Person:

Holmes, A

Background: Depression is a common source of human disability for which etiologic insights remain limited. Although abnormalities of monoamine neurotransmission, including dopamine, are theorized to contribute to the pathophysiology of depression, evidence linking dopamine-related genes to depression has been mixed. The current study sought to address this knowledge-gap by examining whether the combined effect of dopamine polymorphisms was associated with depressive symptomatology in both healthy individuals and individuals with depression. Methods: Data were drawn from three independent samples: (1) a discovery sample of healthy adult participants (n = 273); (2) a replication sample of adults with depression (n = 1,267); and (3) a replication sample of healthy adult participants (n = 382). A genetic risk score was created by combining functional polymorphisms from five genes involved in synaptic dopamine availability (COMT and DAT) and dopamine receptor binding (DRD1, DRD2, DRD3). Results: In the discovery sample, the genetic risk score was associated with depressive symptomatology (β = −0.80, p = 0.003), with lower dopamine genetic risk scores (indicating lower dopaminergic neurotransmission) predicting higher levels of depression. This result was replicated with a similar genetic risk score based on imputed genetic data from adults with depression (β = −0.51, p = 0.04). Results were of similar magnitude and in the expected direction in a cohort of healthy adult participants (β = −0.86, p = 0.15). Conclusions: Sequence variation in multiple genes regulating dopamine neurotransmission may influence depressive symptoms, in a manner that appears to be additive. Further studies are required to confirm the role of genetic variation in dopamine metabolism and depression.

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA’s first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.

The integrity of decision-making under emotionally evocative circumstances is critical to navigating complex environments, and dysfunctions in these processes may play an important role in the emergence and maintenance of various psychopathologies. The goal of the present study was to examine the spatial and temporal dynamics of neural responses to emotional stimuli and emotion-modulated response inhibition. High-density event-related brain potentials (ERPs) were measured as participants (N=25) performed an emotional Go/NoGo task that required button presses to words of a "target" emotional valence (i.e., positive, negative, neutral) and response inhibition to words of a different "distractor" valence. Using scalp ERP analyses in conjunction with source-localization techniques, we identified distinct neural responses associated with affective salience and affect- modulated response inhibition, respectively. Both earlier (similar to 300 ms) and later (similar to 700 ms) ERP components were enhanced with successful response inhibition to emotional distractors. Only ERPs to target stimuli differentiated affective from neutral cues. Moreover, Source localization analyses revealed right ventral lateral prefrontal cortex (VLPFC) activation in affective response inhibition regardless of emotional valence, whereas rostral anterior cingulate activation (rACC) was potentiated by emotional valence but was not modulated by response inhibition. This dissociation was supported by a significant Region x Trial Type x Emotion interaction, confirming that distinct regional dynamics characterize neural responses to affective valence and affective response-inhibition. The results are discussed in the context of an emerging affective neuroscience literature and implications for understanding psychiatric pathologies characterized by a detrimental susceptibility to emotional cues, with an emphasis on major depressive disorder.

Individuals with major depressive disorder (MDD) often exhibit impaired executive function, particularly in experimental tasks that involve response conflict and require adaptive behavioral adjustments. Prior research suggests that these deficits might be due to dysfunction within frontocingulate pathways implicated in response conflict monitoring and the recruitment of cognitive control. However, the temporal unfolding of conflict monitoring impairments in MDD remains poorly understood. To address this issue, we recorded 128-channel event-related potentials while 20 unmedicated participants with MDD and 20 demographically matched, healthy controls performed a Stroop task. Compared to healthy controls, MDD subjects showed larger Stroop interference effects and reduced N2 and N450 amplitudes. Source localization analyses at the time of maximal N450 activity revealed that MDD subjects had significantly reduced dorsal anterior cingulate cortex (dACC; Brodmann area 24/32) and left dorsolateral prefrontal cortex (Brodmann area 10/46) activation to incongruent relative to congruent trials. Consistent with the heterogeneous nature of depression, follow-up analyses revealed that depressed participants with the lowest level of conflict-related dACC activation 620 ms post-stimulus were characterized by the largest Stroop interference effects (relatively increased slowing and reduced accuracy for incongruent trials). Conversely, MDD participants with relatively stronger dACC recruitment did not differ from controls in terms of interference effects. These findings suggest that for some, but not all individuals, MDD is associated with impaired performance in trials involving competition among different response options, and reduced recruitment of frontocingulate pathways implicated in conflict monitoring and cognitive control.

