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.

Differential effects of high-fat diet on endocrine, metabolic and depressive-like behaviors in male and female rats.

The complications of obesity extend beyond the periphery to the central nervous system (CNS) and include an increased risk of developing neuropsychiatric co-morbidities like depressive illness. Preclinical studies support this concept, including studies that have examined the effects of a high-fat diet (HFD) on depressive-like behaviors. Although women are approximately two-fold more likely to develop depressive illness compared to men, most preclinical studies have focused on the effects of HFD in male rodents. Accordingly, the goal of this study was to examine depressive-like behaviors in male and female rats provided access to a HFD. In agreement with prior studies, male and female rats provided a HFD segregate into an obesity phenotype (i.e., diet-induced obesity; DIO) or a diet resistant (DR) phenotype. Upon confirmation of the DR and DIO phenotypes, behavioral assays were performed in control chow, DR, and DIO rats. In the sucrose preference test, male DIO rats exhibited significant decreases in sucrose consumption (i.e., anhedonia) compared to male DR and male control rats. In the forced swim test (FST), male DIO rats exhibited increases in immobility and decreases in climbing behaviors in the pre-test sessions. Interestingly, male DR rats exhibited these same changes in both the pre-test and test sessions of the FST, suggesting that consumption of a HFD, even in the absence of the development of an obesity phenotype, has behavioral consequences. Female rats did not exhibit differences in sucrose preference, but female DIO rats exhibited increases in immobility exclusively in the test session of the FST, behavioral changes that were not affected by the stage of the estrous cycle. Collectively, these studies demonstrate that access to a HFD elicits different behavioral outcomes in male and female rats.

Evaluation of New Approaches to Depression Treatment Using an Animal Model of Pharmacoresistant Depression.

Depression is emerging as the predominant psychiatric disorder globally. Despite the wide availability of antidepressants, up to 30% of patients exhibit poor response to treatment, falling into the category of treatment-resistant depression (TRD). This underscores the need for the exploration of novel therapeutic options. Our work aims to study the effect of chronic administration of the pyridoindole derivative SMe1EC2M3, a triple reuptake inhibitor, and the combination of zoletil and venlafaxine under conditions of stress induced by a 4-week chronic mild stress (CMS) procedure in Wistar-Kyoto male rats as an animal model of TRD. Therefore, we investigated the possible effect of the selected compounds in four experimental groups, i.e., stress + vehicle, stress + venlafaxine, stress + zoletil + venlafaxine and stress + SMe1EC2M3. The following variables were assessed: anhedonia in sucrose preference test (SPT), spontaneous locomotion and exploration in open field test (OF), anxiety-like behavior in elevated plus maze test (EPM), motivation and depressive-like behavior in forced swim test (FST) and nociception in tail flick test. We also evaluated cognition, particularly recognition memory, in the novel object recognition test (NOR). Sucrose preference was significantly increased in the SMe1EC2M3 group (p < 0.05) in comparison with the venlafaxine animals. In the OF, we observed a significantly higher number of entries into both the central and peripheral zones in the venlafaxine (p < 0.05 central zone; p ≤ 0.05 periphery zone) and SMe1EC2M3 (p < 0.05 central zone; p < 0.05 periphery zone) groups compared to the venlafaxine + zoletil group. SMe1EC2M3 was able to significantly increase the time of climbing in FST (p < 0.05) in comparison with the venlafaxine and control groups. The NOR test revealed a significantly higher discrimination ratio in the SMe1EC2M3 group (p < 0.05) compared to the control and venlafaxine groups. Analyses of the tail flick test showed a significant increase in reaction time to painful stimuli in the SMe1EC2M3 group (p < 0.05) in comparison to both the control and venlafaxine groups. Our findings suggest that SMe1EC2M3 has the potential to ameliorate some behavioral changes associated with TRD, and the venlafaxine + zoletil combination treatment was not a promising treatment alternative in the animal model of TRD.

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.

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.

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.

Partial mGlu5 receptor NAM, M-5MPEP, induces rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhances (R)-ketamine action in mice.

