 18 months to explore differences between cohorts in their neural responses to vocal stimuli in our language paradigm. Mothers will complete an interview and psychological questionnaires. We shall also complete an infant developmental battery and mother-child interaction play session. Data on recruitment, retention and dropout will be recorded. ETHICS AND DISSEMINATION: It will be made clear that fNIRS is a safe, non-invasive technology widely used in infant clinical and psychological research. We shall reassure mothers that no definitive causal link exists between maternal mental illness and language development in infants, and that individual data will only exist as part of the wider dataset. As the study includes both children and vulnerable adults, all research staff will complete National Health Service (NHS) Safeguarding level 3 training. Dissemination will be via direct feedback to stakeholders, patient and advisory groups, and through presentations at conferences, journal publications and university/NHS trust communications. The study was approved through North West-Greater Manchester West Research Ethics Committee (17/NW/0074) and Health Research Authority (212715).

Cognitive function after electroconvulsive therapy for depression: relationship to clinical response.

BACKGROUND: As uncertainty remains about whether clinical response influences cognitive function after electroconvulsive therapy (ECT) for depression, we examined the effect of remission status on cognitive function in depressed patients 4 months after a course of ECT. METHOD: A secondary analysis was undertaken on participants completing a randomised controlled trial of ketamine augmentation of ECT for depression who were categorised by remission status (MADRS ⩽10 v. >10) 4 months after ECT. Cognition was assessed with self-rated memory and neuropsychological tests of anterograde verbal and visual memory, autobiographical memory, verbal fluency and working memory. Patients were assessed through the study, healthy controls on a single occasion, and compared using analysis of variance. RESULTS: At 4-month follow-up, remitted patients (N = 18) had a mean MADRS depression score of 3.8 (95% CI 2.2-5.4) compared with 27.2 (23.0-31.5) in non-remitted patients (N = 19), with no significant baseline differences between the two groups. Patients were impaired on all cognitive measures at baseline. There was no deterioration, with some measures improving, 4-months after ECT, at which time remitted patients had significantly improved self-rated memory, anterograde verbal memory and category verbal fluency compared with those remaining depressed. Self-rated memory correlated with category fluency and autobiographical memory at follow-up. CONCLUSIONS: We found no evidence of persistent impairment of cognition after ECT. Achieving remission improved subjective memory and verbal memory recall, but other aspects of cognitive function were not influenced by remission status. Self-rated memory may be useful to monitor the effects of ECT on longer-term memory.

Frontal haemodynamic responses in depression and the effect of electroconvulsive therapy.

BACKGROUND: Reduced frontal cortex metabolism and blood flow in depression may be associated with low mood and cognitive impairment. Further reduction has been reported during a course of electroconvulsive therapy but it is not known if this relates to mood and cognitive changes caused by electroconvulsive therapy. AIMS: The purpose of this study was to investigate frontal function while undertaking cognitive tasks in depressed patients compared with healthy controls, and following electroconvulsive therapy in patients. METHODS: We measured frontal haemodynamic responses to a category verbal fluency task and a working memory N-back task using portable functional near infra-red spectroscopy (fNIRS) in 51 healthy controls and 18 severely depressed patients, 12 of whom were retested after the fourth treatment of a course of electroconvulsive therapy. Mood was assessed using the Montgomery Åsberg Depression Rating Scale and cognitive function using category Verbal Fluency from the Controlled Oral Word Association Test and Digit Span backwards. RESULTS: Compared to healthy controls, depressed patients had bilaterally lower frontal oxyhaemoglobin responses to the cognitive tasks, although this was only significant for the N-Back task where performance correlated inversely with depression severity in patients. After four electroconvulsive therapy treatments oxyhaemoglobin responses were further reduced during the Verbal Fluency task but the changes did not correlate with mood or cognitive changes. DISCUSSION: Our results confirmed a now extensive literature showing impaired frontal fNIRS oxyhaemoglobin responses to cognitive tasks in depression, and showed for the first time that these are further reduced during a course of electroconvulsive therapy. Further research is needed to investigate the biology and clinical utility of frontal fNIRS in psychiatric patients.

