Applying Neurobiological Insights on Stress to Foster Resilience Across Life Stages: Proceedings of a Workshop (2025)
Chapter: 7 Advancing Resilience Research: Key Insights and Potential Next Steps
7
Advancing Resilience Research: Key Insights and Potential Next Steps
Highlights
- Broader influences, including workplace stress and rapid societal changes, are unexplored key factors that may interact with biological and behavioral elements of resilience, underscoring the importance of incorporating these external stressors into research and intervention strategies. (Jensen, Nestler)
- Biomarkers, behavioral indicators, and computational modeling provide critical insights into resilience-related brain circuits, helping rapidly test new hypotheses and define predictive markers for resilience. (Jensen, Vicentic)
- Redefining resilience as a dynamic biological trait with farreaching intergenerational effects forces the field to rethink how resilience is measured. (Akil, Krystal, Nelson)
- Personal narratives and metaphors illustrated that stress recovery is an ongoing process and highlighted concerns that disruptions in underlying mechanisms could lead to “diseases of resilience,” where even treatments might inadvertently affect recovery trajectories. (Krystal, Nelson)
- Interventions such as pretreatment with N-methyl-D-aspartate (NMDA) antagonists (e.g., ketamine) and the use of lithium not only provide acute symptom relief but also appear to enhance synaptic plasticity and bolster long-term resilience through molecular pathways. (Manji)
NOTE: This list is the rapporteurs’ summary of points made by the individual speakers identified, and the statements have not been endorsed or verified by the National Academies of Sciences, Engineering, and Medicine. They are not intended to reflect a consensus among workshop participants.
Eric Nestler highlighted the workshop’s exploration of key topics, including the biological foundations of stress responses with an emphasis on resilience, critical developmental periods, and the bidirectional interaction between peripheral organs and the brain in regulating stress susceptibility. He also acknowledged discussions on the broader societal and policy implications of this research. This chapter examines gaps in knowledge and considers where resources may be allocated to enhance resilience and mitigate the negative effects of stress on society.
LEVERAGING BIOLOGICAL MECHANISMS FOR EARLY DETECTION AND INTERVENTION
Aleksandra Vicentic outlined how studies on stress‐mediated changes in neuroplasticity (the brain’s ability to reorganize itself) have illuminated sensitive periods of risk and resilience during development. She described how employing quantitative behavioral tasks as proxies of the engagement of brain circuits that reflect resilience may help define prospective neurobehavioral markers of resilience. Such studies can reveal differences between resilient and stress-prone phenotypes and point out strategies by which stress-susceptible individuals could become more resilient. Vicentic emphasized that recent advances in computational modeling can rapidly test hypotheses about important features of resilience that would be difficult to address experimentally. By incorporating environmental, social, and neurophysiological variables important for resilience into different models, predictions about specific features of resilience can be tested. These approaches might reveal novel theoretical frameworks of resilience and illuminate factors that influence resilient responses to stress.
Frances Jensen expanded on the understanding of resilience as an adaptive phenomenon shaped by an evolving environment. She observed that in today’s world—bombarded by digital media and unforeseen societal shifts—the brain’s capacity for adaptability (or neuroplasticity) is continually challenged. Jensen introduced the concept of domain-specific resilience, suggesting that individuals may display resilience in certain aspects of life while remaining vulnerable in others. She elaborated on the promise of integrating molecular assessments such as transcriptomics, neuroendocrine markers, and behavioral indicators to detect subtle deficits in resilience before overt symptoms of toxic stress emerge. Recognizing the importance of a precision approach, Jensen emphasized aligning early biomarkers across multiple levels with targeted intervention strategies. She underscored the need for an expanded research agenda that integrates mechanistic, behavioral, and clinical dimensions to capture the prodromal signals of diminished resilience.
Reconceptualizing resilience as a biological trait, John Krystal offered a multifaceted view of resilience through the metaphor of a rock climber navigating perilous heights. A climber was shown ascending a risky route without a rope—Krystal delineated four aspects of resilience:
- Low baseline stress activation: The climber maintains a steady composure even in high-stress situations.
- Active coping: Despite facing dangerous conditions, the climber engages challenges dynamically.
- Rebound capability: After moments of acute stress (illustrated by episodes of panic), the climber regains composure.
- Traumatic growth: Post-adversity, the climber is propelled to take on even greater challenges.