BACKGROUND: Partial negative allosteric modulators (NAM) of the metabotropic glutamate 5 (mGlu5) receptor are an excellent alternative to full antagonists and NAMs because they retain therapeutic effects and have a much broader therapeutic window. Here, we investigated whether partial mGlu5 NAM, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), induced a fast and sustained antidepressant-like effect, characteristic of rapid-acting antidepressant drugs (RAADs) like ketamine, in mice. METHODS: A tail suspension test (TST) was used to investigate acute antidepressant-like effects. Sustained effects were studied 24 h after the four intraperitoneal (ip) administrations using the splash test, designed to measure apathy-like state, the sucrose preference test (SPT), reflecting anhedonia, and the TST. Western blot and ELISA techniques were used to measure brain-derived neurotrophic factor (BDNF) and selected protein levels. METHODS: A tail suspension test (TST) was used to investigate acute antidepressant-like effects. Sustained effects were studied 24 h after the four intraperitoneal (ip) administrations using the splash test, designed to measure apathy-like state, the sucrose preference test (SPT), reflecting anhedonia, and the TST. Western blot and ELISA techniques were used to measure brain-derived neurotrophic factor (BDNF) and selected protein levels. CONCLUSION: Partial mGlu5 receptor NAM, M-5MPEP, induced rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhanced (R)-ketamine action in mice, indicating both substances' convergent mechanisms of action and the possibility of their practical use in treating depression as RAAD.

Effect of venlafaxine on anhedonia and amotivation in patients with major depressive disorder.

OBJECTIVE: Serotonin norepinephrine reuptake inhibitors (SNRIs) have been postulated to afford benefits in alleviating anhedonia and amotivation. This post hoc pooled analysis evaluated the effect of venlafaxine XR, an SNRI, on these symptoms in patients with major depressive disorder (MDD). METHODS: Data was pooled from five short-term randomized, placebo-controlled studies of venlafaxine XR for the treatment of MDD, comprising 1087 (venlafaxine XR, n = 585; placebo, n = 502) adult subjects. The change from baseline score in the MADRS anhedonia factor (based on items 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]) for anhedonia, and in motivational deficits (based on 3 items of HAM-D17: involvement in work and activities, psychomotor retardation, and energy level [ie, general somatic symptoms]) for amotivation, were measured through 8 weeks. Mixed model repeated measures (MMRMs) were used to analyze changes over time and ANCOVA to analyze the change from baseline at week 8 with LOCF employed to handle missing data. RESULTS: At the end of 8 weeks, the change from baseline was significantly greater in patients on venlafaxine XR in both anhedonia (mean, 95% CI: -2.73 [-3.63, -1.82], p < 0.0001) and amotivation scores (mean, 95% CI: -0.78 [-1.04, -0.52], p < 0.0001) than those on placebo. For both measures, the between-group separation from baseline was statistically significant starting from week 2 onwards, and it increased over time. CONCLUSION: This analysis demonstrates that venlafaxine XR is effective in improving symptoms of anhedonia and motivational deficits in patients with MDD.

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.

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.

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).

Non-invasive vagus nerve stimulation conditions increased invigoration and wanting in depression.

BACKGROUND: Major depressive disorder (MDD) is often marked by impaired motivation and reward processing, known as anhedonia. Many patients do not respond to first-line treatments, and improvements in motivation can be slow, creating an urgent need for rapid interventions. Recently, we demonstrated that transcutaneous auricular vagus nerve stimulation (taVNS) acutely boosts effort invigoration in healthy participants, but its effects on depression remain unclear. OBJECTIVE: To assess the impact of taVNS on effort invigoration and maintenance in a sample that includes patients with MDD, evaluating the generalizability of our findings. METHODS: We used a single-blind, randomized crossover design in 30 patients with MDD and 29 matched (age, sex, and BMI) healthy control participants (HCP). RESULTS: Consistent with prior findings, taVNS increased effort invigoration for rewards in both groups during Session 1 (p = .040), particularly for less wanted rewards in HCP (pboot < 0.001). However, invigoration remained elevated in all participants, and no acute changes were observed in Session 2 (Δinvigoration = 3.3, p = .12). Crucially, throughout Session 1, we found taVNS-induced increases in effort invigoration (pboot = 0.008) and wanting (pboot = 0.010) in patients with MDD, with gains in wanting maintained across sessions (Δwanting = 0.06, p = .97). CONCLUSIONS: Our study replicates the invigorating effects of taVNS in Session 1 and reveals its generalizability to depression. Furthermore, we expand upon previous research by showing taVNS-induced conditioning effects on invigoration and wanting within Session 1 in patients that were largely sustained. While enduring motivational improvements present challenges for crossover designs, they are highly desirable in interventions and warrant further follow-up research.

