Improving dietary patterns in obese mice: Effects on body weight, adiposity, anhedonia-like behavior, pro-BDNF expression and 5-HT system.

INTRODUCTION: The excessive fat accumulation in obesity, resulting from an unbalanced diet, can lead to metabolic and neurological disorders and increase the risk of developing anxiety and depression. AIM: Assess the impact of dietary intervention (DI) on the serotonergic system, brain-derived neurotrophic factor (BDNF) expression and behaviors of obese mice. METHODS: Male C57BL/6 mice, 5 weeks old, received a high-fat diet (HFD) for 10 weeks for the induction of obesity. After this period, for 8 weeks, half of these animals received a control diet (CD), group obese (OB) + control diet (OB + CD, n = 10), and another half continued being fed HFD, group obese + HFD (OB + HFD, n = 10). At the end of the eighth week of intervention, behavioral tests were performed (sucrose preference test, open field, novel object recognition, elevated plus maze and tail suspension). Body weight and food intake were assessed weekly. Visceral adiposity, the hippocampal and hypothalamic protein expression of BDNF, 5-HT1A (5-HT1A serotonin receptor) and TPH2 (key enzyme in serotonin synthesis), were evaluated after euthanasia. RESULTS: The dietary intervention involved changing from a HFD to a CD over an 8-week period, effectively reduced body weight gain, adiposity, and anhedonia-like behavior. In the OB + HFD group, we saw a lower sucrose preference and shorter traveled distance in the open field, along with increased pro-BDNF expression in the hypothalamus compared to the OB + CD mice. However, the levels of TPH2 and 5-HT1A remained unchanged. CONCLUSION: The HFD model induced both obesity and anhedonia, but the dietary intervention successfully improved these conditions.

Comparison between sub-chronic and chronic sleep deprivation-induced behavioral and neuroimmunological abnormalities in mice: Focusing on glial cell phenotype polarization.

BACKGROUND: Sleep disorders, depression, and Alzheimer's disease (AD) are extensively reported as comorbidity. Although neuroinflammation triggered by microglial phenotype M1 activation, leading to neurotransmitter dysfunction and Aß aggregation, is considered as the leading cause of depression and AD, whether and how sub-chronic or chronic sleep deprivation (SD) contribute to the onset and development of these diseases remains unclear. METHODS: Memory and depression-like behaviors were evaluated in both SDs, and then circadian markers, glial cell phenotype polarization, cytokines, depression-related neurotransmitters, and AD-related gene/protein expressions were measured by qRT-PCR, enzyme-linked immunosorbent assay, high-performance liquid chromatography, and western-blotting respectively. RESULTS: Both SDs induced give-up behavior and anhedonia and increased circadian marker period circadian regulator 2 (PER2) expression, which were much worse in chronic than in the sub-chronic SD group, while brain and muscle ARNT-like protein-1 only decreased in the chronic-SD. Furthermore, increased microglial M1 and astrocyte A1 expression and proinflammatory cytokines, interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α was observed in both SDs, which were more significant in chronic SD. Similarly, decreased norepinephrine and 5-hydroxytryptamine/5-hydroxyindoleacetic acid ratio were more significant, which corresponds to the worse depression-like behavior in chronic than sub-chronic-SD. With regard to AD, increased amyloid precursor protein (APP) and soluble (s)-APPß and decreased sAPPα in both SDs were more significant in the chronic. However, sAPPα/sAPPß ratio was only decreased in chronic SD. CONCLUSION: These findings suggest that both SDs induce depression-like changes by increasing PER2, leading to neuroinflammation and neurotransmitter dysfunction. However, only chronic SD induced memory impairment likely due to severer circadian disruption, higher neuroinflammation, and dysregulation of APP metabolism.

The role of KCNQ channel activators in management of major depressive disorder.

