Depressed individuals typically show poor memory for positive events, potentiated memory for negative events, and impaired recollection. These phenomena are clinically important but poorly ...understood. Compelling links between stress and depression suggest promising candidate mechanisms. Stress can suppress hippocampal neurogenesis, inhibit dopamine neurons, and sensitize the amygdala. We argue that these phenomena may impair pattern separation, disrupt the encoding of positive experiences, and bias retrieval toward negative events, respectively, thus recapitulating core aspects of memory disruption in depression. Encouragingly, optogenetic reactivation of cells engaged during the encoding of positive memories rapidly reduces depressive behavior in preclinical models. Thus, many memory deficits in depression appear to be downstream consequences of chronic stress, and addressing memory disruption can have therapeutic value.
Unipolar depression is associated with impaired recollection, poor memory for positive events, and enhanced memory for negative events, but the relevant neural mechanisms are poorly understood.
Stress is a common trigger of initial depressive episodes, and chronic stress can suppress hippocampal neurogenesis, inhibit mesolimbic dopamine neurons, and sensitize the amygdala’s response to negative information. Animal studies indicate that these three effects of stress can disrupt pattern separation, impair memory consolidation, and promote overgeneralized fear responses, respectively.
We review data indicating that these mechanisms may also explain poor pattern separation, disrupted memory for positive material, and enhanced memory for negative material in depressed adults.
Thus, we propose that memory disruptions in depression are downstream consequences of chronic stress.
Major depressive disorder (MDD) is characterized by abnormal resting-state functional connectivity (RSFC), especially in medial prefrontal cortical (MPFC) regions of the default network. However, ...prior research in MDD has not examined dynamic changes in functional connectivity as networks form, interact, and dissolve over time. We compared unmedicated individuals with MDD (n=100) to control participants (n=109) on dynamic RSFC (operationalized as SD in RSFC over a series of sliding windows) of an MPFC seed region during a resting-state functional magnetic resonance imaging scan. Among participants with MDD, we also investigated the relationship between symptom severity and RSFC. Secondary analyses probed the association between dynamic RSFC and rumination. Results showed that individuals with MDD were characterized by decreased dynamic (less variable) RSFC between MPFC and regions of parahippocampal gyrus within the default network, a pattern related to sustained positive connectivity between these regions across sliding windows. In contrast, the MDD group exhibited increased dynamic (more variable) RSFC between MPFC and regions of insula, and higher severity of depression was related to increased dynamic RSFC between MPFC and dorsolateral prefrontal cortex. These patterns of highly variable RSFC were related to greater frequency of strong positive and negative correlations in activity across sliding windows. Secondary analyses indicated that increased dynamic RSFC between MPFC and insula was related to higher levels of recent rumination. These findings provide initial evidence that depression, and ruminative thinking in depression, are related to abnormal patterns of fluctuating communication among brain systems involved in regulating attention and self-referential thinking.
Anhedonia (hyposensitivity to rewards) and negative bias (hypersensitivity to punishments) are core features of major depressive disorder (MDD), which could stem from abnormal reinforcement learning. ...Emerging evidence highlights blunted reward learning and reward prediction error (RPE) signaling in the striatum in MDD, although inconsistencies exist. Preclinical studies have clarified that ventral tegmental area (VTA) neurons encode RPE and habenular neurons encode punishment prediction error (PPE), which are then transmitted to the striatum and cortex to guide goal-directed behavior. However, few studies have probed striatal activation, and functional connectivity between VTA-striatum and VTA-habenula during reward and punishment learning respectively, in unmedicated MDD. To fill this gap, we acquired fMRI data from 25 unmedicated MDD and 26 healthy individuals during a monetary instrumental learning task and utilized a computational modeling approach to characterize underlying neural correlates of RPE and PPE. Relative to controls, MDD individuals showed impaired reward learning, blunted RPE signal in the striatum and overall reduced VTA-striatal connectivity to feedback. Critically, striatal RPE signal was increasingly blunted with more major depressive episodes (MDEs). No group differences emerged in PPE signals in the habenula and VTA or in connectivity between these regions. However, PPE signals in the habenula correlated positively with number of MDEs. These results highlight impaired reward learning, disrupted RPE signaling in the striatum (particularly among individuals with more lifetime MDEs) as well as reduced VTA-striatal connectivity in MDD. Collectively, these findings highlight reward-related learning deficits in MDD and their underlying pathophysiology.
