Anhedonia and depression severity dissociated by dmPFC resting-state functional connectivity in adolescents

Introduction: Given the heterogeneity within depression, in this study we aim to examine how RSFC in adolescents is related to anhedonia and depression severity on a continuum in line with the RDoC approach. Methods: We examined how RSFC in the dorsal medial prefrontal cortex (dmPFC), nucleus accumbens (NAcc) and pregenual anterior cingulate cortex (pgACC) was related to anhedonia and depression severity in eighty six adolescents (13-21 yrs.). Results: We found both anhedonia and depression severity related to decreased dmPFC RSFC with the precuneus, a part of the default mode network. However we also found that increased dmPFC connectivity with the ACC/paracingulate gyrus related to anhedonia whereas increased RSFC with the frontal pole related to depression severity. Discussion: This work extends the view that the dmPFC is a potential therapeutic target for depression in two ways. 1. We report dmPFC connectivity in adolescents and 2. We show different dmPFC RSFC specific to anhedonia and depression severity, providing neural targets for intervention in young people at risk of depression

Dimensional anhedonia and the adolescent brain: reward and aversion anticipation, effort and consummation

Given the heterogeneity of depression the Research Domain Criteria Framework suggests a dimensional approach to understanding the nature of mental illness. Neural reward function has been suggested as underpinning the symptom of anhedonia in depression but how anhedonia is related to aversion processing is unclear. We examined neural activity during reward and aversion processing in adolescents and emerging adults (N=84) in the age range 13-21yrs. Using a dimensional approach we examined how anhedonia and depression related to physical effort to gain reward or avoid aversion and neural activity during the anticipation, motivation/effort and consummation of reward and aversion. We show for the first time that as anhedonia increased physical effort to gain reward and avoid aversion decreased. Further that as anhedonia increased neural activity in the precuneus and insula (trend) decreased during effort to avoid and increased in the caudate during aversive consummation. Using a categorical approach we found participants with depression symptoms invested less physical effort to gain reward and avoid aversion than controls and had blunted neural anticipation of reward and aversion in the precuneus, insula, and prefrontal cortex and blunted neural activity during effort for reward in the putamen. We show for the first time that both physical effort and neural activity during effort correlate with anhedonia in adolescents and that amotivation might be a specific deficit of anhedonia irrespective of valence. Future work will assess if these neural mechanisms can be used to predict blunted approach and avoidance in adolescents at risk of depression

Investigating the predictive value of functional MRI to appetitive and aversive stimuli: a pattern classification approach

Abstract Background. Dysfunctional neural responses to appetitive and aversive stimuli have been investigated as possible biomarkers for psychiatric disorders. However it is not clear to what degree these are separate processes across the brain or in fact overlapping systems. To help clarify this issue we used Gaussian process classifier (GPC) analysis to examine appetitive and aversive processing in the brain. Method. 25 healthy controls underwent functional MRI whilst seeing pictures and receiving tastes of pleasant and unpleasant food. We applied GPCs to discriminate between the appetitive and aversive sights and tastes using functional activity patterns. Results. The diagnostic accuracy of the GPC for the accuracy to discriminate appetitive taste from neutral condition was 86.5% (specificity = 81%, sensitivity =92%, p=0.001). If a participant experienced neutral taste stimuli the probability of correct classification was 92. The accuracy to discriminate aversive from neutral taste stimuli was 82.5% (specificity = 73%, sensitivity =92%, p=0.001) and appetitive from aversive taste stimuli was 73% (specificity = 77%, sensitivity =69%, p=0.001). In the sight modality, the accuracy to discriminate appetitive from neutral condition was 88.5% (specificity = 85%, sensitivity =92%, p=0.001), to discriminate aversive from neutral sight stimuli was 92% (specificity = 92%, sensitivity =92%, p=0.001), and to discriminate aversive from appetitive sight stimuli was 63.5% (specificity = 73%, sensitivity =54%, p=0.009). Conclusions. Our results demonstrate the predictive value of neurofunctional data in discriminating emotional and neutral networks of activity in the healthy human brain. It would be of interest to use pattern recognition techniques and fMRI to examine network dysfunction in the processing of appetitive, aversive and neutral stimuli in psychiatric disorders. Especially where problems with reward and punishment processing have been implicated in the pathophysiology of the disorder

Effects of serotonin and dopamine depletion on neural prediction computations during social learning

