Adult major depressive disorder (MDD) is associated with reduced cortico-limbic functional connectivity thought to indicate decreased top-down control of emotion. However, it is unclear whether such connectivity alterations are also present in early childhood onset MDD.
Fifty-one children ages 7–11 years, prospectively studied since preschool age, completed resting state fMRI and were assigned to four groups: 1) C-MDD (N=13) personal history of early childhood onset MDD; 2) M-MDD (N=11) a maternal history of affective disorders; 3) CM-MDD (N=13) both maternal and early childhood onset MDD or 4) CON (N=14) without either a personal or maternal history. We used seed-based resting state functional connectivity (rsfcMRI) analysis in an independent sample of adults to identify networks showing both positive (e.g., limbic regions) and negative (e.g., dorsal frontal/parietal regions) connectivity with the amygdala. These regions were then used in ROI based analyses of our child sample.
We found a significant interaction between maternal affective disorder history and the child's MDD history for both positive and negative rsfcMRI networks. Specifically, when copared to CON, we found reduced connectivity between the amygdala and the “Negative Network” in children with C-MDD, M-MDD and CM-MDD. Children with either C-MDD or a maternal history of MDD (but not CM-MDD) displayed reduced connectivity between the amygdala and the “Positive Network”.
Our finding of an attenuated relationship between the amygdala, a region affected in MDD and involved in emotion processing, and cognitive control regions is consistent with a hypothesis of altered regulation of emotional processing in C-MDD suggesting developmental continuity of this alteration into early childhood.
Functional Connectivity; Depression; Amygdala; fMRI; Childhood-Onset
Major depressive disorder (MDD) has been associated with abnormal prefrontal-limbic interactions and altered catecholaminergic neurotransmission. The val158met polymorphism on the catechol-O-methyltransferase (COMT) gene has been shown to influence prefrontal cortex (PFC) activation during both emotional processing and working memory (WM). Although COMT-genotype is not directly associated with MDD, it may affect MDD pathology by altering PFC activation, an endophenotype associated with both COMT and MDD. 125 participants, including healthy controls (HC, n=28) and MDD patients were genotyped for the COMT val158met polymorphism and underwent functional magnetic resonance imaging (fMRI-neuroimaging) during emotion processing (viewing of emotional facial expressions) and a WM task (visuospatial planning). Within HC, we observed a positive correlation between the number of met-alleles and right inferior frontal gyrus activation during emotional processing, whereas within patients the number of met-alleles was not correlated with PFC activation. During WM a negative correlation between the number of met-alleles and middle frontal gyrus activation was present in the total sample. In addition, during emotional processing there was an effect of genotype in a cluster including the amygdala and hippocampus. These results demonstrate that COMT genotype is associated with relevant endophenotypes for MDD. In addition, presence of MDD only interacts with genotype during emotional processing and not working memory.
The present study was designed to examine neural correlates of inhibitory dysfunction in individuals diagnosed with Major Depressive Disorder (MDD). Twelve MDD participants and 12 never-depressed controls completed the negative affective priming (NAP) task in the scanner. Results indicated that, in depressed participants, increased activation in the rostral anterior cingulate cortex (rACC) is associated with inhibition of negative, but not positive, words; in contrast, in nondepressed participants, inhibition of positive, but not negative, words is associated with increased activation in the rACC. These findings indicate that abnormalities in neural function, especially in the rACC, may underlie difficulties experienced by depressed individuals in inhibiting negative thoughts. These results underscore the importance of continuing to examine the relation between cognitive and neural functioning in depression in order to gain a broader and more integrative understanding of this disorder.