Krystal introduced the provocative idea that if resilience is indeed a biological trait, then disruptions in the underlying mechanisms might be conceptualized as “diseases of resilience.” He underscored findings from a metaanalysis of antidepressant trials that examined trajectories of response among thousands of patients to show that a subset of patients had responses even less favorable than placebo (Gueorguieva et al., 2011). This observation raised considerations about whether certain treatments may inadvertently compromise an individual’s intrinsic capacity for resilience. He also referenced work by Peter Kramer, among others, to illustrate emerging evidence that some pharmacotherapies may operate not only by dampening symptoms but also by promoting a resilient epigenetic profile (Gueorguieva et al., 2011, 2017; Kramer, 1997; Krishnan et al., 2007; Nestler and Russo, 2024).
Husseini Manji built upon these themes by highlighting interventions that target the circuitry underlying stress responses. He noted that emerging
data regarding AMPA (α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)–mediated plasticity, which facilitates synaptic communication, suggest that pretreatment with NMDA antagonists (agents that modulate glutamate signaling) may protect against behavioral deficits induced by stress. Manji highlighted studies from Columbia University and Mount Sinai in which researchers demonstrated that interventions such as ketamine not only alleviate symptoms acutely but may also trigger adaptive processes within brain circuits. In discussing pharmacological agents, he mentioned that lithium—long valued for its mood-stabilizing properties—has been observed to reduce the duration of manic and depressive episodes and is linked to lower suicide rates (Kessing et al., 2005; Lewitzka et al., 2015; Sarai et al., 2018; Tondo and Baldessarini, 2024). These observations point to a dual role for some medications: both reducing immediate distress and potentially reinforcing resilience mechanisms by turning on resilience-promoting molecules like BAG1 (which regulates glucocorticoid receptor trafficking).
CHALLENGES AFTER STRESS RECOVERY
Jon Nelson shared a personal narrative that illustrated the complexities of stress recovery. He recounted the challenges of shifting from a state marked by overwhelming fatigue and depressive inertia to one where he must relearn how to feel and respond to emotional triggers. He even observed his children’s responses to environmental cues (e.g., the sound of a barking dog or Nelson taking a nap) to anticipate his behavior before his recovery. These cues still trigger a stress response in his children today. Nelson emphasized that even after his recovery from a disease state, for him and his family, adapting to everyday stressors is a continual process, revealing the real-world implications of building resilience intergenerationally.
Nelson also reflected on a pivotal conversation with his doctor, Helen Mayberg, that helped him understand that his inability to engage in daily activities was due to abulia, a neurological impairment affecting motivation. While this revelation was validating, it also raised new concerns for him. Despite knowing that exercise and other healthy habits would improve his well-being, Nelson found himself unable to engage in them. Nelson wondered whether a form of behavioral abulia might persist even after recovery, making it difficult to fully reintegrate into daily life.
DISCUSSION
The Impact of the Digital Era
The potential of communication tools to extend education on stress and resilience across the lifespan was a recurring theme during the discussion. Jensen remarked that our modern environment inundates us with “terabytes of information” through digital media—a factor that, on one hand, can tax the brain’s adaptive capacities yet, on the other, offers an opportunity. One online participant suggested that the formation of new social networks, driven by digital connectivity, might provide essential support for students leaving familiar environments and could help foster resilience in academic and professional settings.
The Importance of Interdisciplinary Collaboration and Research
Deanna Barch discussed a critical gap that remains in the measurement of resilience. She pointed to Nadine Burke Harris’s earlier statement that research efforts are often siloed, with different studies focusing either on molecular markers or on clinical and behavioral assessments. By championing multidisciplinary projects that evaluate stress responses from the cellular to the societal level, researchers may better capture the multidimensional nature of resilience. For instance, Herman Taylor discussed some investigations in cardiovascular research that have employed pragmatic measures such as Life’s Simple 71 to serve as proxies for resilience in primary care settings (Taylor et al., 2022). These integrative approaches underscore the possibility that clarity on resilience measurement will emerge only when diverse perspectives converge.
Burke Harris provided a detailed perspective on resilience measures, explaining how her team, both in clinical work and the surgeon general’s office, has focused on regulating the physiologic stress response and addressing neuroendocrine immune and genetic disruptions. She highlighted the importance of examining resilience across different levels—molecular, physiologic, clinical, and community—and emphasized the need to connect basic science research with practical applications in primary care. Burke Harris advocated for measures that support early detection and intervention, noting
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1 Life’s Simple 7, as defined by the American Heart Association, outlines seven key metrics for ideal cardiovascular health: maintaining a nonsmoking status, a body mass index below 25 kg/m2, adherence to a heart-healthy diet, engaging in at least 150 minutes of moderate physical activity per week, keeping total blood cholesterol under 200 mg/dL, maintaining blood pressure below 120/80 mmHg, and ensuring fasting blood glucose remains under 100 mg/dL (Diaz-Gutierrez et al., 2023).
that California’s precision medicine investments aim to identify therapeutic targets for toxic stress. She emphasized the importance of aligning research approaches with intended therapeutic goals, pointing to stem cell research as a model. Burke Harris stated that California funds these initiatives to advance the discovery of new treatments, demonstrating how a research framework can be strategically designed to develop therapeutic targets. She proposed that a similar approach could be applied to toxic stress, ensuring interventions address its underlying biological mechanisms rather than just its symptoms.