Depression, a complex disorder with significant treatment challenges, necessitates innovative therapeutic approaches to address its multifaceted nature and enhance treatment outcomes. The modulation of KCNQ potassium (K+) channels, pivotal regulators of neuronal excitability and neurotransmitter release, is a promising innovative therapeutic target in psychiatry. Widely expressed across various tissues, including the nervous and cardiovascular systems, KCNQ channels play a crucial role in modulating membrane potential and regulating neuronal activity. Recent preclinical evidence suggests that KCNQ channels, particularly KCNQ3, contribute to the regulation of neuronal excitability within the reward circuitry, offering a potential target for alleviating depressive symptoms, notably anhedonia. Studies using animal models demonstrate that interventions targeting KCNQ channels can restore dopaminergic firing balance and mitigate depressive symptoms. Human studies investigating the effects of KCNQ channel activators, such as ezogabine, have shown promising results in alleviating depressive symptoms and anhedonia. The aforementioned observations underscore the therapeutic potential of KCNQ channel modulation in depression management and highlight the need and justification for phase 2 and phase 3 dose-finding studies as well as studies prespecifying symptomatic targets in depression including anhedonia.

Understanding the role of early life stress and schizophrenia on anxiety and depressive like outcomes: An experimental study.

BACKGROUND: Adverse experiences due to early life stress (ELS) or parental psychopathology such as schizophrenia (SZ) have a significant implication on individual susceptibility to psychiatric disorders in the future. However, it is not fully understood how ELS affects social-associated behaviors as well as the developing prefrontal cortex (PFC). OBJECTIVE: The aim of this study was to investigate the impact of ELS and ketamine induced schizophrenia like symptoms (KSZ) on anhedonia, social behavior and anxiety-like behavior. METHODS: Male and female Sprague-Dawley rat pups were allocated randomly into eight experimental groups, namely control, gestational stress (GS), GS+KSZ, maternal separation (MS), MS+KSZ pups, KSZ parents, KSZ parents and Pups and KSZ pups only. ELS was induced by subjecting the pups to GS and MS, while schizophrenia like symptoms was induced through subcutaneous administration of ketamine. Behavioral assessment included sucrose preference test (SPT) and elevated plus maze (EPM), followed by dopamine testing and analysis of astrocyte density. Statistical analysis involved ANOVA and post hoc Tukey tests, revealing significant group differences and yielding insights into behavioral and neurodevelopmental impacts. RESULTS: GS, MS, and KSZ (dams) significantly reduced hedonic response and increased anxiety-like responses (p < 0.05). Notably, the presence of normal parental mental health demonstrated a reversal of the observed decline in Glial Fibrillary Acidic Protein-positive astrocytes (GFAP+ astrocytes) (p < 0.05) and a reduction in anxiety levels, implying its potential protective influence on depressive-like symptoms and PFC astrocyte functionality. CONCLUSION: The present study provides empirical evidence supporting the hypothesis that exposure to ELS and KSZ on dams have a significant impact on the on development of anxiety and depressive like symptoms in Sprague Dawley rats, while positive parenting has a reversal effect.

Association of anhedonia with brain-derived neurotrophic factor and interleukin-10 in major depressive disorder.