anterior cingulate cortex; inhibition; negative priming; functional magnetic resonance imaging
Major Depressive Disorder (MDD) is a mood disorder that is not traditionally considered to affect the visual system. However, recent findings have reported decreased cortical levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in occipital cortex. To explore possible functional consequences of MDD on visual processing, we applied a psychophysical visual motion processing task in which healthy young adults typically exhibit impaired perceptual discrimination of large high contrast stimuli. It has been suggested that this phenomenon, spatial suppression, is mediated by GABAergic center-surround antagonism in visual pathways. Based on previous findings linking MDD to occipital GABA dysfunction, we hypothesized that MDD patients would exhibit decreased spatial suppression, leading to the counterintuitive hypothesis of better psychophysical performance. Indeed, motion perception for typically suppressed stimuli was enhanced in patients with MDD compared to age-matched controls. Furthermore, the degree of spatial suppression correlated with an individual’s illness load; patients with greater lifetime duration of depression exhibited the least spatial suppression and performed the best in the high contrast motion discrimination task. Notably, this decrease in spatial suppression persisted beyond recovery and without the confound of acute illness or treatment; all patients had been clinically recovered and unmedicated for several months at the time of testing, suggesting that depression has ubiquitous consequences that may persist long after mood symptoms have receded. This finding raises the possibility that spatial suppression may represent a sensitive endophenotypic marker of trait vulnerability in MDD.
visual motion; center-surround; depression; GABA; suppression; perception deficit
Difficulties in emotion processing and poor social function are common to bipolar disorder (BD) and major depressive disorder (MDD) depression, resulting in many BD depressed individuals being misdiagnosed with MDD. The amygdala is a key region implicated in processing emotionally salient stimuli, including emotional facial expressions. It is unclear, however, whether abnormal amygdala activity during positive and negative emotion processing represents a persistent marker of BD regardless of illness phase or a state marker of depression common or specific to BD and MDD depression.
Sixty adults were recruited: 15 depressed with BD type 1 (BDd), 15 depressed with recurrent MDD, 15 with BD in remission (BDr), diagnosed with DSM-IV and Structured Clinical Interview for DSM-IV Research Version criteria; and 15 healthy control subjects (HC). Groups were age- and gender ratio-matched; patient groups were matched for age of illness onset and illness duration; depressed groups were matched for depression severity. The BDd were taking more psychotropic medication than other patient groups. All individuals participated in three separate 3T neuroimaging event-related experiments, where they viewed mild and intense emotional and neutral faces of fear, happiness, or sadness from a standardized series.
The BDd—relative to HC, BDr, and MDD—showed elevated left amygdala activity to mild and neutral facial expressions in the sad (p < .009) but not other emotion experiments that was not associated with medication. There were no other significant between-group differences in amygdala activity.
Abnormally elevated left amygdala activity to mild sad and neutral faces might be a depression-specific marker in BD but not MDD, suggesting different pathophysiologic processes for BD versus MDD depression.
Amygdala; bipolar disorder; emotional processing; fMRI; major depressive disorder; mood disorders
Major depressive disorder (MDD) is associated with difficulty disengaging attention from emotionally negative information. Few studies have investigated whether euthymic individuals with a history of depression (remitted MDD [rMDD]) show similar deficits, and little is known about concomitant neurophysiological features of such deficits. To fill these gaps, we investigated cognitive control over emotional stimuli in participants with rMDD and controls without history of depression or psychopathology.
We collected 128-channel event-related potentials (ERPs) while participants performed a cued emotional conflict task. During the task, a cue instructed the participant to respond to the actual or opposite valence of an upcoming happy or sad face.
We enrolled 15 individuals with rMDD and 18 controls in our study. Event-related potentials showed no group differences in response to the cues, highlighting preserved preparatory processes when anticipating an emotional conflict. However, relative to the control group, the rMDD group responded more slowly and showed reduced N450 amplitudes on trials that required disengaging from negative faces (pressing “happy” in response to a sad face).
The sample size was small, and the null finding in the cue-locked N2 analyses may be owing to low power.
Our results suggest a selective deficit in cognitive control over sad stimuli in individuals with rMDD. Additional studies will be required to pinpoint whether the current findings stem from impairments in response conflict, conflict monitoring and/or attentional disengagement in response to sad stimuli. Moreover, future studies are warranted to evaluate whether decreased cognitive control in response to negative information might increase the risk for future depressive episodes.
Anxiety is relatively common in depression and capable of modifying the severity and course of depression. Yet our understanding of how anxiety modulates frontal and limbic activation in depression is limited.
We used functional magnetic resonance imaging and two emotional information processing tasks to examine frontal and limbic activation in ten patients with major depression and comorbid with preceding generalized anxiety (MDD/GAD) and ten non-depressed controls.
Consistent with prior studies on depression, MDD/GAD patients showed hypoactivation in medial and middle frontal regions, as well as in the anterior cingulate, cingulate and insula. However, heightened anxiety in MDD/GAD patients was associated with increased activation in middle frontal regions and the insula and the effects varied with the type of emotional information presented.