Regional default mode network connectivity in major depressive disorder: modulation by acute intravenous citalopram.

The relationship between altered default mode network (DMN) connectivity and abnormal serotonin function in major depressive disorder (MDD) has not been investigated. Using intravenous citalopram and resting-state fMRI, we investigated DMN intra-network connectivity and serotonin function in 77 healthy controls and patients with MDD. There were no significant main effects of MDD or citalopram on DMN intra-network connectivity; however, significant interactions indicated that group differences under saline were modified by citalopram. In MDD patients during saline infusion, in contrast with controls, the DMN (i) did not include the precuneus that was instead part of an anti-correlated network but (ii) did include amygdala that was part of the anti-correlated network in controls. Citalopram infusion in MDD patients restored the pattern seen in controls under saline. In healthy controls, citalopram infusion disengaged the precuneus from the DMN and engaged the amygdala, partially reproducing the abnormalities seen under saline in MDD. In exploratory analyses within the MDD group, greater rumination self-ratings were associated with greater intra-network connectivity of the anterior cingulate cortex with the DMN. We hypothesise that, in MDD, disengagement of the precuneus from the DMN relates to overgeneral memory bias in rumination. The opposite effect, with greater engagement of the amygdala in the DMN, reflects the negative valence of rumination. Reversal of these abnormalities by citalopram suggests that they may be related to impaired serotonin function. That citalopram engaged the amygdala in the DMN in controls may relate to the paradoxical effects on aversive processing seen with acute SSRIs in healthy subjects.

Neural pathways of maternal responding: systematic review and meta-analysis.

Functional magnetic resonance imaging (fMRI) has increasingly been employed to establish whether there is a specific brain neural network dedicated to maternal responsiveness. We undertook systematic review and meta-analysis of all studies in which healthy new mothers were exposed to visual stimuli of own versus other infants to determine the quality of evidence for a dedicated maternal neural network. Systematic literature review revealed a pattern of specific neural responses commonly induced by visual infant paradigms. Brain areas consistently reported as activated in mothers in response to own versus unknown infant included the left thalamus, bilateral pre-central gyrus, left limbic lobe, uncus, amygdala and left caudate. These regions are implicated in reward, attention, emotion processing and other core social cognitive skills. Meta-analysis, however, revealed a more limited subset of brain areas activated in mothers specifically in response to their own versus unknown infant and suggested considerable inter-study variability. Further work is needed if functional imaging is to become an objective tool for the assessment of neural pathways associated with distinct patterns of maternal care behaviour. Such a tool would be invaluable in developing biomarkers of neural activity associated with healthy maternal care and for monitoring treatment/intervention effects of costly parenting interventions.

Ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT): a multicentre, double-blind, randomised, parallel-group, superiority trial.

BACKGROUND: The use of electroconvulsive therapy (ECT) is limited by concerns about its cognitive adverse effects. Preliminary evidence suggests that administering the glutamate antagonist ketamine with ECT might alleviate cognitive adverse effects and accelerate symptomatic improvement; we tested this in a randomised trial of low-dose ketamine. METHODS: In this multicentre, randomised, parallel-group study in 11 ECT suites serving inpatient and outpatient care settings in seven National Health Service trusts in the North of England, we recruited severely depressed patients, who were diagnosed as having unipolar or bipolar depressive episodes defined as moderate or severe by DSM-IV criteria, aged at least 18 years, and were able and willing to provide written consent to participate in the study. Patients were randomly assigned (1:1) to ketamine (0·5 mg/kg intravenous bolus) or saline adjunctive to the anaesthetic for the duration of their ECT course. Patients and assessment and ECT treatment teams were masked to treatment allocation, although anaesthetists administering the study medication were not. We analysed the primary outcome, Hopkins Verbal Learning Test-Revised delayed verbal recall (HVLT-R-DR) after four ECT treatments, using a Gaussian repeated measures model in all patients receiving the first ECT treatment. In the same population, safety was assessed by adverse effect monitoring. This trial was registered with International Standard Randomised Controlled Trial Number, number ISRCTN14689382. FINDINGS: Between early December, 2012, and mid-June, 2015, 628 patients were screened for eligibility, of whom 79 were randomly assigned to treatment (40 in the ketamine group vs 39 in the saline group). Ketamine (mean 5·17, SD 2·92), when compared with saline (5·54, 3·42), had no benefit on the primary outcome (HVLT-R-DR; difference in means -0·43 [95% CI -1·73 to 0·87]). 15 (45%) of 33 ketamine-treated patients compared with 10 (27%) of 37 patients receiving saline experienced at least one adverse event which included two (6%) of 33 patients who had ketamine-attributable transient psychological effects. Psychiatric adverse events were the most common in both groups (six [27%] of 22 adverse events in the ketamine group vs seven [54%] of 13 in the saline group). INTERPRETATION: No evidence of benefit for ketamine was found although the sample size used was small; however, the results excluded greater than a small to moderate benefit with 95% confidence. The results do not support the use of adjunctive low-dose ketamine in routine ECT treatment. FUNDING: National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme, an MRC and NIHR partnership.

