Temporal Interactions between Neural Proxies forMemory Recall, Negative Affect, and EmotionRegulation in Major Depression.

Dysfunction in emotion regulation (ER) and autobiographical memory are components of major depressive disorder (MDD). However, little is known about how they mechanistically interact with mood disturbances in real time. Using machine learning-based neural signatures, we can quantify negative affect (NA), ER, and memory continuously to evaluate how these processes dynamically interact in MDD. Unmedicated individuals with MDD (N=45) and healthy volunteers (HV; N=38) completed a negative autobiographical memory functional magnetic resonance imaging task wherein they recalled, distanced from (an ER strategy), and immersed into memories. We used a negative affect signature (PINES) and an emotion regulation signature (ERS) to quantify moment-to-moment NA and ER. We then examined whether memory engagement, indexed by hippocampal activity, predicted subsequent change in PINES and ERS over time. During memory recall and immersion, greater hippocampal activity predicted increased PINES across groups. During distancing, greater hippocampal activity in HVs predicted increased ERS but not PINES. In MDD, greater hippocampal activity predicted increased PINES but not ERS. Findings suggest abnormalities in the real-time relationship between memory, NA, and ER in MDD. During distancing, as predicted, HVs showed an attenuation of the linkage between memory engagement and NA, and they had subsequent increases in ER following memory reactivation. In contrast, MDD was characterized by continued linkage between memory engagement and NA, without subsequent increases in ER. Deficits in engagement of ER and ineffective modulation of NA following negative memory recall may contribute to the mood disturbances in MDD and are potential targets for clinical intervention.

Neural correlates of deceased-related attention during acute grief in suicide-related bereavement.

BACKGROUND: Individuals who have lost a loved one to suicide demonstrate an attentional bias to deceased-related stimuli during early grief. Regulating attention toward reminders of the deceased during acute bereavement may be linked to grief trajectory and pathological grief development. Despite the potential prognostic importance, little is known about underlying neural circuitry correlates of deceased-related grief processing. The current study examines neural substrates of deceased-related attentional processing during acute grief in individuals bereaved by suicide. METHODS: Thirty-seven participants grieving the loss of a first-degree relative or partner to suicide in the prior six months, underwent functional magnetic resonance imaging (fMRI) while performing an emotional Stroop task using words related to the deceased and a living attachment figure, in order to examine neural correlates of deceased-specific attentional processing. Clinical interviews were conducted at baseline. RESULTS: Deceased-related attentional bias was associated with blood oxygen level-dependent (BOLD) activation in a brain network, including dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), orbitofrontal cortex (OFC), and insula. Greater activation of a bilateral prefrontal cluster during deceased-specific attention was negatively correlated with self-reported grief avoidance behaviors. LIMITATIONS: Lack of non-suicide grief control and small sample size. CONCLUSIONS: These data, if confirmed, indicate a neural network specific to deceased-related attention, and that cognitive control regions within this network appear to be related to grief avoidance behaviors during acute bereavement.

Attentional bias during acute grief predicts clinical outcome in suicide-related bereavement.

BACKGROUND: Individuals who have lost a loved one to suicide are at increased risk for developing complicated grief (CG). It is unclear why only a subgroup of bereaved develops pathological forms of grief. Vulnerability may be related to the ability to regulate attention toward reminders of the deceased during the acute phase of grief. Using a longitudinal design, we determined whether loss-related attentional bias during acute grief predicts grief severity one year later. METHODS: Thirty-seven participants grieving a first-degree relative or partner to suicide in the prior 6 months performed an emotional Stroop task using words related to the deceased, a living attachment figure, living non-attachment figure, and color congruent Stroop to quantify related attentional bias during the acute grief period. Clinical interviews were conducted at baseline (N = 37) and one year later (N = 35). RESULTS: Participants showed greater attentional bias to deceased-related word trials compared with living attachment, non-attachment, and congruent trials, controlling for age, time since loss, depression, and psychiatric medication. A greater reduction in grief severity over time was associated with more deceased-related attentional bias at baseline. Self-reported grief avoidance was related to deceased-related attentional bias, with lower avoidance scores associated with greater bias. LIMITATIONS: Lack of non-suicide grief control and small sample size. CONCLUSIONS: Less deceased-related bias following the loss may hinder the transition from acute to integrated grief and result in poorer grief trajectories.

The Temporal Dynamics of Emotion Regulation in Subjects With Major Depression and Healthy Control Subjects.