BACKGROUND: Anhedonia, a core symptom of major depressive disorder (MDD), manifests in two forms: anticipatory and consummatory, reflecting a diminished capacity to anticipate or enjoy pleasurable activities. Prior studies suggest that brain-derived neurotrophic factor (BDNF) and interleukin-10 (IL-10) may play key roles in the emergence of anhedonia in MDD. The specific relationships between these biomarkers and the two forms of anhedonia remain unclear. This study investigated the potential links between BDNF, IL-10, and both forms of anhedonia in MDD patients. METHODS: This study included 43 participants diagnosed with MDD and 58 healthy controls. It involved detailed assessments of depression and anxiety levels, anticipatory and consummatory pleasure, cognitive functions, and a broad spectrum of plasma biomarkers, such as C-reactive protein, various interleukins, and BDNF. Using partial correlation, variables related to pleasant experiences were identified. Stepwise multiple linear regression analysis was applied to pinpoint the independent predictors of anhedonia in the MDD group. RESULTS: Demographically, both groups were comparable in terms of age, sex, body mass index, educational year, and marital status. Individuals with MDD displayed markedly reduced levels of anticipatory and consummatory pleasure, higher anxiety, and depression scores compared to healthy controls. Additionally, cognitive performance was notably poorer in the MDD group. These patients also had lower plasma diamine oxidase levels. Analysis linked anhedonia to impaired delayed memory. Regression results identified IL-10 and BDNF as independent predictors of anticipatory and consummatory anhedonia, respectively. CONCLUSION: These findings demonstrate that anticipatory and consummatory anhedonia are influenced by independent factors, thereby providing critical insights into the distinct neuroimmunological mechanisms that underlie various forms of anhedonia. Clinicl Trial Registration Number: NCT03790085.

Aberrant effort-based reward dynamics in anhedonia.

Anhedonia is a transdiagnostic symptom and associated with a spectrum of reward deficits among which the motivational dysfunction is poorly understood. Previous studies have established the abnormal cost-benefit trade-off as a contributor to motivational deficits in anhedonia and its relevant psychiatric diseases. However, it remains elusive how the anhedonic neural dynamics underlying reward processing are modulated by effort expenditure. Using an effort-based monetary incentive delay task, the current event-related potential study examined the neural dynamics underlying the effort-reward interplay in anhedonia using a nonclinical sample who scored high or low on an anhedonia questionnaire. We found that effort prospectively decreased reward effect on the contingent variation negativity and the target-P3 but retrospectively enhanced outcome effect on the feedback-P3 following effort expenditure. Compared to the low-anhedonia group, the high-anhedonia group displayed a diminished effort effect on the target-P3 during effort expenditure and an increased effort-enhancement effect for neutral trials during the feedback-P3 period following effort expenditure. Our findings suggest that anhedonia is associated with an inefficient control and motivation allocation along the efforted-based reward dynamics from effort preparation to effort production.

Anhedonia reflects an encoding deficit for pleasant stimuli in schizophrenia: Evidence from the emotion-induced memory trade-off eye-tracking paradigm.

OBJECTIVE: The present study explored the hypothesis that anhedonia reflects an emotional memory impairment for pleasant stimuli, rather than diminished hedonic capacity in individuals with schizophrenia (SZ). METHOD: Participants included 30 SZ and 30 healthy controls (HCs) subjects who completed an eye-tracking emotion-induced memory trade-off task where contextually relevant pleasant, unpleasant, or neutral items were inserted into the foreground of neutral background scenes. Passive viewing and poststimulus elaboration blocks were administered to assess differential encoding mechanisms, and immediate and 1-week recognition testing phases were completed to assess the effects of delay interval. Participants also made self-reports of positive emotion, negative emotion, and arousal in response to the stimuli. RESULTS: Results indicated that SZ experienced stimuli similarly to HC. Both groups demonstrated the typical emotion-induced memory trade-off during the passive viewing and poststimulus elaboration encoding blocks, as indicated by more hits for emotional than neutral items and fewer hits for backgrounds paired with emotional than neutral items. Eye-tracking data also indicated that both groups were more likely to fixate earlier and have longer dwell time on emotional than neutral items. At the 1-week delay, the emotion-induced memory trade-off was eliminated in both groups, and SZ showed fewer overall hits across valence conditions. Greater severity of anhedonia was specifically associated with impaired recognition for pleasant stimuli at the immediate recognition phase. CONCLUSIONS: Findings suggest that anhedonia in SZ is associated with emotional memory impairment, particularly a deficit in encoding positive stimuli. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Effects of anhedonia on health-related quality of life and functional outcomes in major depressive disorder: A systematic review and meta-analysis.

