Subcortical shape alterations in major depressive disorder: Findings from the ENIGMA major depressive disorder working group.

Alterations in regional subcortical brain volumes have been investigated as part of the efforts of an international consortium, ENIGMA, to identify reliable neural correlates of major depressive disorder (MDD). Given that subcortical structures are comprised of distinct subfields, we sought to build significantly from prior work by precisely mapping localized MDD-related differences in subcortical regions using shape analysis. In this meta-analysis of subcortical shape from the ENIGMA-MDD working group, we compared 1,781 patients with MDD and 2,953 healthy controls (CTL) on individual measures of shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Harmonized data processing and statistical analyses were conducted locally at each site, and findings were aggregated by meta-analysis. Relative to CTL, patients with adolescent-onset MDD (≤ 21 years) had lower thickness and surface area of the subiculum, cornu ammonis (CA) 1 of the hippocampus and basolateral amygdala (Cohen's d = -0.164 to -0.180). Relative to first-episode MDD, recurrent MDD patients had lower thickness and surface area in the CA1 of the hippocampus and the basolateral amygdala (Cohen's d = -0.173 to -0.184). Our results suggest that previously reported MDD-associated volumetric differences may be localized to specific subfields of these structures that have been shown to be sensitive to the effects of stress, with important implications for mapping treatments to patients based on specific neural targets and key clinical features.

Effects of salience-network-node neurofeedback training on affective biases in major depressive disorder.

Neural models of major depressive disorder (MDD) posit that over-response of components of the brain's salience network (SN) to negative stimuli plays a crucial role in the pathophysiology of MDD. In the present proof-of-concept study, we tested this formulation directly by examining the affective consequences of training depressed persons to down-regulate response of SN nodes to negative material. Ten participants in the real neurofeedback group saw, and attempted to learn to down-regulate, activity from an empirically identified node of the SN. Ten other participants engaged in an equivalent procedure with the exception that they saw SN-node neurofeedback indices from participants in the real neurofeedback group. Before and after scanning, all participants completed tasks assessing emotional responses to negative scenes and to negative and positive self-descriptive adjectives. Compared to participants in the sham-neurofeedback group, from pre- to post-training, participants in the real-neurofeedback group showed a greater decrease in SN-node response to negative stimuli, a greater decrease in self-reported emotional response to negative scenes, and a greater decrease in self-reported emotional response to negative self-descriptive adjectives. Our findings provide support for a neural formulation in which the SN plays a primary role in contributing to negative cognitive biases in MDD.

Meta-analysis of Functional Neuroimaging of Major Depressive Disorder in Youth.

IMPORTANCE: Despite its high prevalence and morbidity, the underlying neural basis of major depressive disorder (MDD) in youth is not well understood. OBJECTIVES: To identify in youth diagnosed as having MDD the most reliable neural abnormalities reported in existing functional neuroimaging studies and characterize their relations with specific psychological dysfunctions. DATA SOURCES: Searches were conducted in PubMed and Web of Science to identify relevant studies published from November 2006 through February 2015. The current analysis took place from August 21, 2014, to March 28, 2015. STUDY SELECTION: We retained articles that conducted a comparison of youth aged 4 to 24 years diagnosed as having MDD and age-matched healthy controls using task-based functional magnetic resonance imaging and a voxelwise whole-brain approach. DATA EXTRACTION AND SYNTHESIS: We extracted coordinates of brain regions exhibiting differential activity in youth with MDD compared with healthy control participants. Multilevel kernel density analysis was used to examine voxelwise between-group differences throughout the whole brain. Correction for multiple comparisons was performed by computing null hypothesis distributions from 10 000 Monte Carlo simulations and calculating the cluster size necessary to obtain the familywise error rate control at P < .05. MAIN OUTCOMES AND MEASURES: Abnormal levels of activation in youth diagnosed as having MDD compared with control participants during a variety of affective processing and executive functioning tasks. RESULTS: Compared with age-matched healthy control participants (n = 274), youth with MDD (n = 246) showed reliable patterns of abnormal activation, including the following task-general and task-specific effects: hyperactivation in subgenual anterior cingulate cortex (P < .05) and ventrolateral prefrontal cortex (P < .05) and hypoactivation in caudate (P < .01) across aggregated tasks; hyperactivation in thalamus (P < .03) and parahippocampal gyrus (P < .003) during affective processing tasks; hypoactivation in cuneus (P < .001), dorsal cingulate cortex (P < .05), and dorsal anterior insula (P < .05) during executive functioning tasks; hypoactivity in posterior insula (P < .005) during positive valence tasks; and hyperactivity in dorsolateral prefrontal cortex (P < .001) and superior temporal cortex (P < .003) during negative valence tasks. CONCLUSIONS AND RELEVANCE: Altered activations in several distributed brain networks may help explain the following seemingly disparate symptoms of MDD in youth: hypervigilance toward emotional stimuli from the overactivation of central hubs in the subgenual anterior cingulate cortex and thalamus that lead to a cascade of other symptoms; ineffective emotion regulation despite increased activation of the dorsolateral prefrontal cortex and ventrolateral prefrontal cortex during affective processing, which may reverse across development or the clinical course; maladaptive rumination and poor executive control from difficulties shifting from default mode network activity to task-positive network activity during cognitively demanding tasks; and anhedonia from hypoactivation of the cuneus and posterior insula during reward processing.