Anhedonia, the reduced propensity to experience pleasure, is a promising endophenotype and vulnerability factor for several psychiatric disorders, including depression and schizophrenia. In the ...present study, we used resting electroencephalography, functional magnetic resonance imaging, and volumetric analyses to probe putative associations between anhedonia and individual differences in key nodes of the brain's reward system in a non-clinical sample. We found that anhedonia, but not other symptoms of depression or anxiety, was correlated with reduced nucleus accumbens (NAcc) responses to rewards (gains in a monetary incentive delay task), reduced NAcc volume, and increased resting delta current density (i.e., decreased resting activity) in the rostral anterior cingulate cortex (rACC), an area previously implicated in positive subjective experience. In addition, NAcc reward responses were inversely associated with rACC resting delta activity, supporting the hypothesis that delta might be lawfully related to activity within the brain's reward circuit. Taken together, these results help elucidate the neural basis of anhedonia and strengthen the argument for anhedonia as an endophenotype for depression.
Converging evidence indicates that groups of patients with nominally distinct psychiatric diagnoses are not separated by sharp or discontinuous neurobiological boundaries. In healthy populations, ...individual differences in behavior are reflected in variability across the collective set of functional brain connections (functional connectome). These data suggest that the spectra of transdiagnostic symptom profiles observed in psychiatric patients may map onto detectable patterns of network function. To examine the manner through which neurobiological variation might underlie clinical presentation, we obtained fMRI data from over 1,000 individuals, including 210 diagnosed with a primary psychotic disorder or affective psychosis (bipolar disorder with psychosis and schizophrenia or schizoaffective disorder), 192 presenting with a primary affective disorder without psychosis (unipolar depression, bipolar disorder without psychosis), and 608 demographically matched healthy comparison participants recruited through a large-scale study of brain imaging and genetics. Here, we examine variation in functional connectomes across psychiatric diagnoses, finding striking evidence for disease connectomic “fingerprints” that are commonly disrupted across distinct forms of pathology and appear to scale as a function of illness severity. The presence of affective and psychotic illnesses was associated with graded disruptions in frontoparietal network connectivity (encompassing aspects of dorsolateral prefrontal, dorsomedial prefrontal, lateral parietal, and posterior temporal cortices). Conversely, other properties of network connectivity, including default network integrity, were preferentially disrupted in patients with psychotic illness, but not patients without psychotic symptoms. This work allows us to establish key biological and clinical features of the functional connectomes of severe mental disease.
Abstract Background Deficits in attentional control have been hypothesized to cause rumination, suggesting that the relationships between attentional control and clinical symptoms may be mediated in ...part by rumination. However, to date, no clinical study has examined these constructs transdiagnostically in a path analysis model. Methods Fifty-one adults presenting for treatment completed measures of self-reported attentional control, rumination, and depression and anxiety symptoms. A bias-corrected path analysis-based approach was employed to test whether indirect (i.e., mediating) effects of rumination were significantly associated with the direct effects of attentional control on depression and anxiety symptoms. Separate models for depression and anxiety symptoms were tested along with reverse models using attentional control as a proposed mediator. Results The relationship between attentional control and clinical symptomatology (i.e., both depression and anxiety symptoms) was mediated by rumination. Poor attentional control was associated with more rumination and consequently more severe symptoms of depression and anxiety. The reverse relationship (i.e., attentional control mediating the relationship between rumination and depression or anxiety symptoms) was not significant. Limitations Study design did not allow testing of temporal precedence for the mediation models. All constructs were assessed via self-report. Conclusions Attentional control appears to impact depression and anxiety symptoms through rumination. The pathway between poor attentional control and emotion dysregulation via rumination suggests that interventions targeting attentional control may decrease maladaptive ruminative processes, leading to improved emotion regulation and reduced clinical symptomatology. Future studies should examine the stability of this mediational relationship over time (and in the face of targeted interventions).
Major depressive disorder is characterized by reduced reward-related striatal activation and dysfunctional reward learning, putatively reflecting decreased dopaminergic signaling. The goal of this ...study was to test whether a pharmacological challenge designed to facilitate dopaminergic transmission can enhance striatal responses to reward and improve reward learning in depressed individuals.
In a double-blind placebo-controlled design, 46 unmedicated depressed participants and 43 healthy control participants were randomly assigned to receive either placebo or a single low dose (50 mg) of the D
/D
receptor antagonist amisulpride, which is believed to increase dopamine signaling through presynaptic autoreceptor blockade. To investigate the effects of increased dopaminergic transmission on reward-related striatal function and behavior, a monetary incentive delay task (in conjunction with functional MRI) and a probabilistic reward learning task were administered at absorption peaks of amisulpride.
Depressed participants selected previously rewarded stimuli less frequently than did control participants, indicating reduced reward learning, but this effect was not modulated by amisulpride. Relative to depressed participants receiving placebo (and control participants receiving amisulpride), depressed participants receiving amisulpride exhibited increased striatal activation and potentiated corticostriatal functional connectivity between the nucleus accumbens and the midcingulate cortex in response to monetary rewards. Stronger corticostriatal connectivity in response to rewards predicted better reward learning among depressed individuals receiving amisulpride as well as among control participants receiving placebo.