BACKGROUND: Major depressive disorder (MDD) is a heterogeneous group of mood disorders. A prominent symptom domain is anhedonia narrowly defined as a loss of interest and ability to experience pleasure. Anhedonia is associated with depressive symptom severity, MDD prognosis, and suicidality. We perform a systematic review and meta-analysis of extant literature investigating the effects of anhedonia on health-related quality of life (HRQoL) and functional outcomes in persons with MDD. METHODS: A literature search was conducted on PubMed, OVID databases, and SCOPUS for published articles from inception to November 2023, reporting on anhedonia and patient-reported outcomes in persons with MDD. The reported correlation coefficients between anhedonia and self-reported measures of both HRQoL and functional outcomes were pooled using a random effects model. RESULTS: We identified 20 studies that investigated anhedonia with HRQoL and/or functional outcomes in MDD. Anhedonia as measured by the Snaith-Hamilton Pleasure Scale (SHAPS) scores had a statistically significant correlation with patient-reported HRQoL (r = -0.41 [95 % CI = -0.60, -0.18]) and functional impairment (r = 0.39 [95 % CI = 0.22, 0.54]). LIMITATIONS: These preliminary results primarily investigate correlations with consummatory anhedonia and do not distinguish differences in anticipatory anhedonia, reward valuation or reward learning; therefore, these results require replication. CONCLUSIONS: Persons with MDD experiencing symptoms of anhedonia are more likely to have worse prognosis including physical, psychological, and social functioning deficits. Anhedonia serves as an important predictor and target for future therapeutic and preventative tools in persons with MDD.

Chronic defeat stress induces monoamine level dysregulation in the prefrontal cortex but not in the hippocampus of OF1 male mice.

Chronic social stress can increase susceptibility to chronic diseases such as depression. One of the most used models to study the physiological mechanisms and behavioral outcomes of this type of stress is chronic defeat stress (CDS) in male mice. OF1 male mice were subjected to a stress period lasting 18 days. During that time, non-stressed animals were housed in groups. The cluster analysis of the behavioral profile displayed during the first social interaction divided subjects into two groups: active/aggressive (AA) and passive/reactive (PR). The day after the end of the stress period, the following behavioral analyses were performed: the sucrose preference test (SPT) on day 19, the open field test (OFT) on day 20, and the forced swim test (FST) on day 21. Immediately after completing the last test, animals were weighed, and blood samples were obtained. Then, they were sacrificed, and their prefrontal cortices and hippocampi were removed and stored to analyze monoamine levels. Stressed animals displayed anhedonia, and solely the PR mice continued to show higher levels of immobility in the OFT and FST. All stressed animals, regardless of the coping strategy, presented higher plasma corticosterone levels. In addition, stressed mice showed lower levels of tyrosine, dopamine, DOPAC, MHPG, kynurenine, kynurenic acid, and 5-HIAA levels but higher serotonin levels in the prefrontal cortex, not in the hippocampus. In conclusion, our results show that CSD induces differences in monoamine levels between brain areas, and these differences did not respond to the coping strategy adopted.

Predictive coding in musical anhedonia: A study of groove.

Groove, or the pleasurable urge to move to music, offers unique insight into the relationship between emotion and action. The predictive coding of music model posits that groove is linked to predictions of music formed over time, with stimuli of moderate complexity rated as most pleasurable and likely to engender movement. At the same time, listeners vary in the pleasure they derive from music listening: individuals with musical anhedonia report reduced pleasure during music listening despite no impairments in music perception and no general anhedonia. Little is known about musical anhedonics' subjective experience of groove. Here we examined the relationship between groove and music reward sensitivity. Participants (n = 287) heard drum-breaks that varied in perceived complexity, and rated each for pleasure and wanting to move. Musical anhedonics (n = 13) had significantly lower ratings compared to controls (n = 13) matched on music perception abilities and general anhedonia. However, both groups demonstrated the classic inverted-U relationship between ratings of pleasure & move and stimulus complexity, with ratings peaking for intermediately complex stimuli. Across our entire sample, pleasure ratings were most strongly related with music reward sensitivity for highly complex stimuli (i.e., there was an interaction between music reward sensitivity and stimulus complexity). Finally, the sensorimotor subscale of music reward was uniquely associated with move, but not pleasure, ratings above and beyond the five other dimensions of musical reward. Results highlight the multidimensional nature of reward sensitivity and suggest that pleasure and wanting to move are driven by overlapping but separable mechanisms.