BACKGROUND: Emotion regulation (ER) processes help support well-being, but ineffective ER is implicated in several psychiatric disorders. Engaging ER flexibly by going online and offline as needs and capacities shift may be more effective than engaging ER rigidly across time. Here, we sought to observe the neural temporal dynamics of an ER process, reappraisal, during regulation of responses to negative memories in healthy control subjects (n = 33) and subjects with major depressive disorder (n = 36). METHODS: To track the temporal dynamics of reappraisal neural systems, we used a functional magnetic resonance imaging neural decoding approach. In task 1, subjects explicitly engaged reappraisal on instruction in response to aversive images, and we used this task to develop the decoder for detecting reappraisal. In task 2, subjects experienced negative autobiographical memories from a distant (third person, ER condition) or immersed (first person, control condition) perspective. RESULTS: The neural decoder, trained to detect reappraisal in task 1, predicted greater reappraisal occurring during the task 2 distance versus immerse trials and was engaged more intensely during memories that were rated as being more negative. Across time, decoder output manifested a temporal dynamic of early engagement followed by disengagement. These results were replicated in an independent subject dataset (n = 59). Relative to healthy control subjects, subjects with major depressive disorder had a comparable initial increase in decoder engagement at the beginning of the trial but an attenuated decrease at the end. CONCLUSIONS: Subjects with major depressive disorder evidenced a more rigid neural dynamic of reappraisal compared with healthy control subjects. Rigid ER may indicate diminished ability to flexibly and effectively regulate emotion.

Large-scale network dynamics in neural response to emotionally negative stimuli linked to serotonin 1A binding in major depressive disorder.

Serotonergic dysfunction is implicated in major depressive disorder (MDD), but the mechanisms of this relationship remain elusive. Serotonin 1A (5-HT1A) autoreceptors regulate brain-wide serotonin neuron firing and are positioned to assert large-scale effects on negative emotion. Here we investigated the relationship between raphe 5-HT1A binding and brain-wide network dynamics of negative emotion. 22 healthy-volunteers (HV) and 27 medication-free participants with MDD underwent positron emission tomography (PET) using [11C]CUMI-101 (CUMI) to quantify 5-HT1A binding in midbrain raphe nuclei and functional magnetic resonance imaging (fMRI) scanning during emotionally negative picture viewing. Causal connectivity across regions responsive to negative emotion was estimated in the fMRI data using a multivariate dynamical systems model. During negative picture viewing, MDD subjects demonstrated significant hippocampal inhibition of amygdala, basal-ganglia, thalamus, orbital frontal cortex, inferior frontal gyrus and dorsomedial prefrontal cortex (IFG, dmPFC). MDD-related connectivity was not associated with raphe 5-HT1A binding. However, greater hippocampal inhibition of amygdala, thalamus, IFG and dmPFC correlated with hippocampal 5-HT1A binding. Correlation between hippocampal 5-HT1A binding and the hippocampal inhibition network was specific to MDD but not HV. MDD and HV groups also differed with respect to the correlation between raphe and hippocampal 5-HT1A binding which was more pronounced in HV. These findings suggest that increased hippocampal network inhibition in MDD is linked to hippocampal serotonergic dysfunction which may in turn arise from disrupted linkage in raphe to hippocampus serotonergic circuitry.

Self-generated Unconscious Processing of Loss Linked to Less Severe Grieving.

BACKGROUND: The intense loss processing that characterizes grieving may help people to adapt to the loss. However, empirical studies show that more conscious loss-related thinking and greater reactivity to reminders of the deceased correspond to poorer adaptation. These findings raise the possibility that loss processing that is unconscious rather than conscious and is self-generated rather than reactive may facilitate adaptation. Here, we used machine learning to detect a functional magnetic resonance imaging (fMRI) signature of self-generated unconscious loss processing that we hypothesized to correlate with lower grief severity. METHODS: A total of 29 subjects bereaved within the past 14 months participated. Participants performed a modified Stroop fMRI task using deceased-related words. A machine-learning regression, trained on Stroop fMRI data, learned a neural pattern for deceased-related selective attention (d-SA), the allocation of attention to the deceased. Expression of this pattern was tracked during a subsequent sustained attention fMRI task interspersed with deceased-related thought probes (SART-PROBES). d-SA pattern expression during SART-PROBES blocks without reported thoughts of loss indicated self-generated unconscious loss processing. Grief severity was measured with the Inventory for Complicated Grief. RESULTS: d-SA expression during SART-PROBES blocks without conscious deceased-related thinking correlated negatively with Inventory for Complicated Grief score (r25 = -.711, p < .001, 95% confidence interval = -0.89 to -0.42), accounting for 50% of variance. This relationship remained significant independent of demographic correlates of Inventory for Complicated Grief (B25 = -30, t = -2.64, p = .02, 95% confidence interval = -56.2 to -4.6). Unconscious d-SA pattern expression also correlated with activity in dorsolateral prefrontal cortex and temporal parietal junction during the SART-PROBES (voxel: p < .001, cluster: p < .05). CONCLUSIONS: Self-generated unconscious loss processing correlated with reduced grief severity. This activity, supported by a cognitive social neural architecture, may advance adaptation to the loss.