Acute enhancement of dopaminergic transmission potentiated reward-related striatal activation and corticostriatal functional connectivity in depressed individuals but had no behavioral effects. Taken together, the results suggest that targeted pharmacological treatments may normalize neural correlates of reward processing in depression; despite such acute effects on neural function, behavioral modification may require more chronic exposure. This is consistent with previous reports that antidepressant effects of amisulpride in depression emerged after sustained administration.
Abstract Background Longitudinal studies of illness progression in patients with major depressive disorder (MDD) indicate that the onset of subsequent depressive episodes becomes increasingly ...decoupled from external stressors. A possible mechanism underlying this phenomenon is that multiple episodes induce long-lasting neurobiological changes that confer increased risk for recurrence. Prior morphometric studies have frequently reported volumetric reductions in patients with MDD—especially in medial prefrontal cortex (mPFC) and the hippocampus—but few studies have investigated whether these changes are exacerbated by prior episodes. Methods In a sample of 103 medication-free patients with depression and control subjects with no history of depression, structural magnetic resonance imaging was performed to examine relationships between number of prior episodes, current stress, hippocampal subfield volume and cortical thickness. Volumetric analyses of the hippocampus were performed using a recently validated subfield segmentation approach, and cortical thickness estimates were obtained using vertex-based methods. Participants were grouped on the basis of the number of prior depressive episodes and current depressive diagnosis. Results Number of prior episodes was associated with both lower reported stress levels and reduced volume in the dentate gyrus. Cortical thinning of the left mPFC was associated with a greater number of prior depressive episodes but not current depressive diagnosis. Conclusions Collectively, these findings are consistent with preclinical models suggesting that the dentate gyrus and mPFC are especially vulnerable to stress exposure and provide evidence for morphometric changes that are consistent with stress-sensitization models of recurrence in MDD.
Abstract Functional magnetic resonance imaging (fMRI) was used to examine cognitive regulation of negative emotion in 12 unmedicated patients with major depressive disorder (MDD) and 24 controls. The ...participants used reappraisal to increase ( real condition) and reduce ( photo condition) the personal relevance of negative and neutral pictures during fMRI as valence ratings were collected; passive viewing ( look condition) served as a baseline. Reappraisal was not strongly affected by MDD. Ratings indicated that both groups successfully reappraised negative emotional experience. Both groups also showed better memory for negative vs. neutral pictures 2 weeks later. Across groups, increased brain activation was observed on negative/ real vs. negative/ look and negative/ photo trials in left dorsolateral prefrontal cortex (DLPFC), rostral anterior cingulate, left parietal cortex, caudate, and right amygdala. Depressive severity was inversely correlated with activation modulation in the left DLPFC, right amygdala, and right cerebellum during negative reappraisal. The lack of group differences suggests that depressed adults can modulate the brain activation and subjective experience elicited by negative pictures when given clear instructions. However, the negative relationship between depression severity and effects of reappraisal on brain activation indicates that group differences may be detectable in larger samples of more severely depressed participants.
Background
Diffusion tensor imaging (DTI) studies report reduced fractional anisotropy (FA) in major depressive disorder (MDD). However, whether FA covaries with key depressive symptoms, such as ...anhedonia, is unclear.
Methods
Magnetic resonance imaging data were acquired from 38 unmedicated adults with MDD and 52 healthy controls. DTI metrics were extracted from regions of interest that have consistently shown reduced FA in MDD. Analyses focused first on identifying group differences, and then determining whether reduced FA in depressed adults was related to individual differences in anhedonia and depressive severity. To establish specificity to depression, these analyses controlled for symptoms of anxiety.
Results
Relative to controls, depressed adults showed reduced FA in the genu of the corpus callosum, the anterior limb of the internal capsule (ALIC), the cingulum bundle near the anterior cingulate cortex, and the uncinate fasciculus (UF). In the depressed group, anhedonia negatively correlated with FA in the genu, cingulum, and UF, but positively correlated with radial diffusivity (RD)—a metric previously linked to demyelination—in the genu and ALIC. Depressive severity positively correlated with RD in the ALIC. These relationships remained significant after accounting for anxiety.
Conclusion
Anhedonia was positively correlated with reduced FA and increased RD in white matter pathways that connect regions critical for value coding, representing stimulus‐reward associations, and guiding value‐based action selection. Thus, a cardinal symptom of MDD—anhedonia—was lawfully related to abnormalities in reward network connectivity.
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