Our findings highlight frontal and limbic hypoactivation in patients with depression and comorbid anxiety and indicate that anxiety level may modulate frontal and limbic activation depending upon the emotional context. One implication of this finding is that divergent findings reported in the imaging literature on depression could reflect modulation of activation by anxiety level in response to different types of emotional information.
One barrier to interpreting past studies of cognition and major depressive disorder (MDD) has been the failure in many studies to adequately dissociate the effects of MDD from the potential cognitive side effects of selective serotonin reuptake inhibitors (SSRIs) use. To better understand how remediation of depressive symptoms affects cognitive function in MDD, we evaluated three groups of subjects: medication-naïve patients with MDD, medicated patients with MDD receiving the SSRI paroxetine, and healthy control (HC) subjects. All were administered a category-learning task that allows for dissociation between learning from positive feedback (reward) vs. learning from negative feedback (punishment). Healthy subjects learned significantly better from positive feedback than medication-naïve and medicated MDD groups, whose learning accuracy did not differ significantly. In contrast, medicated patients with MDD learned significantly less from negative feedback than medication-naïve patients with MDD and healthy subjects, whose learning accuracy was comparable. A comparison of subject’s relative sensitivity to positive vs. negative feedback showed that both the medicated MDD and HC groups conform to Kahneman and Tversky’s (1979) Prospect Theory, which expects losses (negative feedback) to loom psychologically slightly larger than gains (positive feedback). However, medicated MDD and HC profiles are not similar, which indicates that the state of medicated MDD is not “normal” when compared to HC, but rather balanced with less learning from both positive and negative feedback. On the other hand, medication-naïve patients with MDD violate Prospect Theory by having significantly exaggerated learning from negative feedback. This suggests that SSRI antidepressants impair learning from negative feedback, while having negligible effect on learning from positive feedback. Overall, these findings shed light on the importance of dissociating the cognitive consequences of MDD from those of SSRI treatment, and from cognitive evaluation of MDD subjects in a medication-naïve state before the administration of antidepressants. Future research is needed to correlate the mood-elevating effects and the cognitive balance between reward- and punishment-based learning related to SSRIs.
major depressive disorder; selective serotonin reuptake inhibitor; basal ganglia; reward; punishment
Major depressive disorder (MDD) is characterized by affective symptoms and cognitive impairments, which have been associated with changes in limbic and prefrontal activity as well as with monoaminergic neurotransmission. A genome-wide association study implicated the polymorphism rs2522833 in the piccolo (PCLO) gene—involved in monoaminergic neurotransmission—as a risk factor for MDD. However, the role of the PCLO risk allele in emotion processing and executive function or its effect on their neural substrate has never been studied. We used functional magnetic resonance imaging (fMRI) to investigate PCLO risk allele carriers vs noncarriers during an emotional face processing task and a visuospatial planning task in 159 current MDD patients and healthy controls. In PCLO risk allele carriers, we found increased activity in the left amygdala during processing of angry and sad faces compared with noncarriers, independent of psychopathological status. During processing of fearful faces, the PCLO risk allele was associated with increased amygdala activation in MDD patients only. During the visuospatial planning task, we found no genotype effect on performance or on BOLD signal in our predefined areas as a function of increasing task load. The PCLO risk allele was found to be specifically associated with altered emotion processing, but not with executive dysfunction. Moreover, the PCLO risk allele appears to modulate amygdala function during fearful facial processing in MDD and may constitute a possible link between genotype and susceptibility for depression via altered processing of fearful stimuli. The current results may therefore aid in better understanding underlying neurobiological mechanisms in MDD.
emotion processing; executive function; genome-wide association; major depressive disorder; neuroimaging genetics; PCLO
Major depressive disorder (MDD) has been associated with both dysfunction of the central serotonergic system and abnormal responses to emotional stimuli. We used acute tryptophan depletion (ATD) to investigate the effect of temporarily reducing brain serotonin synthesis on neural and behavioural responses to emotional stimuli in remitted MDD subjects (rMDD) and healthy controls.