We have previously shown that individuals with high depression scores demonstrate impaired behavioral and neural responses during social learning. Given that depression is associated with altered dopamine (DA) and serotonin (5-HT) functioning, the current study aimed to elucidate the role of these neurotransmitters in the social learning process using a dietary depletion manipulation. In a double-blind design, 70 healthy volunteers were randomly allocated to a 5-HT depletion (N=24), DA depletion (N = 24), or placebo (N = 22) group. Participants performed a social learning task during fMRI scanning, as part of which they learned associations between name cues and rewarding (happy faces) or aversive (fearful faces) social outcomes. Behaviorally, 5-HT depleted subjects demonstrated impaired social reward learning compared to placebo controls, with a marginal effect in the same direction in the DA depletion group. On the neural level, computational modelling-based fMRI analyses revealed that 5-HT depletion altered social reward prediction signals in the insula, temporal lobe, and prefrontal cortex, while DA depletion affected social reward prediction encoding only in the prefrontal cortex. These results indicate that 5-HT depletion impairs learning from social rewards, on both the behavioral and the neural level, while DA depletion has a less extensive effect. Interestingly, the behavioral and neural responses observed after 5-HT depletion in the current study closely resemble our previous findings in individuals with high depression scores using the same task. It may thus be the case that decreased 5-HT levels contribute to social learning deficits in depression

Bupropion administration increases resting-state functional connectivity in dorso-medial prefrontal cortex

Background: Patients on the selective serotonergic re-uptake inhibitors (SSRI) like citalopram report emotional blunting. We have shown previously that citalopram reduces resting-state functional connectivity (RSFC) in healthy volunteers in a number of brain regions including the dorso-medial prefrontal cortex, which may be related to its clinical effects. Bupropion is a dopaminergic and noradrenergic re-uptake inhibitor (DNRI) and is not reported to cause emotional blunting. However how bupropion affects RSFC in healthy controls remains unknown. Methods: Using a within subjects, repeated measures, double-blind, cross-over design we examined 17 healthy volunteers (9 female, 8 male). Volunteers received 7 days of bupropion (150 mg/day) and 7 days of placebo treatment and underwent resting-state functional Magnetic Resonance Imaging. We selected seed regions in the salience network (SN: amygdala and pregenual anterior cingulate cortex (pgACC)) and the central executive network (CEN: dorsal medial prefrontal cortex (dmPFC)). Mood and anhedonia measures were also recorded and examined in relation to RSFC. Results: Relative to placebo, bupropion increased RSFC in healthy volunteers between the dmPFC seed region and the posterior cingulate cortex and the precuneus cortex, key parts of the default mode network. Conclusions: These results are opposite to that which we found with 7 days treatment of citalopram in healthy volunteers. These results reflect a different mechanism of action of bupropion compared to SSRIs. These results help explain the apparent lack of emotional blunting caused by bupropion in depressed patients

Resting-state functional connectivity following a single dose treatment with CB1 neutral antagonist tetrahydrocannabivarin (THCv) in healthy volunteers

BACKGROUND: The cannabinoid cannabinoid type 1 (CB1) neutral antagonist tetrahydrocannabivarin (THCv) has been suggested as a possible treatment for obesity, but without the depressogenic side-effects of inverse antagonists such as Rimonabant. However, how THCv might affect the resting state functional connectivity of the human brain is as yet unknown. METHOD: We examined the effects of a single 10mg oral dose of THCv and placebo in 20 healthy volunteers in a randomized, within-subject, double-blind design. Using resting state functional magnetic resonance imaging and seed-based connectivity analyses, we selected the amygdala, insula, orbitofrontal cortex, and dorsal medial prefrontal cortex (dmPFC) as regions of interest. Mood and subjective experience were also measured before and after drug administration using self-report scales. RESULTS: Our results revealed, as expected, no significant differences in the subjective experience with a single dose of THCv. However, we found reduced resting state functional connectivity between the amygdala seed region and the default mode network and increased resting state functional connectivity between the amygdala seed region and the dorsal anterior cingulate cortex and between the dmPFC seed region and the inferior frontal gyrus/medial frontal gyrus. We also found a positive correlation under placebo for the amygdala-precuneus connectivity with the body mass index, although this correlation was not apparent under THCv. CONCLUSION: Our findings are the first to show that treatment with the CB1 neutral antagonist THCv decreases resting state functional connectivity in the default mode network and increases connectivity in the cognitive control network and dorsal visual stream network. This effect profile suggests possible therapeutic activity of THCv for obesity, where functional connectivity has been found to be altered in these regions

Understanding anhedonia: a qualitative study exploring loss of interest and pleasure in adolescent depression

