In vivo serotonin 1A receptor hippocampal binding potential in depression and reported childhood adversity.

BACKGROUND: Reported childhood adversity (CA) is associated with development of depression in adulthood and predicts a more severe course of illness. Although elevated serotonin 1A receptor (5-HT1AR) binding potential, especially in the raphe nuclei, has been shown to be a trait associated with major depression, we did not replicate this finding in an independent sample using the partial agonist positron emission tomography tracer [11C]CUMI-101. Evidence suggests that CA can induce long-lasting changes in expression of 5-HT1AR, and thus, a history of CA may explain the disparate findings. METHODS: Following up on our initial report, 28 unmedicated participants in a current depressive episode (bipolar n = 16, unipolar n = 12) and 19 non-depressed healthy volunteers (HVs) underwent [11C]CUMI-101 imaging to quantify 5-HT1AR binding potential. Participants in a depressive episode were stratified into mild/moderate and severe CA groups via the Childhood Trauma Questionnaire. We hypothesized higher hippocampal and raphe nuclei 5-HT1AR with severe CA compared with mild/moderate CA and HVs. RESULTS: There was a group-by-region effect (p = 0.011) when considering HV, depressive episode mild/moderate CA, and depressive episode severe CA groups, driven by significantly higher hippocampal 5-HT1AR binding potential in participants in a depressive episode with severe CA relative to HVs (p = 0.019). Contrary to our hypothesis, no significant binding potential differences were detected in the raphe nuclei (p-values > 0.05). CONCLUSIONS: With replication in larger samples, elevated hippocampal 5-HT1AR binding potential may serve as a promising biomarker through which to investigate the neurobiological link between CA and depression.

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.

Data-driven analysis of kappa opioid receptor binding in major depressive disorder measured by positron emission tomography.

Preclinical studies have implicated kappa opioid receptors (KORs) in stress responses and depression-related behaviors, but evidence from human studies is limited. Here we present results of a secondary analysis of data acquired using positron emission tomography (PET) with the KOR radiotracer [11C]GR103545 in 10 unmedicated, currently depressed individuals with major depressive disorder (MDD; 32.6 ± 6.5 years, 5 women) and 13 healthy volunteers (34.8 ± 10 years, 6 women). Independent component analysis was performed to identify spatial patterns of coherent variance in KOR binding (tracer volume of distribution, VT) across all subjects. Expression of each component was compared between groups and relationships to symptoms were explored using the 17-item Hamilton Depression Rating Scale (HDRS). Three components of variation in KOR availability across ROIs were identified, spatially characterized by [11C]GR103545 VT in (1) bilateral frontal lobe; (2) occipital and parietal cortices, right hippocampus, and putamen; and (3) right anterior cingulate, right superior frontal gyrus and insula, coupled to negative loading in left middle cingulate. In MDD patients, component 3 was negatively associated with symptom severity on the HDRS (r = -0.85, p = 0.0021). There were no group-wise differences in expression of any component between patients and controls. These preliminary findings suggest that KOR signaling in cortical regions relevant to depression, particularly right anterior cingulate, could reflect MDD pathophysiology.

Depression-related anterior cingulate prefrontal resting state connectivity normalizes following cognitive behavioral therapy.