Dopaminergic dysfunction in the left putamen of patients with major depressive disorder.

INTRODUCTION: Dopaminergic transmission impairment has been identified as one of the main neurobiological correlates of both depression and clinical symptoms commonly associated with its spectrum such as anhedonia and psychomotor retardation. OBJECTIVES: We examined the relationship between dopaminergic deficit in the striatum, as measured by 123I-FP-CIT SPECT imaging, and specific psychopathological dimensions in patients with major depressive disorder. METHODS: To our knowledge this is the first study with a sample of >120 subjects. After check for inclusion and exclusion criteria, 121 (67 females, 54 males) patients were chosen retrospectively from an extensive 1106 patients database of 123I-FP-CIT SPECT scans obtained at the Nuclear Medicine Unit of Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome. These individuals had undergone striatal dopamine transporter (DAT) assessments based on the recommendation of their referring clinicians, who were either neurologists or psychiatrists. At the time of SPECT imaging, each participant underwent psychiatric and psychometric evaluations. We used the following psychometric scales: Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Snaith Hamilton Pleasure Scale, and Depression Retardation Rating Scale. RESULTS: We found a negative correlation between levels of depression (p = 0.007), anxiety (p = 0.035), anhedonia (p = 0.028) and psychomotor retardation (p = 0.014) and DAT availability in the left putamen. We further stratified the sample and found that DAT availability in the left putamen was lower in seriously depressed patients (p = 0.027) and in patients with significant psychomotor retardation (p = 0.048). CONCLUSION: To our knowledge this is the first study to have such a high number of sample. Our study reveals a pivotal role of dopaminergic dysfunction in patients with major depressive disorder. Elevated levels of depression, anxiety, anhedonia, and psychomotor retardation appear to be associated with reduced DAT availability specifically in the left putamen.

How are irritability and anhedonia symptoms linked? A network approach.

BACKGROUND: Anhedonia and irritability are two prevalent symptoms of major depressive disorder (MDD) that predict greater depression severity and poor outcomes, including suicidality. Although both symptoms have been proposed to result from paradoxical reward processing dysfunctions, the interactions between these symptoms remain unclear. Anhedonia is a multifaceted symptom reflecting impairments in multiple dimensions of reward processing (e.g., pleasure, desire, motivation, and effort) across distinct reward types (e.g., food, sensory experiences, social activities, hobbies) that may differentially interact with irritability. This study investigated the complex associations between anhedonia and irritability using network analysis. METHOD: Participants (N = 448, Mage = 33.29, SD = 14.58) reported their symptoms of irritability on the Brief Irritability Test (Holtzman et al., 2015) and anhedonia (i.e., pleasure, desire, motivation, and effort dimensions across four reward types) on the Dimensional Anhedonia Rating Scale (Rizvi et al., 2015). A regularized Gaussian Graphical Model was built to estimate the network structure between items. RESULTS: Irritability was negatively related to willingness to expand effort to obtain food/drinks (estimate = -0.18), social activities (-0.13), and hobbies (-0.12) rewards. Irritability was positively associated with a desire for food/drinks (0.12). LIMITATIONS: Only a small proportion (5.8%) of our sample was clinical and the study design was cross-sectional. CONCLUSION: A specific link between irritability and the effort dimension of the hedonic response across three reward types was identified. Investigating effort expenditure deficits with experimental paradigms may help us understand the mechanisms underlying the comorbidity between irritability and anhedonia in the context of MDD.

