An Integrated Immuno-Reward Model of Adolescent Depression: Theory, Evidence, and Implications

Reward Responsiveness and Ruminative Styles Interact to Predict Inflammation and Mood Symptomatology

Altered reward responsiveness and depressive symptoms: An examination of social and monetary reward domains and interactions with rejection sensitivity

Reward and Immune Systems in Emotion (RISE) prospective longitudinal study: Protocol overview of an integrative reward-inflammation model of first onset of major depression in adolescence

Low reward responsiveness (RR) is associated with poor psychological wellbeing, psychiatric disorder risk, and psychotropic treatment resistance. Functional MRI studies have reported decreased activity within the brain’s reward network in individuals with RR deficits, however the neurochemistry underlying network hypofunction in those with low RR remains unclear. This study employed ultra-high field Glutamate Chemical Exchange Saturation Transfer (GluCEST) imaging to investigate the hypothesis that glutamatergic deficits within the reward network contribute to low RR. GluCEST images were acquired at 7.0T from 45 participants (ages 15–29, 30 females) including 15 healthy individuals, 11 with depression, and 19 with psychosis spectrum symptoms. The GluCEST contrast, a measure sensitive to local glutamate concentration, was quantified in a meta-analytically defined reward network comprised of cortical, subcortical, and brainstem regions. Associations between brain GluCEST contrast and Behavioral Activation System Scale RR scores were assessed using multiple linear regressions. Analyses revealed that reward network GluCEST contrast was positively and selectively associated with RR, but not other clinical features. Follow-up analyses identified that this association was driven by the subcortical reward network and network areas that encode the salience of valenced stimuli. We observed no association between RR and the GluCEST contrast within non-reward cortex. This study thus provides new evidence that reward network glutamate levels contribute to individual differences in RR. Decreased reward network excitatory neurotransmission or metabolism may be mechanisms driving reward network hypofunction and RR deficits. These findings provide a framework for understanding the efficacy of glutamate-modulating psychotropics such as ketamine for treating anhedonia.

Deficits in sustaining reward responses in subsyndromal and syndromal major depression

Neighborhood-level disadvantage during childhood is a determinant of health that is hypothesized to confer risk for psychopathology via alterations in neuro-affective processing, including reward responsiveness. However, little research has examined the impact of socioeconomic disadvantage assessed at the community-level on reward processing, which may have important implications for targeted dissemination efforts. Furthermore, not all youth exposed to neighborhood disadvantage may exhibit alterations in reward reactivity, highlighting the need to consider factors that may exacerbate risk for blunted reward reactivity. The current study examined associations between geocoded indices of neighborhood disadvantage and electrocortical reward responsivity in youth and tested whether findings were moderated by maternal history of depression. The sample included 137 youth recruited for studies on the intergenerational transmission of depression. Neighborhood disadvantage was assessed using the Area Deprivation Index (ADI) while the reward positivity (RewP), an event-related potential, indexed reward response. Results revealed a significant interaction between ADI and maternal history of depression on youth RewP, such that greater neighborhood disadvantage was significantly associated with lower reward responsiveness, but only for youth with a maternal history of depression. Results were maintained controlling for youth internalizing symptoms and individual-level socioeconomic factors. Findings suggest that neighborhood disadvantage may impact youth neural reward processing, at least partially independently of individual risk factors, for youth with a maternal history of depression. If replicated, results suggest intervention efforts may be implemented at the community level to enhance reward responsiveness, specifically for youth living in low-resourced neighborhoods with a maternal history of depression.