Twenty controls and 23 rMDD subjects who had been unmedicated and in remission for ≥3 months completed the study. Following tryptophan or sham depletion, participants performed an emotional-processing task during functional magnetic resonance imaging. In addition, resting-state regional blood-flow was measured using arterial spin labelling.
Neither group exhibited significant mood-change following ATD. However, tryptophan depletion differentially affected the groups in terms of hemodynamic responses to emotional words in a number of structures implicated in the pathophysiology of MDD, including medial thalamus and caudate. These interactions were driven by increased responses to emotional words in the controls, with little effect in the patients under the ATD condition. Following ATD, habenula blood-flow increased significantly in the rMDD subjects relative to the controls, and increasing amygdala blood-flow was associated with more negative emotional bias score across both groups.
These data provide evidence for elevated habenula blood-flow and alterations in the neural processing of emotional stimuli following ATD in rMDD subjects, even in the absence of overt mood-change. However, further studies are required to determine whether these findings represent mechanisms of resilience or vulnerability to MDD.
Depression; Serotonin; Acute Tryptophan Depletion; Functional Magnetic Resonance Imaging (fMRI); Emotional Processing; Affective Go/No-go (AGNG)
Anhedonia, the loss of interest or pleasure in normally rewarding activities, is a hallmark feature of unipolar Major Depressive Disorder (MDD). A growing body of literature has identified frontostriatal dysfunction during reward anticipation and outcomes in MDD. However, no study to date has directly compared responses to different types of rewards such as pleasant images and monetary rewards in MDD. To investigate the neural responses to monetary and pleasant image rewards in MDD, a modified Monetary Incentive Delay task was used during fMRI scanning to assess neural responses during anticipation and receipt of monetary and pleasant image rewards. Participants included nine adults with MDD and thirteen affectively healthy controls. The MDD group showed lower activation than controls when anticipating monetary rewards in right orbitofrontal cortex and subcallosal cortex, and when anticipating pleasant image rewards in paracingulate and supplementary motor cortex. The MDD group had relatively greater activation in right putamen when anticipating monetary versus pleasant image rewards, relative to the control group. Results suggest reduced reward network activation in MDD when anticipating rewards, as well as relatively greater hypoactivation to pleasant image than monetary rewards.
Major Depressive Disorder; Reward; Anhedonia; Anticipation; Magnetic Resonance Imaging
Obsessive-compulsive disorder (OCD) and major depressive disorder (MDD) are frequently co-morbid, and dysfunctional frontal-striatal circuits have been implicated in both disorders. Neurobiological distinctions between OCD and MDD are insufficiently clear, and comparative neuroimaging studies are extremely scarce. OCD and MDD may be characterized by cognitive rigidity at the phenotype level, and frontal-striatal brain circuits constitute the neural substrate of intact cognitive flexibility. In the present study, 18 non-medicated MDD-free patients with OCD, 19 non-medicated OCD-free patients with MDD, and 29 matched healthy controls underwent functional magnetic resonance imaging during performance of a self-paced letter/digit task switching paradigm. Results showed that both patient groups responded slower relative to controls during repeat events, but only in OCD patients slowing was associated with decreased error rates. During switching, patients with OCD showed increased activation of the putamen, anterior cingulate and insula, whereas MDD patients recruited inferior parietal cortex and precuneus to a lesser extent. Patients with OCD and MDD commonly failed to reveal anterior prefrontal cortex activation during switching. This study shows subtle behavioral abnormalities on a measure of cognitive flexibility in MDD and OCD, associated with differential frontal-striatal brain dysfunction in both disorders. These findings may add to the development of biological markers that more precisely characterize frequently co-morbid neuropsychiatric disorders such as OCD and MDD.
Patients with major depressive disorder (MDD) clinically exhibit a deficit in positive emotional processing and are often distracted by especially negative emotional stimuli. Such emotional-cognitive interference in turn hampers the cognitive abilities of patients in their ongoing task. While the psychological correlates of such emotional conflict have been well identified in healthy subjects, possible alterations of emotional conflict in depressed patients remain to be investigated. We conducted an exploratory psychological study to investigate emotional conflict in MDD. We also distinguished depression-related stimuli from negative stimuli in order to check whether the depression-related distractors will induce enhanced conflict in MDD.
A typical word-face Stroop paradigm was adopted. In order to account for valence-specificities in MDD, we included positive and general negative as well as depression-related words in the study.