Ongoing monitoring of mindwandering in avoidant grief through cortico-basal-ganglia interactions.

An avoidant grief style is marked by repeated and often unsuccessful attempts to prevent thinking about loss. Prior work shows avoidant grief involves monitoring the external environment in order to avoid reminders of the loss. Here we sought to determine whether avoidant grievers also monitor the internal environment in attempts to minimize conscious awareness of loss-related thoughts. Individuals bereaved of a first-degree relative, spouse or partner within the last 14 months participated in a functional magnetic resonance imaging (fMRI) study (N = 29). We first applied machine learning to train neural patterns for attentional control and representation of the deceased (N = 23). The attentional pattern was trained using fMRI data from a modified Stroop task assessing selective attention to reminders of the deceased. The representational pattern was trained using fMRI data from a task presenting pictures and stories of the deceased. We observed spontaneous fluctuations in these processes occurring during a neutral mindwandering fMRI task (N = 27). At higher levels of avoidant grieving, activation of attentional control disrupted the relationship between the representational process and thoughts of loss. These findings show that avoidant grief involves attentional control to reduce the likelihood that deceased-related representations reach full conscious awareness.

Attentional Bias to Reminders of the Deceased as Compared With a Living Attachment in Grieving.

BACKGROUND: Grieving individuals demonstrate attentional bias toward reminders of the deceased versus neutral stimuli. We sought to assess bias toward reminders of the deceased versus a living attachment figure and to evaluate similarities and differences in the neural correlates of deceased- and living-related attention. We also sought to identify grief process variables associated with deceased-related attentional bias. METHODS: Twenty-five subjects grieving the death of a first-degree relative or partner within 14 months performed an emotional Stroop task, using words related to a deceased or a living attachment figure, and a standard Stroop task, to identify general selective attention, during functional magnetic resonance imaging. Subjects rated word sadness, complicated grief symptoms, depression severity, attachment style, emotional pain, nonacceptance, yearning, and intrusions. RESULTS: We identified an attentional bias to deceased-related versus living-related words, independent of age, depression severity/history, loss type, word sadness, medication use, and time since loss. Attentional bias correlated with complicated grief severity and intrusive thinking. A conjunction analysis identified joint activation in the fusiform gyrus, posterior cingulate, and temporal parietal junction across living- and deceased-related attention versus general selective attention. Insecure-avoidant attachment style correlated with decreased engagement of this network in deceased-related attention. CONCLUSIONS: We have demonstrated an attentional bias to reminders of the deceased versus a living attachment in grieving. Overlapping neural circuits related to living- and deceased-related attention suggest that the bereaved employ similar processes in attending to the deceased as they do in attending to the living. Deceased-related attentional bias appears to be linked primarily to intrusive thinking about the loss.

Network Configurations in the Human Brain Reflect Choice Bias during Rapid Face Processing.

Network interactions are likely to be instrumental in processes underlying rapid perception and cognition. Specifically, high-level and perceptual regions must interact to balance pre-existing models of the environment with new incoming stimuli. Simultaneous electroencephalography (EEG) and fMRI (EEG/fMRI) enables temporal characterization of brain-network interactions combined with improved anatomical localization of regional activity. In this paper, we use simultaneous EEG/fMRI and multivariate dynamical systems (MDS) analysis to characterize network relationships between constitute brain areas that reflect a subject's choice for a face versus nonface categorization task. Our simultaneous EEG and fMRI analysis on 21 human subjects (12 males, 9 females) identifies early perceptual and late frontal subsystems that are selective to the categorical choice of faces versus nonfaces. We analyze the interactions between these subsystems using an MDS in the space of the BOLD signal. Our main findings show that differences between face-choice and house-choice networks are seen in the network interactions between the early and late subsystems, and that the magnitude of the difference in network interaction positively correlates with the behavioral false-positive rate of face choices. We interpret this to reflect the role of saliency and expectations likely encoded in frontal "late" regions on perceptual processes occurring in "early" perceptual regions.SIGNIFICANCE STATEMENT Our choices are affected by our biases. In visual perception and cognition such biases can be commonplace and quite curious-e.g., we see a human face when staring up at a cloud formation or down at a piece of toast at the breakfast table. Here we use multimodal neuroimaging and dynamical systems analysis to measure whole-brain spatiotemporal dynamics while subjects make decisions regarding the type of object they see in rapidly flashed images. We find that the degree of interaction in these networks accounts for a substantial fraction of our bias to see faces. In general, our findings illustrate how the properties of spatiotemporal networks yield insight into the mechanisms of how we form decisions.