Opportunities for Intervention
A workshop participant emphasized that workplace stress is increasingly linked to declines in employee well-being and productivity. The participant called for greater research attention on resilience in professional settings, highlighting the critical role workplaces play within every community.
The discussion also explored cognitive behavioral therapy (CBT) as a tool for reprogramming thought patterns—an approach metaphorically likened to updating a space probe’s software to fix hardware malfunctions. A workshop participant noted that, just as NASA finds ways to work around technical limitations, CBT helps individuals adapt by restructuring their cognitive responses to psychological challenges. Nestler added that this underscores the idea that resilience is not merely an inherent trait but a skill that can be taught.
Looking Forward
By interweaving insights from basic biological research, clinical practice, and public health communication, the discussions captured in this session offer a multifaceted view of resilience. Workshop participants reflected on the opportunities ahead to identify early biological markers, advance clinical interventions that not only alleviate symptoms but also strengthen innate adaptive mechanisms, and harness digital and social media to expand these strategies within communities.
CONCLUDING REMARKS
In reflecting on the workshop’s discussions, there is growing recognition that the understanding of resilience is evolving into a more nuanced picture—one that goes beyond simply mitigating stress (for key points raised throughout the workshop, see Box 7-1). As Huda Akil explained, “It’s like we’ve been studying microbes, but we don’t know about antibodies,” a metaphor that challenged the audience to not only investigate the threats individuals might
BOX 7-1
Key Points Raised Throughout the Workshop by Individual Speakers
- Researchers emphasized the importance of refining methods for translating findings across species and shifting from a trauma-informed approach to resilience-building, considering factors like timing of stress exposure and mechanisms for positive adaptation. Even reverse translation, taking results from human studies and studying them in preclinical models, can be a powerful approach for identifying therapeutic targets. (Baratta, Cameron, Dias, Kheirbek, Peña)
- Identifying reproducible biomarkers, molecular targets, and neural circuits can allow for more objective and biologically grounded diagnoses and resilience-building interventions that could have lasting generational effects. (Jensen, Manji, Ressler, Russo, Saxbe)
- There remain challenges in defining resilience, especially across animal models, disorders, and life stage. (Hyde, Ressler, Vicentic)
- Resilience happens dynamically over the lifespan, from infancy to adulthood. Systemic and social support are critical to the development and maintenance of resilience. (Akil, Birto, Hyde, Minnis, Nelson, Nestler)
- Chronic adversity does not just increase susceptibility to mental health challenges—it interacts dynamically with biological development, and environmental exposures over time impact multiple body systems like the microbiome and cardiovascular and immune systems. (Bremner, Burke Harris, Gur, Krystal, Montalvo-Ortiz)
- Public health interventions, such as childhood cognitive flexibility training, prenatal emotional regulation programs, stress management apps, and structured sleep education programs, could foster resilience on a population level and improve long-term well-being. (Burke Harris, Cameron, McBride Murry, Meaney, Rogers)
- Early intervention, childhood adversity, and systemic resiliencebuilding could be positioned as public health priorities with nationwide implications. (Burke Harris, McBride Murry)
face but to also learn more about the mechanisms that could protect them. Her remarks on measuring stress fitness to help gauge whether an individual’s stress levels are facilitating adaptation or signaling wear—whether through stress biomarkers, cardiovascular response, sleep tracking, or learned coping mechanisms—underscore a key area still ripe for inquiry. The conversation raised an important question about how to accurately measure resilience.
Akil’s concept of an “emotional algebra” further anchored this discussion, suggesting that resilience is built on the calibrated mix of negative and positive experiences. By framing stress as both a challenge and a resource, she encouraged the consideration of different coping strategies across both individuals and communities, without casting any one approach as superior. Akil remarked that while the dialogue has sharpened the focus on these ideas, this also presents open questions about how best to integrate these measures into practical frameworks. Akil emphasized that the wisdom shared by those with lived experience is not only valuable but essential—shaping physiological, psychological, medical, and economic outcomes. She urged the scientific community to embrace and advocate for resilience as a legitimate field of study, underscoring its profound impact and its transformative potential for the greater good.
