The immune system is not a single switch that turns on during illness. It is a distributed network involving immune cells, signalling molecules, blood vessels, the nervous system and endocrine organs. During an acute response, immune cells can release cytokines and other mediators that coordinate inflammation, alter metabolism and recruit additional defences. These processes are essential for controlling infection and repairing tissue, but their intensity and timing matter. An insufficient response can leave threats unchecked, while excessive or poorly regulated inflammation can damage healthy tissue. Because the brain receives information about immune activity and can alter autonomic and hormonal states, scientists have increasingly investigated whether cognitive processes can influence this balance. Mizrachi and colleagues focus on voluntary attention as one such process: a mental operation that can be intentionally directed and sustained.

The study’s central question is more precise than whether “positive thinking” improves immunity. It concerns whether attention itself can act as a regulatory input during an immediate immune response. Voluntary attention requires the brain to allocate limited processing resources toward selected information while reducing the priority of competing signals. When this allocation is directed toward bodily sensations, internal physiological information may become more salient. When attention is directed elsewhere, signals from the body may be processed differently, even though they do not disappear. In principle, these changes could affect autonomic pathways linking the brain to organs and immune tissues, as well as the hypothalamic–pituitary–adrenal axis, which coordinates stress-related hormonal responses. The research therefore addresses a mechanistic question at the intersection of cognitive neuroscience, psychophysiology and immunology.

Acute immune responses are especially useful for testing this relationship because they unfold over a defined period and can be measured through biological markers. Researchers can examine changes in circulating immune cells, cytokines, inflammatory proteins or other physiological indicators before and after an experimentally controlled challenge. Such measurements do not simply reveal whether the immune system is “strong” or “weak”; they provide a time-sensitive picture of how the response develops. A change in one marker may reflect altered immune activation, redistribution of cells between tissues and blood, or a shift in inflammatory signalling. Interpreting these results requires careful attention to timing, baseline differences and the distinction between correlation and causation. The importance of the new work lies in testing a cognitive variable under conditions in which immune activity can be observed directly, rather than relying only on long-term associations between psychological traits and health outcomes.

The proposed link between attention and immunity may operate through several biological routes. The autonomic nervous system can influence immune organs through sympathetic and parasympathetic signalling, changing the release of neurotransmitters and the behaviour of immune cells. Stress hormones can also modify cytokine production and alter the movement of immune cells through the bloodstream. In addition, attention can change breathing, muscle tension, heart rate and the interpretation of bodily sensations, all of which may feed back into physiological regulation. These pathways are not independent. A person who focuses on an internal sensation may notice it more clearly, experience it as more intense or interpret it differently; each of those responses can influence autonomic state. The study does not imply that attention can consciously command every immune cell. Rather, it suggests that deliberate mental allocation may enter existing regulatory circuits connecting cognition, physiology and inflammation.

The findings are likely to attract attention because they challenge a familiar division between “mental” and “physical” health. Modern medicine already recognises that sleep, stress, pain, emotion and social experience can influence inflammatory biology. However, voluntary attention is a particularly interesting factor because it is, at least in principle, trainable in real time. Practices such as mindfulness, focused breathing and certain forms of biofeedback are built around directing attention, but their biological effects have often been difficult to separate from relaxation, expectation, breathing changes or broader reductions in stress. By isolating attention as a behavioural variable, the research may help scientists determine which components of these practices matter, for whom and under what circumstances. The result is not a prescription to concentrate on illness, but a possible clue about how mental training could be studied with the same experimental precision applied to drugs and other interventions.

At the same time, the findings should not be inflated into a claim that people can think themselves healthy or that attention can replace vaccination, antimicrobial treatment or clinical care. Acute immune regulation is not equivalent to protection from infection, and a laboratory change in an inflammatory marker does not automatically translate into fewer illnesses or faster recovery. Immune responses are context-dependent: a reaction beneficial during one challenge may be harmful during another. The direction, size and duration of any attention-related effect are therefore crucial. It is also possible that attention influences subjective symptoms more strongly than underlying pathology, or that biological changes occur without a meaningful effect on health outcomes. These distinctions will need to be tested in larger studies with diverse participants, repeated measurements and clinically relevant endpoints.