Tracking Deceased-Related Thinking with Neural Pattern Decoding of a Cortical-Basal Ganglia Circuit.

BACKGROUND: Deceased-related thinking is central to grieving and potentially critical to processing of the loss. Self-report measurements might fail to capture important elements of deceased-related thinking and processing. Here, we used a machine learning approach applied to fMRI - known as neural decoding - to develop a measure of ongoing deceased-related processing. METHODS: 23 subjects grieving the loss of a first-degree relative, spouse or partner within 14 months underwent two fMRI tasks. They first viewed pictures and stories related to the deceased, a living control and a demographic control figure while providing ongoing valence and arousal ratings. Second, they performed a 10-minute Sustained Attention to Response Task (SART) with thought probes every 25-35 seconds to identify deceased, living and self-related thoughts. RESULTS: A conjunction analysis, controlling for valence/arousal, identified neural clusters in basal ganglia, orbital prefrontal cortex and insula associated with both types of deceased-related stimuli vs. the two control conditions in the first task. This pattern was applied to fMRI data collected during the SART, and discriminated deceased-related but not living or self-related thoughts, independently of grief-severity and time since loss. Deceased-related thoughts on the SART correlated with self-reported avoidance. The neural model predicted avoidance over and above deceased-related thoughts. CONCLUSIONS: A neural pattern trained to identify mental representations of the deceased tracked deceased-related thinking during a sustained attention task and also predicted subject-level avoidance. This approach provides a new imaging tool to be used as an index of processing the deceased for future studies of complicated grief.

Relationship of recent stress to amygdala volume in depressed and healthy adults.

BACKGROUND: The amygdala is an integral part of the extrahypothalamic stress-response system, and its volume related to childhood trauma has been studied, but less is known of associations with recent stressful life events. Amygdala volume differences also have been studied in depression, with conflicting results. We hypothesized that effects of stress may be a confound for amygdala volumetric differences in the context of depression. METHODS: Right-handed participants (n=61) experiencing a major depressive episode during major depressive disorder (n=40) or bipolar depression (n=21) and healthy volunteers (n=60) underwent 1.5T magnetic resonance imaging (MRI). The amygdala perimeter was manually traced with an electronic mouse, based on anatomical landmarks on consecutive coronal slices, by raters blind to diagnosis. The effects of stress on amygdala volume were examined in linear regression models with self-reported physical/sexual abuse or highest category score on the St. Paul-Ramsey scale of stressful life events within the past 6 months as predictors, testing separately for age, sex, race, and depression status as covariates. RESULTS: Diagnostic groups did not differ significantly with respect to mean age (depressed, 37.8±11.8yrs; healthy, 34.9±13.8yrs) or proportion of males (depressed, 39%, healthy, 50%). We found no association between physical and/or sexual abuse history and amygdala volume. Life stress within the last six months, however, was associated with smaller left amygdala volume. The association between stress and amygdala volume did not differ by diagnostic group. LIMITATIONS: Most depressed patients were off medications for at least 2 weeks; however, this may not have been long enough to reverse effects of medications on amygdala structure. CONCLUSIONS: That life stress of relatively short duration was associated with amygdala size in the entire sample, while temporally distant life stress was not, suggests that amygdala volume changes may occur rapidly and reversibly, and independent of depression status.

Relationship of the serotonin transporter gene promoter polymorphism (5-HTTLPR) genotype and serotonin transporter binding to neural processing of negative emotional stimuli.

BACKGROUND: The lower-expressing (S') alleles of the serotonin transporter (5-HTT) gene promoter polymorphism (5-HTTLPR) are linked to mood and anxiety related psychopathology. However, the specific neural mechanism through which these alleles may influence emotional and cognitive processing remains unknown. We examined the relationship between both 5-HTTLPR genotype and in vivo 5-HTT binding quantified via PET with amygdala reactivity to emotionally negative stimuli. We hypothesized that 5-HTT binding in both raphe nuclei (RN) and amygdala would be inversely correlated with amygdala reactivity, and that number of S' alleles would correlate positively with amygdala reactivity. METHODS: In medication-free patients with current major depressive disorder (MDD; N=21), we determined 5-HTTLPR genotype, employed functional magnetic resonance imaging (fMRI) to examine amygdala responses to negative emotional stimuli, and used positron emission tomography with [(11)C]DASB to examine 5-HTT binding. RESULTS: [(11)C]DASB binding in RN and amygdala was inversely correlated with amygdala response to negative stimuli. 5-HTTLPR S' alleles were not associated with amygdala response to negative emotional stimuli. LIMITATIONS: Primary limitations are small sample size and lack of control group. CONCLUSIONS: Consistent with findings in healthy volunteers, 5-HTT binding is associated with amygdala reactivity to emotional stimuli in MDD. 5-HTT binding may be a stronger predictor of emotional processing in MDD as compared with 5-HTTLPR genotype.