Natural variation in maternal sensitivity is reflected in maternal brain responses to infant stimuli.

Increasing evidence suggests that discrete neural networks that mediate emotion processing are activated when mothers respond to infant's images or cries. Accumulating data also indicate that natural variation in maternal caregiving behavior is related to maternal oxytocin (OT) levels. However, brain activation to infant cues has not been studied comparing mothers at disparate ends of the "maternal sensitivity" spectrum. Based on observed mother-infant play interaction at 4-6 months postpartum in 80 antenatally recruited mothers, 15 mothers with the highest sensitivity (HSMs) and 15 mothers with the lowest sensitivity (LSMs) were followed at 7-9 months using functional magnetic resonance imaging (fMRI) to examine brain responses to viewing videos of their "own" versus an "unknown" infant in 3 affect states (neutral, happy, and sad). Plasma OT measurements were taken from mothers following play interactions with their infant. Compared with LSMs, HSMs showed significantly greater brain activation in right superior temporal gyrus (STG) in response to own versus unknown neutral infant and to own happy versus neutral control. Changes in brain activation were significantly negatively correlated with plasma OT responses in HSMs mothers. Conversely, compared with HSMs, LSMs showed no significant activation difference in response to own infant separately or in contrast to unknown infant. Activation of STG may index sensitive maternal response to own infant stimuli. Sensitive parenting may have its unique profile in relation to brain responses which can act as biomarkers for future intervention studies that enhance sensitivity of maternal care. (PsycINFO Database Record

Comparing the actions of lanicemine and ketamine in depression: key role of the anterior cingulate.

Intravenous infusion of lanicemine (formerly AZD6765), a low trapping non-selective N-methyl-D-aspartate (NMDA) receptor antagonist, induces antidepressant effects with a similar time course to ketamine. We investigated whether a single dose lanicemine infusion would reproduce the previously reported decrease in subgenual anterior cingulate cortex (sgACC) activity evoked by ketamine, a potential mechanism of antidepressant efficacy. Sixty un-medicated adults meeting the criteria for major depressive disorder were randomly assigned to receive constant intravenous infusions of ketamine, lanicemine or saline during a 60min pharmacological magnetic resonance imaging (phMRI) scan. Both ketamine and lanicemine gradually increased the blood oxygen level dependent signal in sgACC and rostral ACC as the primary outcome measure. No decreases in signal were seen in any region. Interviewer-rated psychotic and dissociative symptoms were minimal following administration of lanicemine. There was no significant antidepressant effect of either infusion compared to saline. The previously reported deactivation of sgACC after ketamine probably reflects the rapid and pronounced subjective effects evoked by the bolus-infusion method used in the previous study. Activation of the ACC was observed following two different NMDA compounds in both Manchester and Oxford using different 3T MRI scanners, and this effect predicted improvement in mood 1 and 7 days post-infusion. These findings suggest that the initial site of antidepressant action for NMDA antagonists may be the ACC (NCT01046630. A Phase I, Multi-centre, Double-blind, Placebo-controlled Parallel Group Study to Assess the pharmacoMRI Effects of AZD6765 in Male and Female Subjects Fulfilling the Criteria for Major Depressive Disorder; http://clinicaltrials.gov/show/NCT01046630).