To investigate the effects of (a) nicotine abstinence and (b) cigarette smoking after abstinence, on reward responsiveness and cognitive functions which are putatively dependent on activity in the dopaminergic system implicated in smoking. During Ramadhan, Muslim smokers elected to abstain from smoking either for the whole month (RAMQUIT) or during daylight hours (DAYQUIT). These groups, and non-smokers (NOSMOKE), were assessed on two occasions 6 hours apart (TEST1 and TEST2). DAYQUIT participants had abstained for 6 hours at TEST1 and smoked a single cigarette immediately prior to TEST2. RAMQUIT participants had abstained for at least 10 days prior to TEST1 and remained abstinent at TEST2. NOSMOKE and RAMQUIT participants are a small snack prior to TEST2 to control for non-specific consummatory effects. TEST1 was conducted at the mosque and TEST2 in participants' homes. All were male; mean age was 26.7 years. Modal cigarette consumption prior to Ramadhan by both the 13 DAYQUIT and the 11 RAMQUIT smokers was 21-30 per day. DAYQUIT subjects rated themselves as more dependent. The Card Arranging Reward Responsivity Objective Test (CARROT), testing behavioural responsiveness to small financial incentive; digit span, measuring attention; verbal fluency, indexing frontal lobe function; and the two-choice guessing test (2CGT; at TEST1 only), measuring response stereotypy. At TEST1, compared with non-smokers, both smoking groups showed greater stereotypy (2CG) and lower reward responsiveness (CARROT). DAYQUIT participants improved on all measures after smoking a single cigarette. No marked changes were seen in the other groups. These data suggest that (i) abstaining smokers have impaired dopaminergic function and (ii) nicotine consumption may boost their dopaminergic activity.

Self-injurious thoughts and behaviors and alterations in positive valence systems: A systematic review of the literature

Beyond symptom severity: The differential impact of distress tolerance and reward responsiveness on quality of life in depressed and non-depressed individuals

Depression is a prevalent, heterogeneous, and debilitating disorder that often emerges in adolescence, and there is a need to better understand vulnerability processes to inform more targeted intervention efforts. Psychophysiological methods, like event-related potentials (ERPs), can offer unique insights into the cognitive and emotional processes underlying depression vulnerability. I review my and others' research examining ERP measures of reward responsiveness in youth depression and present a conceptual model of the development of low reward responsiveness, its role in depression vulnerability, and potential windows for targeted intervention. There is evidence that ablunted reward positivity (RewP) is observable in children at risk for depression, appears to be shaped in part by early social experiences, and predicts later depressive symptoms in combination with other risk factors like stress exposure. Further, a component consistent with RewP is reliably elicited in response to social acceptance feedback in computerized peer interaction tasks and demonstrates unique associations with social contextual factors and depressive symptoms, supporting the utility of developing psychophysiological tasks that may better capture youths' real-world experiences and social risk processes. In addition, I address the translational implications of clinical psychophysiological research and describe a series of studies showing that a reduced RewP predicts greater reductions in depressive symptoms with treatment but is not modifiable by current treatments like cognitive behavioral therapy. Finally, I describe our preliminary efforts to develop a positive emotion-focused intervention for the offspring of depressed mothers, informed by the RewP literature, and describe future directions for translating psychophysiological research to intervention and prevention.

Contrasting neuroendocrine responses in depression and chronic fatigue syndrome

Contrasting neuroendocrine responses in depression and chronic fatigue syndrome

Increased rates of depression beginning in adolescence are thought to be attributed in part to marked developmental changes in reward systems and interpersonal relationships. Blunted reward response has been observed in depression and this may be shaped in part by social experiences, raising questions about the combined associations of parental conflict, depression, and reward response in both social and monetary domains. The present study used the reward positivity (RewP), an event-related potential that indexes both monetary and social reward processing, to examine the unique and combined associations of parental conflict and depressive symptoms on reward responsiveness in adolescents with clinical depression (N = 70) 14-18 years of age (M = 15.81, SD = 1.46; 65.7% female). Results indicated that depressive symptoms interacted with maternal conflict in characterizing the RewP to social, but not monetary, rewards. Specifically, higher levels of current depressive symptoms and potentiated maternal conflict together were associated with an attenuated RewP to social rewards in this clinical sample. We found no significant effects of paternal conflict. This investigation highlights maternal conflict as an important environmental factor for reward responsiveness and also emphasizes the utility of examining social reward responsiveness in depression in order to better understand the impacts of contextual factors.

