A key objective in the field of translational psychiatry over the past few decades has been to identify the brain correlates of major depressive disorder (MDD). Identifying measurable indicators of brain processes associated with MDD could facilitate the detection of individuals at risk, and the development of novel treatments, the monitoring of treatment effects, and predicting who might benefit most from treatments that target specific brain mechanisms. However, despite intensive neuroimaging research towards this effort, underpowered studies and a lack of reproducible findings have hindered progress. Here, we discuss the work of the ENIGMA Major Depressive Disorder (MDD) Consortium, which was established to address issues of poor replication, unreliable results, and overestimation of effect sizes in previous studies. The ENIGMA MDD Consortium currently includes data from 45 MDD study cohorts from 14 countries across six continents. The primary aim of ENIGMA MDD is to identify structural and functional brain alterations associated with MDD that can be reliably detected and replicated across cohorts worldwide. A secondary goal is to investigate how demographic, genetic, clinical, psychological, and environmental factors affect these associations. In this review, we summarize findings of the ENIGMA MDD disease working group to date and discuss future directions. We also highlight the challenges and benefits of largescale data sharing for mental health research.

Prediction error signals are fundamental to learning. Here, in mice, we show that aversive prediction signals are found in the hemodynamic responses and theta oscillations recorded from the basolateral amygdala. During fear conditioning, amygdala responses evoked by footshock progressively decreased, whereas responses evoked by the auditory cue that predicted footshock concomitantly increased. Unexpected footshock evoked larger amygdala responses than expected footshock. The magnitude of the amygdala response to the footshock predicted behavioral responses the following day. The omission of expected footshock led to a decrease below baseline in the amygdala response suggesting a negative aversive prediction error signal. Thus, in mice, amygdala activity conforms to temporal difference models of aversive learning.

BackgroundGene association studies detect an influence of natural variation in the 5-hydroxytryptamine transporter (5-HTT) gene on multiple aspects of individuality in brain function, ranging from personality traits through to susceptibility to psychiatric disorders such as anxiety and depression. The neural substrates of these associations are unknown. Human neuroimaging studies suggest modulation of the amygdala by 5-HTT variation, but this hypothesis is controversial and unresolved, and difficult to investigate further in humans.MethodsWe used a mouse model in which the 5-HTT is overexpressed throughout the brain and recorded hemodynamic responses (using a novel in vivo voltammetric monitoring method, analogous to blood oxygen level–dependent functional magnetic resonance imaging) and local field potentials during Pavlovian fear conditioning.ResultsIncreased 5-HTT expression impaired, but did not prevent, fear learning and significantly reduced amygdala hemodynamic responses to aversive cues. Increased 5-HTT expression was also associated with reduced theta oscillations, which were a feature of aversive cue presentation in controls. Moreover, in control mice, but not those with high 5-HTT expression, there was a strong correlation between theta power and the amplitude of the hemodynamic response.ConclusionsDirect experimental manipulation of 5-HTT expression levels throughout the brain markedly altered fear learning, amygdala hemodynamic responses, and neuronal oscillations.

Trait anxiety is associated with an excessive processing of danger-related stimuli, predisposing individuals to quickly detect threatening cues. Early, automatic mechanisms are believed to be responsible for the production of these cognitive biases; however, limitations in the paradigms most commonly used to achieve visual suppression or attentional unawareness have left open the possibility of strategic mechanisms influencing these early stages of information processing. Establishing whether symptoms of anxiety are associated with truly automatic biases in processing is an essential step in determining their etiology and in developing targeted cognitive interventions. We addressed this question using continuous flash suppression (CFS), a novel and robust method of visual suppression capable of rendering a stimulus invisible from awareness for extended durations. We specifically investigated the degree to which trait anxiety influenced the suppression of threatening, positive, and neutral faces. Forty-nine individuals, with no reported history of psychological problems and varying levels of anxiety, were recruited. Higher trait anxiety scores were associated with an increased speed to detect fearful compared with happy faces. These results indicate that the bias toward threatening information associated with symptoms of anxiety operates, at least partly, at an early stage of information processing. This suggests that cognitive interventions for anxiety may benefit from directly targeting such early and potentially preconscious processes.