Brain-based graph-theoretical predictive modeling to map the trajectory of anhedonia, impulsivity, and hypomania from the human functional connectome.

Clinical assessments often fail to discriminate between unipolar and bipolar depression and identify individuals who will develop future (hypo)manic episodes. To address this challenge, we developed a brain-based graph-theoretical predictive model (GPM) to prospectively map symptoms of anhedonia, impulsivity, and (hypo)mania. Individuals seeking treatment for mood disorders (n = 80) underwent an fMRI scan, including (i) resting-state and (ii) a reinforcement-learning (RL) task. Symptoms were assessed at baseline as well as at 3- and 6-month follow-ups. A whole-brain functional connectome was computed for each fMRI task, and the GPM was applied for symptom prediction using cross-validation. Prediction performance was evaluated by comparing the GPM to a corresponding null model. In addition, the GPM was compared to the connectome-based predictive modeling (CPM). Cross-sectionally, the GPM predicted anhedonia from the global efficiency (a graph theory metric that quantifies information transfer across the connectome) during the RL task, and impulsivity from the centrality (a metric that captures the importance of a region) of the left anterior cingulate cortex during resting-state. At 6-month follow-up, the GPM predicted (hypo)manic symptoms from the local efficiency of the left nucleus accumbens during the RL task and anhedonia from the centrality of the left caudate during resting-state. Notably, the GPM outperformed the CPM, and GPM derived from individuals with unipolar disorders predicted anhedonia and impulsivity symptoms for individuals with bipolar disorders. Importantly, the generalizability of cross-sectional models was demonstrated in an external validation sample. Taken together, across DSM mood diagnoses, efficiency and centrality of the reward circuit predicted symptoms of anhedonia, impulsivity, and (hypo)mania, cross-sectionally and prospectively. The GPM is an innovative modeling approach that may ultimately inform clinical prediction at the individual level.

Sleep deprivation induces late deleterious effects in a pharmacological model of Parkinsonism.

Parkinson's disease is a degenerative, chronic and progressive disease, characterized by motor dysfunctions. Patients also exhibit non-motor symptoms, such as affective and sleep disorders. Sleep disorders can potentiate clinical and neuropathological features and lead to worse prognosis. The goal of this study was to evaluate the effects of sleep deprivation (SD) in mice submitted to a progressive pharmacological model of Parkinsonism (chronic administration with a low dose of reserpine). Male Swiss mice received 20 injections of reserpine (0.1 mg/kg) or vehicle, on alternate days. SD was applied before or during reserpine treatment and was performed by gentle handling for 6 h per day for 10 consecutive days. Animals were submitted to motor and non-motor behavioral assessments and neurochemical evaluations. Locomotion was increased by SD and decreased by reserpine treatment. SD during treatment delayed the onset of catalepsy, but SD prior to treatment potentiated reserpine-induced catalepsy. Thus, although SD induced an apparent beneficial effect on motor parameters, a delayed deleterious effect on alterations induced by reserpine was found. In the object recognition test, both SD and reserpine treatment produced cognitive deficits. In addition, the association between SD and reserpine induced anhedonic-like behavior. Finally, an increase in oxidative stress was found in hippocampus of mice subjected to SD, and tyrosine hydroxylase immunoreactivity was reduced in substantia nigra of reserpine-treated animals. Results point to a possible late effect of SD, aggravating the deficits in mice submitted to the reserpine progressive model of PD.

Anhedonia in bipolar depression treated with ketamine.