The involvement of neuroinflammation in an animal model of dementia and depression.

Alzheimer's disease (AD) and depression are inflammatory pathologies, leading to increased inflammatory response and neurotoxicity. Therefore, this study aimed to evaluate the effect of the treatment with fluoxetine and/or galantamine and/or donepezil on the levels of proinflammatory and anti-inflammatory cytokines in a mixed animal model of depression and dementia. Adult male Wistar rats underwent chronic mild stress (CMS) protocol for 40 days and were subjected to stereotaxic surgery for intra-hippocampal administration of amyloid-beta (Aꞵ) peptide or artificial cerebrospinal fluid (ACSF) to mimic the dementia animal model. On the 42nd day, animals were treated with water, galantamine, donepezil, and/or fluoxetine, orally for 17 days. On the 57th and 58th days, the Splash and Y-maze tests for behavior analysis were performed. The frontal cortex and hippocampus were used to analyze the tumor necrosis factor alfa (TNF-α), interleukin 1 beta (IL-1ꞵ), IL-6, and IL-10 levels. The results of this study show that animals subjected to CMS and administration of Aꞵ had anhedonia, cognitive impairment, increased TNF-α and IL-1ꞵ levels in the frontal cortex, and reduced IL-10 levels in the hippocampus. All treatment groups were able to reverse the cognitive impairment. Only donepezil did not decrease the TNF-α levels in the hippocampus. Fluoxetine + galantamine and fluoxetine + donepezil reversed the anhedonia. Fluoxetine reversed the anhedonia and IL-1ꞵ levels in the frontal cortex. In addition, fluoxetine + donepezil reversed the reduction of IL-10 levels in the hippocampus. The results indicate a pathophysiological interaction between AD and depression, and the association of medications in the future may be a possible therapeutic strategy to reduce inflammation, especially the fluoxetine-associated treatments.

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.

Adding to the neuroimmune network model: A commentary on Nusslock et al. (2024).

Work by many groups demonstrate links between peripheral markers of inflammation and symptoms of depression. Here, Nusslock and colleagues present an update to their neuroimmune network model to incorporate a developmental lens. They propose that specific neural circuits may be responsible for causing heightened inflammation. One principal circuit includes the amygdala and prefrontal cortex and is proposed to be involved in threat detection. Thus, heightened threat sensitivity resulting from early life stress is suggested to cause increases in inflammatory signaling. Second, the authors suggest that reward circuits, including the striatum, may be targets of increased inflammation leading to symptoms of anhedonia. In this commentary, I add context to the model proposed by Nusslock et al., suggesting that taking a learning perspective and considering additional circuits, including the hippocampus and midline structures may be necessary to more fully account for the phenomena described by the authors.

Ultrasound Stimulation Attenuates CRS-Induced Depressive Behavior by Modulating Dopamine Release in the Prefrontal Cortex.

Depression is one of the most serious mental disorders affecting modern human life and is often caused by chronic stress. Dopamine system dysfunction is proposed to contribute to the pathophysiology of chronic stress, especially the ventral tegmental area (VTA) which mainly consists of dopaminergic neurons. Focused ultrasound stimulation (FUS) is a promising neuromodulation modality and multiple studies have demonstrated effective ultrasonic activation of cortical, subcortical, and related networks. However, the effects of FUS on the dopamine system and the potential link to chronic stress-induced depressive behaviors are relatively unknown. Here, we measured the effects of FUS targeting VTA on the improvement of depression-like behavior and evaluated the dopamine concentration in the downstream region - medial prefrontal cortex (mPFC). We found that targeting VTA FUS treatment alleviated chronic restraint stress (CRS) -induced anhedonia and despair behavior. Using an in vivo photometry approach, we analyzed the dopamine signal of mPFC and revealed a significant increase following the FUS, positively associated with the improvement of anhedonia behavior. FUS also protected the dopaminergic neurons in VTA from the damage caused by CRS exposure. Thus, these results demonstrated that targeting VTA FUS treatment significantly rescued the depressive-like behavior and declined dopamine level of mPFC induced by CRS. These beneficial effects of FUS might be due to protection in the DA neuron of VTA. Our findings suggest that FUS treatment could serve as a new therapeutic strategy for the treatment of stress-related disorders.

