Developmental changes in neurobiological and psychological systems render adolescence a vulnerable period for the emergence of risk factors associated with psychopathology. Anhedonia (i.e., the reduced ability to anticipate or experience pleasure) is a core characteristic of multiple psychopathologies that increase during adolescence. Aberrant stress responsivity and recovery across multiple physiological systems may contribute to anhedonia [1], however current research is limited in its focus on singular biological systems (i.e., neural or physiological). Examining the additive and interactive activity across multiple systems offers a more nuanced approach, which may uncover individualized treatments for anhedonia (i.e., “precision psychiatry”).

Neural mechanisms

Evidence implicates disruptions of fronto-striatal and fronto-limbic circuits that are involved in the anticipation, expectation, and consumption of pleasurable experiences. Prefrontal cortical regions and their connectivity, which mature through adolescence, are involved in executive functioning, decision-making, and impulse control. An immature prefrontal cortex can impair the ability to regulate emotions and stress responses. The limbic system, including the amygdala and the hippocampus, also becomes more reactive to stress during adolescence. Disruptions in the maturation of neural circuits can contribute to aberrant stress responses and long-term risk for anhedonia.

Physiological and hormonal mechanisms

Research examining the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis reveal dysregulation marked by exaggerated and/or blunted stress responsivity are associated with the severity of adolescent-onset anhedonia [2].

An integrated model

Physiological and neural tress response systems dynamically calibrate their activity through reciprocal feedback mechanisms, as activation of key fronto-limbic brain regions regulate endocrine responses to stress. Yet, most research examines their functioning individually. The Adaptive Calibration Model (ACM) is a multisystem model that proposes latent profiles of integrated activity across the ANS and HPA axis (termed Sensitive, Buffered, and Vigilant profiles) [3]. Our research has documented ACM-inspired profiles and observed associations between the Sensitive profile (characterized by exaggerated HPA axis activity and low/moderate ANS activity) and internalizing symptoms, which bear conceptual similarity to anhedonia. The Buffered profile (high resting parasympathetic nervous system activity and moderate HPA axis activity) appeared protective against the emergence of clinical symptoms [4,5,6]. While these findings establish the importance of integrating multiple physiological stress systems, a notable omission from this work is neural functioning.

Thus, it is critical to broaden existing multisystem models of stress responsivity that reflect the integratio of both neural and physiological systems (i.e., termed “multisystem stress response biotypes”). We will examine the three biotypes that emerged from our prior work (i.e., Sensitive, Buffered, Vigilant) and their associations with the onset and trajectory of anhedonia in adolescence (Fig. 1). This approach may capture important sources of inter-individual variability in risk factors for anhedonia, though large sample sizes could be required to detect all possible multisystem profiles.

Fig. 1: Conceptual Model of Multisystem Stress Response Biotypes: acute stress activates neural and physiological systems critical for the onset and regulation of adaptive stress responses.
figure 1

Neural Regulators: Coordinated prefrontal cortex, hippocampus, and amygdala activation works together to regulate the acute stress response. This coordinated activity of prefrontal (PFC), hippocampal (Hipp), and amygdala (Amyg) systems ensures that the stress response is appropriate to the situation and that the body can return to a state of balance once the stressor is no longer present. The amygdala detects threats and initiates the stress response, the hippocampus provides contextual information and feedback to regulate the HPA axis (hypothalamus -Hyp and ventral striatum – VS), and the prefrontal cortex helps to assess the situation, plan responses, and inhibit excessive emotional reactions. Physiological Regulators: Coordinated activation of the Autonomic Nervous System (ANS) through its Parasympathetic and Sympathetic arms (PSN and SNS, respectively) and the HPA (hypothalamic-pituitary-adrenal Axis) has been associated with multiple stress response profiles, including the ACM-derived Buffered profile, marked by greater activation of the PNS, a Vigilant Profile, marked by hyperactivation of the HPA, and a Sensitive Profile, marked by greater activation of the HPA and low/moderate ANS activity. Balancing and Coordinating Activation: The neural and physiological systems are highly interdependent and interlinked: The hippocampus and PFC provide feedback to the HPA axis to modulate and eventually terminate the stress response. High levels of cortisol signal the hippocampus to inhibit further activation of the HPA axis, while the PFC helps to re-evaluate the stressor and diminish the emotional response. The PFC further helps to balance the activation of the amygdala and the stress response. Under acute stress, the PFC can help to downregulate the amygdala’s activity, reducing the overall stress response. The Multisystem Stress Response Biotypes Model posits that dysregulation in the coordination between these stress systems differentially modulates risk for anhedonia and may represent early risk markers for targeted early interventions. Arrow thickness represents relative strength of activation of individual systems leading to distinct profiles as in Glier et al. [6].

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Applications to prevention and intervention strategies

Integrating objective multisystem biological measures with self-report of symptoms may help prevent and treat anhedonia using multimodal prevention and intervention strategies that offer a personalized approach. Early interventions targeting these systems can promote healthy stress management and emotional regulation during adolescence.