MDD patients demonstrated a specific pattern of emotional conflict clearly distinguishable from the healthy control group. In MDD, the positive distractor words did not significantly interrupt the processing of the negative target faces, while they did in healthy subjects. On the other hand, the depression-related distractor words induced significant emotional conflict to the positive target faces in MDD patients but not in the healthy control group.
Our findings demonstrated for the first time an altered valence-specific pattern in emotional conflict in MDD patients. The study sheds a novel and specific light on the affective mechanisms underlying the abnormal emotional-cognitive interference in MDD. Such emotional conflict bears important clinical relevance since it may trigger the widespread cognitive dysfunctions frequently observed in MDD. The present findings may have important clinical implications in both prediction and psychotherapy of MDD.
Questions have been raised about whether poor performance on memory tasks by individuals with major depressive disorder (MDD) might be the result of poor or variable effort or disease-related disruption of neural circuits supporting memory functions. The present study examined performance on a measure of task engagement and on an auditory memory task among 45 patients with MDD (M age = 47.82, SD = 19.55) relative to 32 healthy controls (HC; M age = 51.03, SD = 22.09). One-hundred percent of HC and MDD volunteers performed above the threshold for adequate effort on a formal measure of task engagement. The MDD subjects performed significantly more poorly than the HC subjects on an auditory learning and memory test. The present results suggest that auditory memory difficulties do occur among those with MDD and that decrements in performance in this group may be related to factors other than lack of effort.
Depression; Malingering/symptom validity testing; Learning and memory
Previous work indicates that emotive processing, such as of facial expressions, may be altered in major depressive disorder (MDD). Individuals with MDD tend to exhibit a mood-congruent processing bias, though MDD may also be characterized by blunted emotive processing in general. Females tend to exhibit enhanced facial emotive processing than males. Few groups have examined temporal electrophysiological event-related potential (ERP)-indexed profiles, spanning preconscious to sustained, conscious processing of facial expressions in MDD; systematic comparisons of ERPs to emotive stimuli between depressed males and females are also lacking.
This study examined the temporal ERP profile to a simple expression recognition task in adult depressed males and females (N=52; 29 females) and controls (N=43; 23 females).
The MDD group rated facial expressions as sadder overall than controls. Females exhibited enhanced and speeded pre- and conscious face processing than males. Subtle group differences emerged to specific expressions at mid-latency ERPs (N2, P2) indicating both blunted late pre-conscious perceptual processing of expressions and prolonged processing of intensely sad faces.
A more involved emotive processing task, employing threatening faces, may have revealed more robust group ERP differences. Menstrual cycle should be controlled for in future work.
This is the first study to systematically assess the temporal ERP profile, including of ERPs preceding the face-sensitive N170/VPP, to expressions in MDD. Overall, early perceptual and late conscious expression processing did not differ fundamentally between groups. Altered emotive processing may be a candidate index for monitoring and predicting antidepressant treatment outcome.
Depression; event-related potentials (ERP); emotion; faces; sex
In patients with major depressive disorder (MDD), enhanced activation of the rostral anterior cingulate cortex (rACC) during conflict resolution has been demonstrated with the use of functional magnetic resonance imaging (fMRI), which suggests dysregulation of the affective compartment of the ACC associated with error monitoring and cognitive control. Moreover, several previous studies have reported disrupted structural integrity in limbic brain areas and the orbitofrontal cortex in MDD. However, the relation between structural and functional alterations remains unclear. Therefore, the present study sought to investigate whether structural brain aberrations in terms of grey matter decreases directly in the medial frontal regions or in anatomically closely connected areas might be related to our previously reported functional alterations.
A sample of 16 female, drug-free patients with an acute episode of MDD and 16 healthy control subjects matched for age, sex and education were examined with structural high-resolution T1-weighted MRI; fMRI images were obtained in the same session.
Voxel-based morphometry (VBM) revealed grey matter decreases in the orbitofrontal and subgenual cortex, in the hippocampus-amygdala complex and in the middle frontal gyrus. The relative hyperactivation of the rACC in terms of inability to deactivate this region during the Stroop Color-Word Test showed an inverse correlation with grey matter reduction in the orbitofrontal cortex.