Study protocol for the randomised controlled trial: Ketamine augmentation of ECT to improve outcomes in depression (Ketamine-ECT study).

BACKGROUND: There is a robust empirical evidence base supporting the acute efficacy of electroconvulsive therapy (ECT) for severe and treatment resistant depression. However, a major limitation, probably contributing to its declining use, is that ECT is associated with impairment in cognition, notably in anterograde and retrograde memory and executive function. Preclinical and preliminary human data suggests that ketamine, used either as the sole anaesthetic agent or in addition to other anaesthetics, may reduce or prevent cognitive impairment following ECT. A putative hypothesis is that ketamine, through antagonising glutamate receptors, protects from excess excitatory neurotransmitter stimulation during ECT. The primary aim of the ketamine-ECT study is to investigate whether adjunctive ketamine can attenuate the cognitive impairment caused by ECT. Its secondary aim is to examine if ketamine increases the speed of clinical improvement with ECT. METHODS/DESIGN: The ketamine ECT study is a multi-site randomised, placebo-controlled, double blind trial. It was originally planned to recruit 160 moderately to severely depressed patients who had been clinically prescribed ECT. This recruitment target was subsequently revised to 100 patients due to recruitment difficulties. Patients will be randomly allocated on a 1:1 basis to receive either adjunctive ketamine or saline in addition to standard anaesthesia for ECT. The primary neuropsychological outcome measure is anterograde verbal memory (Hopkins Verbal Learning Test-Revised delayed recall task) after 4 ECT treatments. Secondary cognitive outcomes include verbal fluency, autobiographical memory, visuospatial memory and digit span. Efficacy is assessed using observer and self-report efficacy measures of depressive symptomatology. The effects of ECT and ketamine on cortical activity during cognitive tasks will be studied in a sub-sample using functional near-infrared spectroscopy (fNIRS). DISCUSSION: The ketamine-ECT study aims to establish whether or not adjunctive ketamine used together with standard anaesthesia for ECT will significantly reduce the adverse cognitive effects observed after ECT. Potential efficacy benefits of increased speed of symptom improvement and a reduction in the number of ECT treatments required will also be assessed, as will safety and tolerability of adjunctive ketamine. This study will provide important evidence as to whether adjunctive ketamine is routinely indicated for ECT given for depression in routine NHS clinical practice. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN14689382 (assigned 30/07/2012); EudraCT Number: 2011-005476-41.

fMRI and MRS measures of neuroplasticity in the pharyngeal motor cortex.

INTRODUCTION: Paired associative stimulation (PAS), is a novel non-invasive technique where two neural substrates are employed in a temporally coordinated manner in order to modulate cortico-motor excitability within the motor cortex (M1). In swallowing, combined pharyngeal electrical and transcranial-magnetic-stimulation induced beneficial neurophysiological and behavioural effects in healthy subjects and dysphagic stroke patients. Here, we aimed to investigate the whole-brain changes in neural activation during swallowing using functional magnetic resonance imaging (fMRI) following PAS application and in parallel assess associated GABA changes with magnetic resonance spectroscopy (MRS). METHODS: Healthy adults (n=11, 38±9years old) were randomised to receive real and sham PAS to the 'stronger' motor cortex pharyngeal representation, on 2 separate visits. Following PAS, event-related fMRI was performed to assess changes in brain activation in response to water and saliva swallowing and during rest. Data were analysed (SPM8) at P<.001. MRS data were acquired using MEGA-PRESS before and after the fMRI acquisitions on both visits and GABA concentrations were measured (AMARES, jMRUI). RESULTS: Following real PAS, BOLD signal changes (group analyses) increased at the site of stimulation during water and saliva swallowing, compared to sham PAS. It is also evident that PAS induced significant increases in BOLD signal to contralateral (to stimulation) hemispheric areas that are of importance to the swallowing neural network. Following real PAS, GABA:creatine ratio showed a trend to increase contralateral to PAS. CONCLUSION: Targeted PAS applied to the human pharyngeal motor cortex induces local and remote changes in both primary and non-primary areas for water and saliva tasks. There is a possibility that changes of the inhibitory neurotransmitter, GABA, may play a role in the changes in BOLD signal. These findings provide evidence for the mechanisms underlying the beneficial effects of PAS on the brain swallowing network.