BACKGROUND: Bipolar depression is the major cause of morbidity in patients with bipolar disorder. It affects psychosocial functioning and markedly impairs occupational productivity. Anhedonia is one of the most debilitating symptoms of depression contributing to treatment resistance. It correlates with suicidality, low quality of life, social withdrawal, and poor treatment response. Currently, there is no approved treatment specifically targeting anhedonia. Emerging evidence suggests that ketamine possesses anti-anhedonic properties in individuals with depression. OBJECTIVES: The aim of this naturalistic open-label study was to investigate the effect of add-on ketamine treatment on anhedonia in treatment resistant bipolar depression. METHODS: Our main interest was the change in patient-reported (Snaith-Hamilton Pleasure Scale) and rater-based anhedonia measure (Montgomery-Åsberg Depression Rating Scale-anhedonia subscale). The secondary aim was to analyze the score change in three Inventory of Depressive Symptomatology-Self Report (IDS-SR) domains: mood/cognition, anxiety/somatic, and sleep. Patients underwent assessments at several time points, including baseline, after the third, fifth, and seventh ketamine infusions. Additionally, a follow-up assessment was conducted 1 week following the final ketamine administration. RESULTS: We found improvement in anhedonia symptoms according to both patient-reported and rater-based measures. The improvement in IDS-SR domains was most prominent in anxiety/somatic factor and mood/cognition factor, improvement in sleep factor was not observed. No serious adverse events occurred. CONCLUSION: Add-on ketamine seems to be a good choice for the treatment of anhedonia in treatment resistant bipolar depression. It also showed a good effect in reducing symptoms of anxiety in this group of patients. Considering unmet needs and the detrimental effect of anhedonia and anxiety, more studies are needed on ketamine treatment in resistant bipolar depression.

Individualized Functional Brain System Topologies and Major Depression: Relationships Among Patch Sizes and Clinical Profiles and Behavior.

BACKGROUND: Neuroimaging studies of major depression have typically been conducted using group-level approaches. However, given interindividual differences in brain systems, there is a need for individualized approaches to brain systems mapping and putative links toward diagnosis, symptoms, and behavior. METHODS: We used an iterative parcellation approach to map individualized brain systems in 328 participants from a multisite, placebo-controlled clinical trial. We hypothesized that participants with depression would show abnormalities in salience, control, default, and affective systems, which would be associated with higher levels of self-reported anhedonia, anxious arousal, and worse cognitive performance. Within hypothesized brain systems, we compared patch sizes (number of vertices) between depressed and healthy control groups. Within depressed groups, abnormal patches were correlated with hypothesized clinical and behavioral measures. RESULTS: Significant group differences emerged in hypothesized patches of 1) the lateral salience system (parietal operculum; t326 = -3.11, p = .002) and 2) the control system (left medial posterior prefrontal cortex region; z = -3.63, p < .001), with significantly smaller patches in these regions in participants with depression than in healthy control participants. Results suggest that participants with depression with significantly smaller patch sizes in the lateral salience system and control system regions experience greater anxious arousal and cognitive deficits. CONCLUSIONS: The findings imply that neural features mapped at the individual level may relate meaningfully to diagnosis, symptoms, and behavior. There is strong clinical relevance in taking an individualized brain systems approach to mapping neural functional connectivity because these associated region patch sizes may help advance our understanding of neural features linked to psychopathology and foster future patient-specific clinical decision making.

The computational structure of consummatory anhedonia.

Anhedonia is a reduction in enjoyment, motivation, or interest. It is common across mental health disorders and a harbinger of poor treatment outcomes. The enjoyment aspect, termed 'consummatory anhedonia', in particular poses fundamental questions about how the brain constructs rewards: what processes determine how intensely a reward is experienced? Here, we outline limitations of existing computational conceptualisations of consummatory anhedonia. We then suggest a richer reinforcement learning (RL) account of consummatory anhedonia with a reconceptualisation of subjective hedonic experience in terms of goal progress. This accounts qualitatively for the impact of stress, dysfunctional cognitions, and maladaptive beliefs on hedonic experience. The model also offers new views on the treatments for anhedonia.

Neural sensitivity following stress predicts anhedonia symptoms: a 2-year multi-wave, longitudinal study.