Objective:Depression is common in persons with MS (PwMS), substantially contributing to morbidity and mortality. Depression can dually impact PwMS as both a psychosocial reaction to living with the disease and a neurological effect of it. Cardinal features of depression include reduced ability to seek and experience pleasure, often attributed to dysregulation of the brain's reward system. People with depression exhibit atypical reward processing, as do fatigued PwMS. However, it is unclear whether MS itself affects reward processing, and whether it interacts with depression. The current study explored the associations of depression, MS, and their interaction on reward responsiveness. We hypothesized that depression and MS would independently be associated with poorer reward responsiveness and that they would interact synergistically to impair reward responsiveness.Participants and Methods:Forty PwMS and 40 healthy age- and education-matched healthy controls (HC) participated in a computerized switching task with high- and low-reward manipulations. The Chicago Multiscale Depression Inventory (CMDI) Mood subscale measured depressive symptoms. The Behavioral Inhibition/Activation Scales (BIS/BAS) measured self-reported reward responsiveness and behavioral inhibition. Switching task performance was measured as response time (RT) and accuracy. Performance differences between the high- and low-reward conditions represented performance-based reward responsiveness. Linear mixed effects models were used to estimate the associations of MS and depression with reward responsiveness, behavioral inhibition, and task performance.Results:Depression, but not MS, was associated with higher BIS scores (p=.007). Neither depression nor MS was associated with BAS subscales. On the switching task, participants who reported lower depression responded to reward such that they were slightly faster in the high-reward condition compared to the low-reward condition (p=.07). By contrast, in participants who reported higher depression, there was no effect of reward on response time. Additionally, MS (p=.009) and depression (p=.018) were each associated with slower response times. Regarding accuracy, no effects of reward were observed; however, there was an interaction between MS and depression. Among HC participants, depression was not related to accuracy. In comparison, PwMS who reported higher depression were more accurate than PwMS who reported less depression (p=.043).Conclusions:Consistent with hypotheses, higher depressive symptoms were associated with increased behavioral inhibition. Depression was not associated with self-reported reward responsiveness, but it was associated with reduced reward responsiveness on a cognitive task. Contrary to hypotheses, MS was not associated with reduced reward responsiveness. Additionally, higher depression and an MS diagnosis were related to slower response time, consistent with prior findings that psychomotor slowing is a hallmark feature of both disorders. Interestingly, we observed a unique behavioral trend in PwMS, such that PwMS with higher depressive symptoms were more accurate than PwMS with lower depressive symptoms, whereas this relationship was not present among HCs. Altogether, depression in both PwMS and cognitively healthy individuals may be associated with blunted reward responsiveness, but MS does not exacerbate this relationship. In fact, PwMS with depression may be more conscientious in their functioning and therefore perform better on cognitive task accuracy. Continued work should examine how reward processing and its underlying mechanisms may differ in depressed PwMS.

Neurodegenerative diseases (NDs) represent a growing public health challenge worldwide. While their clinical manifestations typically emerge late in life, increasing evidence suggests that biological vulnerability may originate much earlier in life. Early childhood adversity, expressed through mechanisms of toxic stress and allostatic load, has been associated with chronic activation of the hypothalamic–pituitary–adrenal axis, mitochondrial dysfunction, oxidative stress, and persistent inflammation—molecular pathways that overlap with those implicated in neurodegeneration. This narrative review highlights recent advances linking early adversity with long-term brain health. It discusses stress-related biomarkers, such as hair cortisol, inflammatory cytokines, and epigenetic modifications, as potential early indicators of neurodegenerative risk. Remarkably, protective and benevolent childhood experiences may mitigate these biological trajectories, underscoring the role of resilience in shaping neurobiological outcomes. We argue that integrating pediatric cohorts, particularly in underrepresented regions such as Latin America, with longitudinal biomarker approaches and omics technologies offers a unique opportunity to identify early predictors and preventive strategies. Understanding neurodegeneration as a lifespan process opens new avenues for early intervention and public health policy.