Cognitive theories of depression posit that automatically activated cognitive schemas, including negative thoughts about the self and the future, predispose individuals to develop depressive disorders. However, prior research has largely examined these constructs using explicit tests in currently depressed individuals. Using the Implicit Association Test (IAT), the present study examined automatic associations between the self and mood state ("depression IAT") and between the future and mood state ("hopelessness IAT") before and after a negative mood induction in 19 remitted depressed individuals and 23 healthy controls. In the depression IAT, remitted depressed participants exhibited an overall lower tendency to associate themselves with happiness relative to the healthy controls before the mood induction. Control, but not remitted depressed, participants' automatic associations between the self and happiness diminished following the mood induction. Contrary to our hypotheses, no significant findings emerged when considering the hopelessness IAT. Consistent with prior studies, no significant correlations emerged between implicit and explicit biases, suggesting that these measures probe different processes. Results extend prior IAT research by documenting the presence of a reduced tendency to associate the self with happiness in a sample at increased risk for depression.

Incentive delay tasks implicate the striatum and medial frontal cortex in reward processing. However, prior studies delivered more rewards than penalties, possibly leading to unwanted differences in signal-to-noise ratio. Also, whether particular brain regions are specifically involved in anticipation or consumption is unclear. We used a task featuring balanced incentive delivery and an analytic strategy designed to identify activity specific to anticipation or consumption. Reaction time data in two independent samples (n = 13 and n = 8) confirmed motivated responding. Functional magnetic resonance imaging revealed regions activated by anticipation (anterior cingulate) versus consumption (orbital and medial frontal cortex). Ventral striatum was active during reward anticipation but not significantly more so than during consumption. Although the study features several methodological improvements and helps clarify the neural basis of incentive processing, replications in larger samples are needed.

CONTEXT: Depression is characterized by executive dysfunctions and abnormal reactions to errors; however, little is known about the brain mechanisms that underlie these deficits. OBJECTIVE: To examine whether abnormal reactions to errors in patients with major depressive disorder (MDD) are associated with exaggerated paralimbic activation and/or a failure to recruit subsequent cognitive control to account for mistakes in performance. DESIGN: Between February 15, 2005, and January 19, 2006, we recorded 128-channel event-related potentials while study participants performed a Stroop task, modified to incorporate performance feedback. SETTING: Patients with MDD and healthy comparison subjects were recruited from the general community. PARTICIPANTS: Study participants were 20 unmedicated patients with MDD and 20 demographically matched comparison subjects. MAIN OUTCOME MEASURES: The error-related negativity and error positivity were analyzed through scalp and source localization analyses. Functional connectivity analyses were conducted to investigate group differences in the spatiotemporal dynamics of brain mechanisms that underlie error processing. RESULTS: Relative to comparison subjects, patients with MDD displayed significantly lower accuracy after incorrect responses, larger error-related negativity, and higher current density in the rostral anterior cingulate cortex (ACC) and medial prefrontal cortex (PFC) (Brodmann area 10/32) 80 milliseconds after committing an error. Functional connectivity analyses revealed that for the comparison subjects, but not the patients with MDD, rostral ACC and medial PFC activation 80 milliseconds after committing an error predicted left dorsolateral PFC (Brodmann area 8/9) activation 472 milliseconds after committing an error. CONCLUSIONS: Unmedicated patients with MDD showed reduced accuracy and potentiated error-related negativity immediately after committing errors, highlighting dysfunctions in the automatic detection of unfavorable performance outcomes. New analytic procedures allowed us to show that abnormal reaction to committing errors was accompanied by hyperactivation in rostral ACC and medial PFC regions 80 milliseconds after committing errors and a failure to recruit dorsolateral PFC-based cognitive control. Future studies are warranted to investigate whether these dysfunctions might foster the emergence and maintenance of negative processing biases and thus increase vulnerability to depression.