Animal models of depression show that acute stress negatively impacts functioning in neural regions sensitive to reward and punishment, often manifesting as anhedonic behaviors. However, few human studies have probed stress-induced neural activation changes in relation to anhedonia, which is critical for clarifying risk for affective disorders. Participants (N = 85, 12-14 years-old, 53 female), oversampled for risk of depression, were administered clinical assessments and completed an fMRI guessing task during a baseline (no-stress) period to probe neural response to receipt of rewards and losses. After the initial task run of the fMRI guessing task, participants received an acute stressor and then, were re-administered the guessing task. Including baseline, participants provided up to 10 self-report assessments of life stress and symptoms over a 2 year period. Linear mixed-effects models estimated whether change in neural activation (post- vs. pre-acute stressor) moderated the longitudinal associations between life stress and symptoms. Primary analyses indicated that adolescents with stress-related reductions in right ventral striatum response to rewards exhibited stronger longitudinal associations between life stress and anhedonia severity (ß = -0.06, 95%CI[-0.11, -0.02], p = 0.008, pFDR = 0.048). Secondary analyses showed that longitudinal positive associations between life stress and depression severity were moderated by stress-related increases in dorsal striatum response to rewards (left caudate ß = 0.11, 95%CI[0.07,0.17], p < 0.001, pFDR = 0.002; right caudate ß = 0.07, 95%CI[0.02,0.12], p = 0.002, pFDR = 0.003; left putamen ß = 0.09, 95%CI[0.04, 0.14], p < 0.001, pFDR = 0.002; right putamen ß = 0.08, 95%CI[0.03, 0.12], p < 0.001, pFDR = 0.002). Additionally, longitudinal positive associations among life stress and anxiety severity were moderated by stress-related reductions in dorsal anterior cingulate cortex (ß = -0.07, 95%CI[-0.12,.02], p = 0.008, pFDR = 0.012) and right anterior insula (ß = -0.07, 95%CI[-0.12,-0.02], p = 0.002, pFDR = 0.006) response to loss. All results held when adjusting for comorbid symptoms. Results show convergence with animal models, highlighting mechanisms that may facilitate stress-induced anhedonia as well as a separable pathway for the emergence of depressive and anxiety symptoms.

Is peripartum anhedonia a missing target?

The perinatal period is an extremely delicate phase that can involve a high risk for onset of depressive disorders. The Edinburgh Postnatal Depression Scale (EPDS) is a widely validated instrument for assessing perinatal depressive symptoms, including the dimension of anhedonia. There are studies suggesting that the neural mechanism underlying the occurrence of anhedonia in patients with major depressive disorder (MDD) and bipolar depression (BD) might be distinct. Anhedonia seems to represent a more stable and frequent symptom in women with postpartum bipolar relative to unipolar depressive disorder and is associated with significantly higher depressive symptom severity. Perinatal medicine is an important component of women's health. Treatment of anhedonia can be challenging, and the most effective treatment can be a combination of psychotherapy and medication, but the screening of anhedonia in peripartum women can prevent the development of other psychiatric disorders and maladaptive behaviors.

Roles of the medial and lateral orbitofrontal cortex in major depression and its treatment.

We describe evidence for dissociable roles of the medial and lateral orbitofrontal cortex (OFC) in major depressive disorder (MDD) from structure, functional activation, functional connectivity, metabolism, and neurochemical systems. The reward-related medial orbitofrontal cortex has lower connectivity and less reward sensitivity in MDD associated with anhedonia symptoms; and the non-reward related lateral OFC has higher functional connectivity and more sensitivity to non-reward/aversive stimuli in MDD associated with negative bias symptoms. Importantly, we propose that conventional antidepressants act to normalize the hyperactive lateral (but not medial) OFC to reduce negative bias in MDD; while other treatments are needed to operate on the medial OFC to reduce anhedonia, with emerging evidence suggesting that ketamine may act in this way. The orbitofrontal cortex is the key cortical region in emotion and reward, and the current review presents much new evidence about the different ways that the medial and lateral OFC are involved in MDD.