Reward processing in adolescents with bipolar I disorder.

OBJECTIVE: Bipolar disorder (BD) is a debilitating psychiatric condition that commonly begins in adolescence, a developmental period that has been associated with increased reward seeking. Because youth with BD are especially vulnerable to negative risk-taking behaviors, understanding the neural mechanisms by which dysregulated affect interacts with the neurobehavioral processing of reward is clearly important. One way to clarify how manic symptoms evolve in BD is to "prime" the affect before presenting rewarding stimuli. The objective of this study was to investigate the neural effects of an affective priming task designed to positively induce mood before reward processing in adolescents with and without BD. METHOD: Neural activity and behaviors during the anticipation of and response to monetary reward and loss after an affective prime were compared using functional magnetic resonance imaging in 13- to 18-year-old adolescents with a recent onset of BD-I (n = 24) and demographically matched healthy comparison youth (n = 24). RESULTS: Compared with the healthy control youth, youth with BD had speeded reaction times and showed decreased activation in the thalamus and inferior temporal gyrus while anticipating gains after priming but increased activations in the middle frontal gyrus and parietal cortices while anticipating losses after priming. Youth with BD also showed less activation in the inferior parietal lobule, thalamus, and superior frontal gyrus while receiving losses after priming. CONCLUSIONS: Aberrant prefrontal and subcortical activations during reward processing suggest mechanisms that may underlie disordered self-awareness during goal pursuit and motivation in BD. Longitudinal studies are needed to examine whether this pattern of neural activation predicts a poorer long-term outcome.

Anomalous functional brain activation following negative mood induction in children with pre-school onset major depression.

While major depressive disorder has been shown to be a significant mental health issue for school-age children, recent research indicates that depression can be observed in children as early as the preschool period. Yet, little work has been done to explore the neurobiological factors associated with this early form of depression. Given research suggesting a relation between adult depression and anomalies in emotion-related neural circuitry, the goal of the current study was to elucidate changes in functional activation during negative mood induction and emotion regulation in school-age children with a history of preschool-onset depression. The results suggest that a history of depression during the preschool period is associated with decreased activity in prefrontal cortex during mood induction and regulation. Moreover, the severity of current depressed mood was associated with increased activity in limbic regions, such as the amygdala, particularly in children with a history of depression. Similar to results observed in adult depression, the current findings indicate disruptions in emotion-related neural circuitry associated with preschool-onset depression.

Modulation of subgenual anterior cingulate cortex activity with real-time neurofeedback.

The advent of real-time neurofeedback techniques has allowed us to begin to map the controllability of sensory and cognitive and, more recently, affective centers in the brain. The subgenual anterior cingulate cortex (sACC) is thought to be involved in generation of affective states and has been implicated in psychopathology. In this study, we examined whether individuals could use real-time fMRI neurofeedback to modulate sACC activity. Following a localizer task used to identify an sACC region of interest, an experimental group of eight women participated in four scans: (1) a pretraining scan in which they were asked to decrease activity in the sACC without neurofeedback; (2) two training scans in which sACC neurofeedback was presented along with instructions to decrease sACC activity; and (3) a neurofeedback-free post-training scan. An additional nine women in a yoked feedback control group saw sACC activity from the participants in the experimental group. Activity in the sACC was significantly reduced during neurofeedback training in the experimental group, but not in the control group. This training effect in the experimental group, however, did not generalize to the neurofeedback-free post-training scan. A psychophysiological interaction analysis showed decreased correlation in the experimental group relative to the sham control group between activity in the sACC and the posterior cingulate cortex during neurofeedback training relative to neurofeedback-free scans. The finding that individuals can down-modulate the sACC shows that a primary emotion center in which functional abnormality has been strongly implicated in affective disorders can be controlled with the aid of neurofeedback.

Reduced caudate gray matter volume in women with major depressive disorder.

Previous brain-imaging studies have reported that major depressive disorder (MDD) is characterized by decreased volumes of several cortical and subcortical structures, including the hippocampus, amygdala, anterior cingulate cortex, and caudate nucleus. The purpose of the present study was to identify structural volumetric differences between MDD and healthy participants using a method that allows a comparison of gray and white matter volume across the whole brain. In addition, we explored the relation between symptom severity and brain regions with decreased volumes in MDD participants. The study group comprised 22 women diagnosed with MDD and 25 healthy women with no history of major psychiatric disorders. Magnetic resonance brain images were analyzed using optimized voxel-based morphometry to examine group differences in regional gray and white matter volume. Compared with healthy controls, MDD participants were found to have decreased gray matter volume in the bilateral caudate nucleus and the thalamus. No group differences were found for white matter volume, nor were there significant correlations between gray matter volumes and symptom severity within the MDD group. The present results suggest that smaller volume of the caudate nucleus may be related to the pathophysiology of MDD and may account for abnormalities of the cortico-striatal-pallido-thalamic loop in MDD.