BACKGROUND: Aberrant activity of the subcallosal cingulate (SCC) is a common theme across pharmacologic treatment efficacy prediction studies. The functioning of the SCC in psychotherapeutic interventions is relatively understudied, as are functional differences among SCC subdivisions. We conducted functional connectivity analyses (rsFC) on resting-state functional magnetic resonance imaging (fMRI) data, collected before and after a course of cognitive behavioral therapy (CBT) in patients with major depressive disorder (MDD), using seeds from three SCC subdivisions. METHODS: Resting-state data were collected from unmedicated patients with current MDD (Hamilton Depression Rating Scale-17 > 16) before and after 14-sessions of CBT monotherapy. Treatment outcome was assessed using the Beck Depression Inventory (BDI). Rostral anterior cingulate (rACC), anterior subcallosal cingulate (aSCC), and Brodmann's area 25 (BA25) masks were used as seeds in connectivity analyses that assessed baseline rsFC and symptom severity, changes in connectivity related to symptom improvement after CBT, and prediction of treatment outcomes using whole-brain baseline connectivity. RESULTS: Pretreatment BDI negatively correlated with pretreatment rACC ~ dorsolateral prefrontal cortex and aSCC ~ lateral prefrontal cortex rsFC. In a region-of-interest longitudinal analysis, rsFC between these regions increased post-treatment (p < 0.05FDR). In whole-brain analyses, BA25 ~ paracentral lobule and rACC ~ paracentral lobule connectivities decreased post-treatment. Whole-brain baseline rsFC with SCC did not predict clinical improvement. CONCLUSIONS: rsFC features of rACC and aSCC, but not BA25, correlated inversely with baseline depression severity, and increased following CBT. Subdivisions of SCC involved in top-down emotion regulation may be more involved in cognitive interventions, while BA25 may be more informative for interventions targeting bottom-up processing. Results emphasize the importance of subdividing the SCC in connectivity analyses.

Dissociable Neural Responses to Monetary and Social Gain and Loss in Women With Major Depressive Disorder.

Neuroimaging studies have revealed aberrant reward and loss processing in patients with major depressive disorder (MDD). While most studies use monetary stimuli to study these processes, it is important to consider social stimuli given that the social environment plays a significant role in the development and maintenance of MDD. In the present study, we examined whether monetary gain/loss and social acceptance/rejection would elicit dissociable salience-related neural responses in women diagnosed with MDD compared to healthy control (HC) women. Twenty women diagnosed with MDD and 20 matched HC women performed the monetary incentive delay task (MID) and the social feedback task (SFT) during functional magnetic resonance imaging (fMRI). This study focused on women since women have a higher rate of MDD, higher frequency of relapse, and are more likely to develop MDD as a consequence of negative interpersonal relationships compared to men. We found that during the MID, HCs but not MDD patients demonstrated strong overlapping activations in the right anterior insula (AI) in response to both monetary gain and loss. During the SFT, MDD patients but not HCs showed overlapping activations in the AI in response to social acceptance and rejection. Our results may suggest a dissociation such that MDD patients show decreased sensitivity to monetary stimuli whether gain or loss, and increased sensitivity to social stimuli whether acceptance or rejection, although this will need to be verified in larger samples with direct comparisons between groups and stimuli. These data demonstrate distinct abnormalities in reward and loss processing that converge within the AI. Our findings also highlight the critical need to assess across both non-social and social domains when examining reward and loss systems in MDD to broaden our understanding of the disorder and identify novel targets for treatment.

Abnormal emotional and neural responses to romantic rejection and acceptance in depressed women.

INTRODUCTION: Responding adaptively to one's social environment is a key factor predicting the course of major depressive disorder (MDD). Socially rejecting events can exacerbate, whereas socially accepting events can ameliorate depressive symptoms. The neural responses to rejection and acceptance in MDD are relatively unexplored. METHODS: We used functional magnetic resonance imaging (fMRI) to measure neural responses to romantic rejection and acceptance in women diagnosed with current MDD (n = 19) and a matched group of healthy controls (HCs) (n = 19). During fMRI, participants received rejecting, accepting, and neutral feedback from self-selected potential romantic partners. RESULTS: In women with MDD but not HCs, rejection significantly increased activity in the right anterior insula relative to neutral feedback. Greater activation during rejection was found in the dorsal anterior cingulate cortex in MDD compared to HCs. Women with MDD reported stronger emotional responses than HCs to both rejection and acceptance. In addition, left and right nucleus accumbens (NAcc) activity mediated the relationship between trait reward responsiveness and increased ratings of feeling "happy and accepted" following acceptance in HCs, but not the MDD group. DISCUSSION: Women with MDD were behaviorally and neurally hyperresponsive to rejection. Although both groups were behaviorally responsive to acceptance, in MDD this was dissociated from NAcc activity. These findings highlight abnormal behavioral and neural responses to social cues in MDD, with implications for disease prognosis and the development of novel and sensitive biomarkers for MDD focused on neural pathways for social-affective processing. LIMITATIONS: Conclusions may be limited to depressed women in a romantic context.