The present study provides strong evidence for an association between structural alterations in the orbitofrontal cortex and disturbed functional activation in the emotional compartment of the ACC in patients with MDD during cognitive control.
magnetic resonance imaging; depressive disorder; depression
Major depressive disorder (MDD) is associated with a high rate of developing serious medical comorbidities such as cardiovascular disease, stroke, dementia, osteoporosis, diabetes, and the metabolic syndrome. These are conditions that typically occur late in life, and it has been suggested that MDD may be associated with “accelerated aging.” We review several moderators and mediators that may accompany MDD and that may give rise to these comorbid medical conditions. We first review the moderating effects of psychological styles of coping, genetic predisposition, and epigenetic modifications (eg, secondary to childhood adversity). We then focus on several interlinked mediators occurring in MDD (or at least in subtypes of MDD) that may contribute to the medical comorbidity burden and to accelerated aging: limbic-hypothalamic-pituitary-adrenal axis alterations, diminution in glucocorticoid receptor function, altered glucose tolerance and insulin sensitivity, excitotoxicity, increases in intracellular calcium, oxidative stress, a proinflammatory milieu, lowered levels of “counter-regulatory” neurosteroids (such as allopregnanolone and dehydroepiandrosterone), diminished neurotrophic activity, and accelerated cell aging, manifest as alterations in telomerase activity and as shortening of telomeres, which can lead to apoptosis and cell death. In this model, MDD is characterized by a surfeit of potentially destructive mediators and an insufficiency of protective or restorative ones. These factors interact in increasing the likelihood of physical disease and of accelerated aging at the cellular level. We conclude with suggestions for novel mechanism-based therapeutics based on these mediators.
depression; cortisol; oxidative stress; inflammation; telomere; child-hood adversity
Dysfunction of serotonergic neurotransmission has been implicated in the etiopathogenesis of major depression (MDD) and alcohol use disorders (AUD). To compare serotonin function in MDD with co-occurring AUD (MDD/AUD), MDD without co-occurring AUD (MDD only) and healthy controls (HC) we sought to study differences in prolactin responses to fenfluramine administration in patients with MDD/AUD, patients with MDD only and HC. In all, 169 subjects (62 MDD/AUD, 75 MDD only, and 32 HC) were entered into the study. Controlling for gender, prolactin responses were lower in the MDD/AUD group compared to the MDD only or the HC group. Controlling for gender and aggression, prolactin responses in the MDD/AUD group remained significantly lower compared to the HC group but the difference between the MDD/AUD and the MDD only groups disappeared. The difference in prolactin responses between MDD/AUD and MDD only could be attributed to higher aggression scores in the MDD/AUD group compared to the MDD group.
Serotonin; Prolactin; Fenfluramine; Depression; Alcohol; Aggression
Pain and depression often occur together. Pain is both a sensation and an affective experience. Similarly, depression is associated frequently with somatic symptoms as well as emotional dysphoria. Existing evidence indicates that major depressive disorder (MDD) may be associated with altered pain processing. However, the extent to which alterations in experimentally controlled heat pain sensations are related to increased affective bias in MDD is unknown. This psychophysical study examined the hypothesis that young adults with MDD would show increased affective bias to painful and non-painful experimental heat stimuli, as evidenced by an increased responsiveness to warm and hot temperatures.
Graded non-noxious and noxious heat stimuli were delivered randomly with a thermode applied to the volar surface of the left arm of 15 unmedicated subjects with current MDD and 15 age- and gender-matched healthy comparison subjects. MDD and non-MDD subjects rated the intensity and unpleasantness of all stimuli.
Two main results were observed. Firstly, MDD relative to non-MDD subjects showed decreased heat pain thresholds. Secondly, a significantly increased affective bias (= unpleasantness/intensity) was observed in MDD subjects, particularly over the range of non-noxious heat stimuli. This bias was independent of the change in sensory pain thresholds.