fMRI response to negative words and SSRI treatment outcome in major depressive disorder: a preliminary study.

Clinically useful predictors of treatment outcome in major depressive disorder (MDD) remain elusive. We examined associations between functional magnetic resonance imaging (fMRI) blood oxygen level dependent (BOLD) signal during active negative word processing and subsequent selective serotonin reuptake inhibitor (SSRI) treatment outcome in MDD. Unmedicated MDD subjects (n=17) performed an emotional word processing fMRI task, and then received eight weeks of standardized antidepressant treatment with escitalopram. Lower pre-treatment BOLD responses to negative words in midbrain, dorsolateral prefrontal cortex, paracingulate, anterior cingulate, thalamus and caudate nuclei correlated significantly with greater improvement following escitalopram treatment. Activation of these regions in response to negative words correlated significantly with reaction time for rating word relevance. Maximally predictive clusters of voxels identified using a cross-validation approach predicted 48% of the variance in response to treatment. This study provides preliminary evidence that SSRIs may be most beneficial in patients who are less able to engage cognitive control networks while processing negative stimuli. Differences between these findings and previous fMRI studies of SSRI treatment outcome may relate to differences in task design. Regional BOLD responses to negative words predictive of SSRI outcome in this study were both overlapping and distinct from those predictive of outcome with cognitive behavioral therapy (CBT) in previous studies using the same task. Future studies may examine prediction of differential outcome across treatments in the context of a randomized controlled trial.

Neural responses to incongruency in a blocked-trial Stroop fMRI task in major depressive disorder.

BACKGROUND: Patients with major depressive disorder (MDD) perform poorly on the Stroop task, which is a measure of the executive control of attention, with impaired interference resolution. The neural correlates of this deficit are not well described. To examine how this deficit relates to pathophysiological abnormalities in MDD, we conducted an fMRI Stroop study comparing MDD subjects to controls. METHODS: Forty-two unmedicated patients with current MDD and 17 control subjects underwent fMRI scanning with a color-word Stroop task. Subjects assessed font color during alternating color identification (e.g., 'XXXX' in blue) and incongruent color/word blocks (e.g., the word 'red' in blue). We examined neural activation that was greater in incongruent than color identification blocks (Z>2.3 and corrected p<0.05), controlling for trial-by-trial reaction time. RESULTS: Compared to controls, MDD subjects exhibited lower activation during incongruent blocks across multiple brain regions, including middle frontal gyrus, paracingulate and posterior cingulate, precuneus, occipital regions, and brain stem. No brain regions were identified in which MDD subjects were more active than controls during incongruent blocks. LIMITATIONS: Not all MDD subjects were antidepressant-naïve. CONCLUSIONS: Brain regions related to executive function, visual processing, and semantic processing are less active during processing of incongruent stimuli in MDD subjects as compared to controls. Deficits of attention in MDD may be the product of a failure to maintain activity across a distributed network in a sustained manner, as is required over the sequential trials in this block design. Further studies may clarify whether the abnormalities represent a trait or state deficit.

Enhanced dorsolateral striatal activity in drug use: the role of outcome in stimulus-response associations.

Prolonged stimulant exposure leads to enhanced dorsolateral striatal (DLS) dopaminergic activity in response to the drug and drug-associated cues. This effect has been interpreted in light of evidence that this brain region supports the generation of habitual stimulus-response (S-R) based behaviors to propose the idea that prolonged drug use leads to the development of drug taking and seeking habits that are insensitive to the value of the rewards they procure. In this review, we discuss evidence supporting a continued role for reward value in the performance of S-R based behaviors. We describe how caching of reward value and Pavlovian to instrumental transfer can provide mechanisms for past and current reward values to regulate the performance of S-R habits. The contribution of these constructs is consistent with evidence indicating the continued interaction between ventral incentive processing and dorsal S-R processing striatal regions in the generation of habitual drug seeking behaviors.