Future research may also clarify whether the effect depends on what people attend to, how long they sustain attention and how they interpret the signals they notice. Attention to bodily sensations is not identical to worry, rumination or deliberate nonjudgmental observation. Each may engage overlapping but distinct neural and physiological processes. Researchers will need to distinguish attention from expectation, perceived control, emotional arousal and changes in breathing or movement. Neuroimaging, continuous heart-rate and respiratory monitoring, endocrine measurements and detailed immune profiling could help map the pathway from an instruction in the laboratory to a change in immune biology. Studies conducted during vaccination, controlled inflammatory challenges or naturally occurring infections could establish whether the phenomenon generalises beyond a single experimental setting. It will also be important to determine whether training produces lasting changes or only short-lived responses during the task itself.

The broader message is that the immune system may be more dynamically integrated with conscious behaviour than traditional diagrams suggest. The brain constantly receives information from the body, while the body responds to signals generated by neural activity, hormones and behaviour. Voluntary attention may be one of the mechanisms that adjusts this two-way exchange, not by overriding immune biology but by changing the conditions under which immune responses are initiated and regulated. Mizrachi, Rottem and Rozenkrantz’s study offers a framework for investigating that possibility in humans, where cognition, physiology and disease risk are inseparable in everyday life. The next challenge is to determine how robust the effect is, which biological pathways carry it and whether carefully designed attention-based interventions can produce reliable benefits without oversimplifying the extraordinary complexity of the immune system.

Subject of Research: The relationship between voluntary attention and acute immune responses in humans

Article Title: Voluntary attention regulates acute immune responses in humans

Article References:

Mizrachi, N., Rottem, M. & Rozenkrantz, L. Voluntary attention regulates acute immune responses in humans. Nat Hum Behav (2026). https://doi.org/10.1038/s41562-026-02541-1

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41562-026-02541-1

Keywords: voluntary attention, acute immune response, human physiology, neuroimmunology, inflammation, brain–immune communication, cognitive control, cytokines

The nervous and immune systems maintain a dynamic conversation, where inflammatory cytokines have long been implicated in the modulation of behavior, particularly in the context of mood disorders such as depression. Emerging evidence supports that these immune signals can disrupt dopaminergic and other neurotransmitter pathways critical for experiencing pleasure and motivation. This study stands at the forefront of translating the molecular dialogue between inflammation and brain function into observable psychological and behavioral changes, crucially dissected by age group.

In this carefully designed randomized controlled trial, female participants spanning a wide age spectrum were administered endotoxin, a bacterial lipopolysaccharide known for its potent activation of the innate immune response. Endotoxin challenges prompt the release of pro-inflammatory cytokines and transient sickness behavior, providing an ethically manageable model for examining how peripheral inflammation can influence central nervous system processes. By comparing responses across younger and older adult females, the investigators sought to chart a developmental trajectory of vulnerability or resilience to inflammation-induced mood and reward alterations.

Behavioral assessments revealed that endotoxin administration reliably induced a depressed mood state and a reduction in reward responsivity, encapsulating hallmark symptoms observed in inflammatory-associated depression. However, the magnitude and specific features of these changes diverged notably across age groups. Younger females demonstrated an acute, but relatively transient, blunting of reward processing, whereas older females exhibited more prolonged and pronounced mood disturbances, suggesting age-related differences in neuroimmune sensitivity.

Neuromodulatory mechanisms underlying the observed age-dependent effects likely pivot on alterations in cytokine receptor expression, neurotransmitter system integrity, and neuroplasticity that evolve over the adult lifespan. Aging is associated with immune senescence, a chronic low-grade inflammatory state, which may predispose older individuals to heightened or prolonged neuroinflammatory responses upon immune challenge. These changes can disrupt dopaminergic transmission within reward circuits such as the ventral striatum, critically impairing reward processing and reinforcing depressive symptomatology.

Moreover, the study probed neuroimaging correlates, mapping changes in brain activity linked to reward anticipation and receipt across the endotoxin and placebo conditions. Consistent with behavioral data, younger participants showed transient reductions in ventral striatum activation post-endotoxin, while older participants exhibited sustained hypoactivity, implicating neural pathways sensitive to inflammation that become dysregulated with age. These neurobiological signatures underscore the intricate crosstalk between peripheral immune activation and central reward circuitry.