Is it more effective for anhedonia and avolition? A systematic review and meta-analysis of non-invasive brain stimulation interventions for negative symptoms in schizophrenia.

BACKGROUND: Noninvasive brain stimulation (NIBS) techniques are a promising tool for treating the negative symptoms of schizophrenia. Growing evidence suggests that different dimensions of negative symptoms have partly distinct underlying pathophysiological mechanisms. Previous randomized controlled trials (RCTs) have shown inconsistent impacts of NIBS across dimensions. OBJECTIVE: This systematic review and meta-analysis evaluated the effects of NIBS on general negative symptoms, and on specific domains, including blunted affect, alogia, asociality, anhedonia, and avolition. DATA SOURCES: PubMed, Web of Science, Embase, Cochrane CENTRAL, PsycINFO, OpenGrey, and Clinicaltrials.gov from the first date available to October, 2023. RESULTS: Among 1049 studies, we identified eight high-quality RCTs. NIBS significantly affects general negative symptoms (SMD = -0.54, 95% CI [-0.88, -0.21]) and all five domains (SMD = -0.32 to -0.63). Among dimensions, better effects have been shown for improvement of avolition (SMD = -0.47, 95% CI [-0.81, -0.13]) and anhedonia (SMD = -0.63, 95% CI [-0.98, -0.28]). Subgroup analyses of studies that applied once daily stimulation or >10 sessions showed significantly reduced negative symptom severity. CONCLUSION: NIBS exerts distinct effects across multiple dimensions of negative symptom, with treatment effects related to stimulation frequency and total sessions. These results need to be confirmed in dedicated studies.

Understanding the paradox: anhedonia and the unexpected divergence from reward seeking during adolescence - A commentary on Gupta et al. (2024).

Anhedonia is a symptom encompassing reduced or absence of motivation and pleasure that often emerges in adolescence and conveys risk for different mental illnesses and other difficulties. In their review, Gupta, Eckstrand, and Forbes (Journal of Child Psychology and Psychiatry, 2024) present an empirically-based conceptual neurodevelopmental model of anhedonia whereby brain development and pubertal maturation create openness to vulnerability to anhedonia that is influenced by early life adversity and chronic inflammation. This commentary considers anhedonia as a paradox of adolescence given its juxtaposition to the expected developmental milestones of adolescence. It highlights the need to consider anhedonia in terms of both variability and universality of children's experiences and biological development, missed opportunities for social relationships and experiences, and forms and functions of rewards and anhedonia.

Lateral hypothalamus orexinergic projection to the medial prefrontal cortex modulates chronic stress-induced anhedonia but not anxiety and despair.

Chronic stress-induced anxiodepression is a common health problem, however its potential neurocircuitry mechanism remains unclear. We used behavioral, patch-clamp electrophysiology, chemogenetic, and optogenetic approaches to clarify the response of the lateral hypothalamus (LH) and the medial prefrontal cortex (mPFC) to stress, confirmed the structural connections between the LH and mPFC, and investigated the role of the LH-mPFC pathway in chronic stress-induced anxiodepression symptoms. Unpredictable chronic mild stress (UCMS) caused anxiodepression-like behaviors, including anxiety, anhedonia, and despair behaviors. We discovered that the activity of the LH and mPFC was both increased after restraint stress (RS), a stressor of UCMS. Then we found that the orexinergic neurons in the LH predominantly project to the glutamatergic neurons in the mPFC, and the excitability of these neurons were increased after UCMS. In addition, overactivated LH orexinergic terminals in the mPFC induced anhedonia but not anxiety and despair behaviors in naive mice. Moreover, chemogenetically inhibited LH-mPFC orexinergic projection neurons and blocked the orexin receptors in the mPFC alleviated anhedonia but not anxiety and despair behaviors in UCMS-treated mice. Our study identified a new neurocircuit from LH orexinergic neurons to mPFC and revealed its role in regulating anhedonia in response to stress. Overactivation of LHOrx-mPFC pathway selectively mediated chronic stress-induced anhedonia. In normal mice, the LHOrx-mPFC pathway exhibits relatively low activity. However, after chronic stress, the activity of orexinergic neuron in LH is overactivated, leading to an increased release of orexin into the mPFC. This heightened orexin concentration results in increased excitability of the mPFC through OX1R and OX2R, consequently triggering anhedonia.