Neuronal nitric oxide synthase (NOS1) polymorphisms interact with financial hardship to affect depression risk.

There is increasing evidence that genetic factors have a role in differential susceptibility to depression in response to severe or chronic adversity. Studies in animals suggest that nitric oxide (NO) signalling has a key role in depression-like behavioural responses to stress. This study investigated whether genetic variation in the brain-expressed nitric oxide synthase gene NOS1 modifies the relationship between psychosocial stress and current depression score. We recruited a population sample of 1222 individuals who provided DNA and questionnaire data on symptoms and stress. Scores on the List of Life-Threatening Experiences (LTE) questionnaire for the last year and self-rated current financial hardship were used as measures of recent/ongoing psychosocial stress. Twenty SNPs were genotyped. Significant associations between eight NOS1 SNPs, comprising two regional haplotypes, and current depression score were identified that survived correction for multiple testing when current financial hardship was used as the interaction term. A smaller three-SNP haplotypes (rs10507279, rs1004356 and rs3782218) located in a regulatory region of NOS1 showed one of the strongest effects, with the A-C-T haplotype associating with higher depression scores at low adversity levels but lower depression scores at higher adversity levels (p=2.3E-05). These results suggest that NOS1 SNPs interact with exposure to economic and psychosocial stressors to alter individual's susceptibility to depression.

The neural basis of maternal bonding.

BACKGROUND: Accumulating evidence suggests that mothers show a different pattern of brain responses when viewing their own compared to other infants. However, there is inconsistency across functional imaging studies regarding the key areas involved, and none have examined relationships between brain and behavioural responses to infants. We examined the brain regions activated when mothers viewed videos of their own infant contrasted with an unknown infant, and whether these are associated with behavioural and self-reported measures of mother-infant relations. METHOD: Twenty right-handed mothers viewed alternating 30-sec blocks of video of own 4-9 month infant and an unfamiliar matched infant, interspersed with neutral video. Whole brain functional magnetic resonance images (fMRI) were acquired on a 1.5T Philips Intera scanner using a TR of 2.55 s. Videotaped mother-infant interactions were systematically evaluated blind to family information to generate behavioural measures for correlational analysis. RESULTS: Enhanced blood oxygenation functional imaging responses were found in the own versus unknown infant contrast in the bilateral precuneus, right superior temporal gyrus, right medial and left middle frontal gyri and left amygdala. Positive mother-infant interaction (less directive parent behaviour; more positive/attentive infant behaviour) was significantly associated with greater activation in several regions on viewing own versus unknown infant, particularly the middle frontal gyrus. Mothers' perceived warmth of her infant was correlated with activations in the same contrast, particularly in sensory and visual areas. CONCLUSION: This study partially replicates previous reports of the brain regions activated in mothers in response to the visual presentation of their own infant. It is the first to report associations between mothers' unique neural responses to viewing their own infant with the quality of her concurrent behaviour when interacting with her infant and with her perceptions of infant warmth. These findings provide support for developing fMRI as a potential biomarker of parenting risk and change.

TOMM40 rs2075650 may represent a new candidate gene for vulnerability to major depressive disorder.