This preliminary evidence suggests that short, group-based psychoeducation benefits currently medicated inpatients following the remission of mania in bipolar I disorder. This intervention warrants further investigation, especially in other Chinese populations. If future studies confirm its benefits, group-based psychoeducation could be incorporated into routine psychiatric inpatient care for bipolar patients in China.

One of the most intriguing characteristics of Williams Syndrome individuals is their hypersociability. The amygdala has been consistently implicated in the etiology of this social profile, particularly given its role in emotional and social behavior. This study examined amygdala volume and symmetry in WS individuals and in age and sex matched controls. Magnetic resonance imaging scans were obtained on a GE 1.5-T magnet with 1.5-mm contiguous slices and were used to measure whole gray matter, white matter and cerebrospinal fluid volumes, as well as amygdala volume (right and left). Results revealed significantly reduced intracranial volume in individuals with WS, compared with controls. There were no differences between groups in absolute amygdalae volume, although there was a relative increase in amygdalae volumes, when adjusted for total intracranial content. There were no inter-hemispheric differences in amygdalae volumes in both groups. These results suggest a relative increase in amygdala volume in WS compared with healthy controls that likely reflects abnormal neurodevelopmental processes of midline brain structures.

Depression in adolescence is frequently characterised by symptoms of irritability. Fluoxetine is the antidepressant with the most favourable benefit:risk ratio profile to treat adolescent depression, but the neural mechanisms underlying antidepressant drugs in the young brain are still poorly understood. Previous studies have characterised the neural effects of long-term fluoxetine treatment in depressed adolescents, but these are limited by concurrent mood changes and a lack of placebo control. There is also recent evidence suggesting that fluoxetine reduces the processing of anger in young healthy volunteers, which is consistent with its effect for the treatment of irritability in this age group, but this remains to be investigated in depressed adolescents. Here we assessed the effects of a single, first dose of 10 mg fluoxetine vs. placebo on neural response to anger cues using fMRI in a sample of adolescents with Major Depressive Disorder (MDD) who had been recently prescribed fluoxetine. As predicted, adolescents receiving fluoxetine showed reduced activity in response to angry facial expressions in the amygdala-hippocampal region relative to placebo. Activity in the dorsal anterior cingulate cortex (dACC) was also increased. No changes in symptoms were observed. These results demonstrate, for the first time in depressed adolescents, that fluoxetine has immediate neural effects on core components of the cortico-limbic circuitry prior to clinical changes in mood. The effect on anger is consistent with our previous work and could represent a key mechanism through which fluoxetine may act to alleviate irritability symptoms in adolescent depression.

Individuals with Williams syndrome display indiscriminate approach towards strangers. Neuroimaging studies conducted so far have linked this social profile to structural and/or functional abnormalities in WS amygdala and prefrontal cortex. In this study, the neuropsychological hypotheses of amygdala and prefrontal cortex involvement in WS hypersociability was explored using three behavioral tasks--facial emotional recognition task, a social approach task and a go no/go task. Thus, a group 15 individuals with Williams syndrome was compared to two groups of normal developing individuals--a group of 15 individuals matched for chronological age (CA) and 15 individuals matched for mental age (MA), and sex. Individuals with WS present a specific impairment in recognizing negative facial expressions and do not display impairments in response inhibition when compared with typically developing groups. Although these findings partially support the amygdala contribution to WS hypersociability, we found that general cognitive functioning predicted this performance. Additionally, individuals with WS did not differ from both CA and MA groups in the recognition of angry facial expressions, a finding suggesting that they are actually able to identify stimuli associated with social threat. Overall, the results seem to indicate that this social profile must be understood within a developmental framework.