These findings represent corroborative evidence of abnormal affective heat pain processing in young adults with MDD, and suggest that MDD is associated with “emotional allodynia”, a qualitatively altered negative emotional response to normally non-aversive thermal stimuli.
psychophysics; allodynia; MDD; thermode; heat; nociception
Although circulating hormones and inhibitory gamma-aminobutyric acid (GABA)-related factors are known to affect mood, considerable knowledge gaps persist for biological mechanisms underlying the female bias in mood disorders. Here, we combine human and mouse studies to investigate sexual dimorphism in the GABA system in the context of major depressive disorder (MDD) and then use a genetic model to dissect the role of sex-related factors in GABA-related gene expression and anxiety-/depressive-like behaviors in mice. First, using meta-analysis of gene array data in human postmortem brain (N = 51 MDD subjects, 50 controls), we show that the previously reported down-regulation in MDD of somatostatin (SST), a marker of a GABA neuron subtype, is significantly greater in women with MDD. Second, using gene co-expression network analysis in control human subjects (N = 214; two frontal cortex regions) and expression quantitative trait loci mapping (N = 170 subjects), we show that expression of SST and the GABA-synthesizing enzymes glutamate decarboxylase 67 (GAD67) and GAD65 are tightly co-regulated and influenced by X-chromosome genetic polymorphisms. Third, using a rodent genetic model [Four Core Genotypes (FCG) mice], in which genetic and gonadal sex are artificially dissociated (N ≥ 12/group), we show that genetic sex (i.e., X/Y-chromosome) influences both gene expression (lower Sst, Gad67, Gad65 in XY mice) and anxiety-like behaviors (higher in XY mice). This suggests that in an intact male animal, the observed behavior represents the outcomes of male genetic sex increasing and male-like testosterone decreasing anxiety-like behaviors. Gonadal sex was the only factor influencing depressive-like behavior (gonadal males < gonadal females). Collectively, these combined human and mouse studies provide mechanistic insight into sexual dimorphism in mood disorders, and specifically demonstrate an unexpected role of male-like factors (XY genetic sex) on GABA-related genes and anxiety-like behaviors.
GABA; genetic sex; mood; somatostatin; anxiety; depression
Cognitive biases play an important role in the onset and maintenance of Social Anxiety Disorder (SAD). Few studies, however, have examined the role of comorbid Major Depressive Disorder (MDD) in the processing of emotional material. In addition, little is known about the relation among different cognitive biases. In the current study, 73 participants (54.79% female) completed an emotion face dot-probe task followed by a recognition memory test. Compared to participants with SAD, participants with comorbid SAD and MDD oriented away from supraliminally presented angry faces. Subsequently, SAD participants with and without comorbidity recognized fewer angry faces than non-disordered controls. Furthermore, attention biases for subliminally presented stimuli predicted recognition accuracy only for comorbid participants. These results suggest that the presence of comorbid MDD affects attentional orienting in SAD participants. In addition, it highlights the interconnectedness of attention and memory biases for comorbid participants.
Unipolar major depressive disorder (MDD) is characterized by impaired cognitive control in affective contexts, but the potential for psychotherapy to affect the neural correlates of these functions has not been evaluated.
Twelve adults with and 15 adults without MDD participated in two identical functional magnetic resonance imaging (fMRI) scans that utilized a task requiring cognitive control in both sad and neutral contexts. Between scans, MDD outpatients received Behavioral Activation Therapy for Depression, a psychotherapy modality designed to increase engagement with positive stimuli and reduce avoidance behaviors.
Seventy-five percent of adults with MDD were treatment responders, achieving post-treatment Hamilton Rating Scale for Depression score of six or below. Consistent with predictions, psychotherapy resulted in decreased activation in response to cognitive control stimuli presented within a sad context in prefrontal structures, including the paracingulate gyrus, the right orbital frontal cortex, and the right frontal pole. Furthermore, the magnitude of pretreatment activation in the paracingulate gyrus cluster responsive to psychotherapy predicted the magnitude of depressive symptom change after psychotherapy.
Replication with larger samples is needed, as are follow-up studies that involve placebo control groups, wait-list control groups, and alternative forms of antidepressant intervention.
Behavioral Activation Therapy for Depression improves depressive symptoms and concomitantly influences brain systems mediating cognitive control in affective contexts.
Unipolar Depression; Target Detection; Cognitive Control; Functional Magnetic Resonance Imaging; Psychotherapy; Prefrontal Cortex; Paracingulate Gyrus
Anhedonia, a core symptom of major depressive disorder (MDD) and highly variable among adolescents with MDD, may involve alterations in the major inhibitory amino acid neurotransmitter system of γ-aminobutyric acid (GABA).