Anhedonia (or loss of interest and pleasure) is a core symptom of depression and may predict poor treatment outcome. However, little is known about the subjective experience of anhedonia, and it is rarely targeted in psychological treatment for depression. The aim of this study is to examine how young people experience anhedonia in the context of depression. Semi-structured interviews were conducted with 34 adolescents with a primary diagnosis of depression (N=12) or elevated depressive symptoms (N=22). Thematic analysis was used to identify important aspects of adolescents’ experiences. Four main themes were identified: 1) Experiencing a loss of joy and a flattening of emotion; 2) Struggling with motivation and active engagement; 3) Losing a sense of connection and belonging; 4) Questioning sense of self, purpose, and the bigger picture. The results challenge the framing of anhedonia as simply the loss of interest and pleasure. Adolescents reported a range of experiences that mapped closely onto the cluster of negative symptoms associated with schizophrenia and were similar to the sense of ‘apathy’ characteristic in Parkinson’s disease. This highlights the potential benefit of taking a trans-diagnostic approach to understanding and treating reward deficits associated with mental health problems

Neural signals of “intensity” but not “wanting” or “liking” of rewards may be trait markers for depression

We have shown previously that particpants “at risk” of depression have decreased neural processing of reward suggesting this might be a neural biomarker for depression. However, how the neural signal related to subjective experiences of reward (wanting, liking, intensity) might differ as trait markers for depression, is as yet unknown. Using SPM8 parametric modulation analysis the neural signal related to the subjective report of wanting, liking and intensity was compared between 25 young people with a biological parent with depression (FH) and 25 age/gender matched controls. In a second study the neural signal related to the subjective report of wanting, liking and intensity was compared between 13 unmedicated recovered depressed (RD) patients and 14 healthy age/gender matched controls. The analysis revealed differences in the neural signal for wanting, liking and intensity ratings in the ventral striatum, dmPFC and caudate respectively in the RD group compared to controls . Despite no differences in the FH groups neural signal for wanting and liking there was a difference in the neural signal for intensity ratings in the dACC and anterior insula compared to controls. These results suggest that the neural substrates tracking the intensity but not the wanting or liking for rewards and punishers might be a trait marker for depression

Increased anticipatory but decreased consummatory brain responses to food in sisters of Anorexia Nervosa patients

Background We have previously shown increased anticipatory and consummatory neural responses to rewarding and aversive food stimuli in women recovered from anorexia nervosa (AN). Aims To determine if these differences are trait markers for anorexia nervosa we examined the neural response in those with a familial history but no personal history of AN. Method 36 volunteers were recruited, 15 who had a sister with anorexia nervosa (FH) and 21 control participants. Using fMRI we examined the neural response during an anticipatory phase (food cues, rewarding and aversive), an effort phase and a consummatory phase (rewarding and aversive tastes). Results FH volunteers showed increased activity in the caudate during the anticipation of both reward and aversive food and in the thalamus and amygdala during anticipation of aversive only. FH had decreased activity in the dorsal anterior cingulate cortex, the pallidum and the superior frontal gyrus during taste consumption. Conclusions Increased neural anticipatory but decreased consummatory responses to food might be a biomarker for AN. Interventions that could normalize these differences may help to prevent disorder onset

Impaired social learning predicts reduced real-life motivation in individuals with depression: a computational fMRI study

Background: Major depressive disorder is associated with altered social functioning and impaired learning, on both the behavioural and the neural level. These deficits are likely related, considering that successful social interactions require learning to predict other people’s emotional responses. Yet, there is little research examining this relation. Methods: Forty-three individuals with high (HD; N=21) and low (LD; N=22) depression scores answered questions regarding their real-life social experiences and performed a social learning task during fMRI scanning. As part of the task, subjects learned associations between name cues and rewarding (happy faces) or aversive (fearful faces) social outcomes. Using computational modelling, behavioural and neural correlates of social learning were examined and related to real-life social experiences. Results: HD participants reported reduced motivation to engage in real-life social activities and demonstrated elevated uncertainty about social outcomes in the task. Moreover, HD subjects displayed altered encoding of social reward predictions in the insula, temporal lobe and parietal lobe. Interestingly, across all subjects, higher task uncertainty and reduced parietal prediction encoding were associated with decreased motivation to engage in real-life social activities. Limitations: The size of the included sample was relatively small. The results should thus be regarded as preliminary and replications in larger samples are called for. Conclusion: Taken together, our findings suggest that reduced learning from social outcomes may impair depressed individuals’ ability to predict other people’s responses in real life, which renders social situations uncertain. This uncertainty, in turn, may contribute to reduced social engagement (motivation) in depression