Evidence suggests that depression is a risk factor for dementia; however, the relationship between the two conditions is not fully understood. A novel gene (TOMM40) has been consistently associated with Alzheimer's disease (AD), but has received no attention in depression. We conducted a three-level cross-sectional study to investigate the association of the TOMM40 rs2075650 SNP with depression. We recruited a community sample of 1220 participants (571 controls, 649 lifetime depression) to complete a psychiatric background questionnaire, the Brief Symptom Inventory, and Big Five Inventory at Level-1, 243 (102 controls, 97 remitted, 44 currently depressed) to complete a face-to-face clinical interview and neuropsychological testing at Level-2 and 58 (33 controls, 25 remitted) to complete an emotional face-processing task during fMRI at Level-3. Our results indicated that the TOMM40 rs2075650 G allele was a significant risk factor for lifetime depression (p = 0.00006) and, in depressed subjects, was a significant predictor of low extraversion (p = 0.009). Currently depressed risk allele carriers showed subtle executive dysfunction (p = 0.004) and decreased positive memory bias (p = 0.021) together with reduced activity in the posterior (p(FWE) = 0.045) and anterior (p(FWE) = 0.041) cingulate during sad face emotion processing. Our results suggest that TOMM40 rs2075650 may be a risk factor for the development of depression characterized by reduced extraversion, impaired executive function, and decreased positive emotional recall, and reduced top-down cortical control during sad emotion processing.

Does oxytocin modulate variation in maternal caregiving in healthy new mothers?

BACKGROUND: Maternal sensitivity to infant cues and developmental needs may be pivotal for social and cognitive development. Animal and recent human studies emphasise a major role for Oxytocin (OT) in mediating sensitive caregiving but no study has examined the relationship between OT and extreme variation in human maternal sensitivity. METHODS: From 105 expectant mothers, 80 underwent blind-rating of maternal sensitivity at 4-6 months postpartum through free-play interaction with their infants. At 7-9 months postpartum, 30 mothers at extremes of maternal sensitivity: 15 'sensitive mothers' (high sensitivity mothers - HSMs, mean=4.47; SD=0.74) and 15 'less sensitive mothers' (low sensitivity mothers - LSMs, mean=2.13; SD=0.52) underwent plasma OT measurements before and after 10 min infant play. RESULTS: Baseline and post-interaction plasma OT was higher in LSMs than HSMs [F(1, 26)=8.42; p=0.01]. HSMs showed a trend towards significant reduction in plasma OT [t(14)=2.01; p=0.06] following play-interaction; no change was shown by LSMs [t(13)=-0.14; p=0.89]. Conclusion Higher baseline OT levels in healthy LSMs may imply greater stress responses to the demands of caring for an infant, or past deficiencies in own parenting relationship and act as a biomarker for poor parental sensitivity. OT may be acting to reduce stress and anxiety in LSMs consistent with studies of plasma OT and stress in women. By contrast, in HSMs, play interaction with their infants maybe relaxing as indicated by significant reduction in plasma OT from baseline. Ascertainment of mothers in well-defined sensitivity groups might facilitate examination of distinct coping strategies in parents and better understanding of variation in parental caregiving behaviour and its potential for modulation by OT. This article is part of a Special Issue entitled Oxytocin and Social Behav.

Genetic variants in the catechol-o-methyltransferase gene are associated with impulsivity and executive function: relevance for major depression.

The catechol-o-methyltransferase (COMT) gene has been extensively investigated in depression with somewhat contradictory results but the role of impulsivity, as a possible intermediate phenotype in this disorder, has not been considered yet. In our study, four tagging SNPs in the COMT gene (rs933271, rs740603, rs4680, rs4646316) were genotyped in two independent population cohorts: Manchester (n = 1267) and Budapest (n = 942). First, we investigated the association between COMT genotypes, impulsivity, neuroticism and depression using haplotype trend regression, and constructed a model using structural equation modeling to investigate the interaction between these factors. Secondly, we tested the effect of executive function on this model in a smaller interviewed sample (n = 207). Our results demonstrated that COMT haplotypes were significantly associated with impulsivity in the combined cohort, showing the same direction of effects in both populations. The COMT effect on depressive symptoms (in subjects without history of depression) and on executive function (interviewed sample) showed the opposite pattern to impulsivity. Structural equation models demonstrated that COMT and impulsivity acted, both together (through neuroticism) and independently, to increase the risk of depression. In addition, better executive function also operated as a risk factor for depression, possibly though reduced ability to flexibly disengage negative emotions. In conclusion, variations in the COMT gene exert complex effects on susceptibility to depression involving various intermediate phenotypes, such as impulsivity and executive function. These findings emphasise that modeling of disease pathways at phenotypic level are valuable for identifying genetic risk factors.

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.

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.

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.

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.