To test whether anterior cingulate cortex (ACC) GABA levels, measured by proton magnetic resonance spectroscopy, are decreased in adolescents with MDD. The associations of GABA alterations with the presence and severity of anhedonia were explored.
Case-control, cross-sectional study using single-voxel proton magnetic resonance spectroscopy at 3 T.
Two clinical research divisions at 2 teaching hospitals.
Twenty psychotropic medication-free adolescents with MDD (10 anhedonic, 12 female, aged 12–19 years) with episode duration of 8 weeks or more and 21 control subjects group matched for sex and age.
Main Outcome Measures
Anterior cingulate cortex GABA levels expressed as ratios relative to unsuppressed voxel tissue water (w) and anhedonia scores expressed as a continuous variable.
Compared with control subjects, adolescents with MDD had significantly decreased ACC GABA/w (t= 3.2; P<.003). When subjects with MDD were categorized based on the presence of anhedonia, only anhedonic patients had decreased GABA/w levels compared with control subjects (t=4.08; P<.001; PTukey<.001). Anterior cingulate cortex GABA/w levels were negatively correlated with anhedonia scores for the whole MDD group (r = −0.50; P = .02), as well as for the entire participant sample including the control subjects (r=−0.54; P<.001). Anterior cingulate cortex white matter was also significantly decreased in adolescents with MDD compared with controls (P=.04).
These findings suggest that GABA, the major inhibitory neurotransmitter in the brain, may be implicated in adolescent MDD and, more specifically, in those with anhedonia. In addition, use of a continuous rather than categorical scale of anhedonia, as in the present study, may permit greater specificity in evaluating this important clinical feature.
Depression is characterised partly by blunted reactions to reward. However, tasks probing this deficiency have not distinguished insensitivity to reward from insensitivity to the prediction errors for reward that determine learning and are putatively reported by the phasic activity of dopamine neurons. We attempted to disentangle these factors with respect to anhedonia in the context of stress, Major Depressive Disorder (MDD), Bipolar Disorder (BPD) and a dopaminergic challenge.
Six behavioural datasets involving 392 experimental sessions were subjected to a model-based, Bayesian meta-analysis. Participants across all six studies performed a probabilistic reward task that used an asymmetric reinforcement schedule to assess reward learning. Healthy controls were tested under baseline conditions, stress or after receiving the dopamine D2 agonist pramipexole. In addition, participants with current or past MDD or BPD were evaluated. Reinforcement learning models isolated the contributions of variation in reward sensitivity and learning rate.
MDD and anhedonia reduced reward sensitivity more than they affected the learning rate, while a low dose of the dopamine D2 agonist pramipexole showed the opposite pattern. Stress led to a pattern consistent with a mixed effect on reward sensitivity and learning rate.
Reward-related learning reflected at least two partially separable contributions. The first related to phasic prediction error signalling, and was preferentially modulated by a low dose of the dopamine agonist pramipexole. The second related directly to reward sensitivity, and was preferentially reduced in MDD and anhedonia. Stress altered both components. Collectively, these findings highlight the contribution of model-based reinforcement learning meta-analysis for dissecting anhedonic behavior.
Anhedonia; Major depressive disorder; Depression; Reinforcement learning; Reward learning; Prediction error; Computational; Meta-analysis; Reward sensitivity; Learning rate
Hypersomnolence in major depressive disorder (MDD) plays an important role in the natural history of the disorder, but the basis of hypersomnia in MDD is poorly understood. Slow wave activity (SWA) has been associated with sleep homeostasis, as well as sleep restoration and maintenance, and may be altered in MDD. Therefore, we conducted a post-hoc study that utilized high density electroencephalography (hdEEG) to test the hypothesis that MDD subjects with hypersomnia (HYS+) would have decreased SWA relative to age and sex-matched MDD subjects without hypersomnia (HYS−) and healthy controls (n=7 for each group). After correcting for multiple comparisons using statistical non-parametric mapping, HYS+ subjects demonstrated significantly reduced parieto-occipital all-night SWA relative to HYS− subjects. Our results suggest hypersomnolence may be associated with topographic reductions in SWA in MDD. Further research using adequately powered prospective design is indicated to confirm these findings.
sleep; depression; spectral analysis