These findings have significant implications for understanding the pathophysiology of depression, particularly the subtype of inflammation-associated depression, which continues to elude universally effective treatments. That the depressive and anhedonic effects of inflammation are not monolithic but instead vary by age demands a reconsideration of therapeutic strategies. Personalized interventions that factor in age-dependent immune-neural interactions could revolutionize clinical practice, especially given the higher prevalence of both inflammation and depression in older female populations.

Notably, the study contributes to a growing body of literature emphasizing female-specific biological pathways in psychiatric illness, addressing a critical gap in translational neuroscience research. Sex hormones, immune function, and brain plasticity interact in complex ways that influence susceptibility to mood disorders, and the current findings reinforce that female adults are not a homogeneous group but differ substantially in neuroimmune responsivity across adulthood.

Moreover, these results underscore the importance of routine monitoring of inflammatory markers in clinical assessments of depression, especially in older women. Biomarker profiles could serve as indicators of treatment response or risk stratification tools, facilitating earlier intervention. As inflammation emerges as a key modulator of reward and mood processing, anti-inflammatory agents or immune-modulating therapies might offer novel options for patients unresponsive to traditional antidepressants.

Beyond clinical applications, the study also invites deeper inquiry into the cellular and molecular underpinnings of age-dependent neuroimmune interactions. Future research could explore how microglial activation, blood-brain barrier integrity, and systemic inflammatory milieu converge to impact brain function throughout aging. Longitudinal designs tracking immune and neural parameters pre- and post-inflammatory insults could elucidate resilience factors or early biomarkers of vulnerability.

Additionally, the use of endotoxin as a model provides a powerful experimental paradigm for dissecting causal relationships between immune activation and changes in mood and motivation. While ethically constrained to transient immune activation, endotoxin challenges permit real-time assessment of inflammatory impacts on neural and behavioral endpoints, a critical advantage over observational studies.

One of the remarkable aspects of this study lies in its integration of cutting-edge neuroimaging, psychometric, and immunological methodologies, yielding a comprehensive portrait of the inflammation-mood nexus. Such multidisciplinary approaches pave the way for more precise characterizations of neuropsychiatric disorders, which often arise from complex, interacting biological systems rather than isolated dysfunctions.

In summary, this pioneering work illuminates the intricate biological cascade linking peripheral inflammation to mood and reward circuit dysregulation in female adults, highlighting a significant modulatory role of aging. The age-dependent patterns of depressive symptoms and diminished reward responsivity following endotoxin administration not only advance our understanding of inflammation’s impact on the brain but also stress the need for tailored therapeutic approaches. As the population ages and the burden of inflammation-related psychiatric illness grows, these insights become increasingly vital for improving mental health outcomes.

The study’s innovative approach and robust findings invite a paradigm shift in how depression, particularly in women, is conceptualized and treated. Rather than a static disorder, depression emerges here as a dynamic interplay of immune status, neural function, and age-related changes. This perspective opens new avenues for prevention and intervention grounded in the biological realities of neuroimmune aging.

By mapping the effects of inflammation across the adult female lifespan, this research equips clinicians and scientists with crucial knowledge to confront the challenge of depression in a more nuanced and effective manner. The visualized alterations in reward processing circuits present tangible targets for future pharmacological and behavioral interventions, promising hope for those for whom current treatments fall short.

As the neuroimmunology field continues to evolve, studies such as this underscore the transformative potential of integrative, lifespan-informed research. They remind us that to truly understand complex mental health disorders, both biological diversity and temporal dynamics must be embraced. This work stands as a landmark contribution, charting a sophisticated roadmap for future exploration and clinical innovation at the intersection of inflammation, aging, and mood.

Subject of Research:
Inflammation-induced depressed mood and reward responsivity across different ages in female adults.

Article Title:
Inflammation-induced depressed mood and reward responsivity as a function of age in female adults: a randomized controlled trial of endotoxin.

Article References:
Boyle, C.C., Cho, J.H., Eisenberger, N.I. et al. Inflammation-induced depressed mood and reward responsivity as a function of age in female adults: a randomized controlled trial of endotoxin. Transl Psychiatry (2025). https://doi.org/10.1038/s41398-025-03752-2

Image Credits:
AI Generated

DOI:
https://doi.org/10.1038/s41398-025-03752-2