Association Between Neighborhood Opportunity, Allostatic Load, and All-Cause Mortality in Patients With Breast Cancer.

PURPOSE: Adverse neighborhood contextual factors may affect breast cancer outcomes through environmental, psychosocial, and biological pathways. The objective of this study is to examine the relationship between allostatic load (AL), neighborhood opportunity, and all-cause mortality among patients with breast cancer. METHODS: Women age 18 years and older with newly diagnosed stage I-III breast cancer who received surgical treatment between January 1, 2012, and December 31, 2020, at a National Cancer Institute Comprehensive Cancer Center were identified. Neighborhood opportunity was operationalized using the 2014-2018 Ohio Opportunity Index (OOI), a composite measure derived from neighborhood level transportation, education, employment, health, housing, crime, and environment. Logistic and Cox regression models tested associations between the OOI, AL, and all-cause mortality. RESULTS: The study cohort included 4,089 patients. Residence in neighborhoods with low OOI was associated with high AL (adjusted odds ratio, 1.21 [95% CI, 1.05 to 1.40]). On adjusted analysis, low OOI was associated with greater risk of all-cause mortality (adjusted hazard ratio [aHR], 1.45 [95% CI, 1.11 to 1.89]). Relative to the highest (99th percentile) level of opportunity, risk of all-cause mortality steeply increased up to the 70th percentile, at which point the rate of increase plateaued. There was no interaction between the composite OOI and AL on all-cause mortality (P = .12). However, there was a higher mortality risk among patients with high AL residing in lower-opportunity environments (aHR, 1.96), but not in higher-opportunity environments (aHR, 1.02; P interaction = .02). CONCLUSION: Lower neighborhood opportunity was associated with higher AL and greater risk of all-cause mortality among patients with breast cancer. Additionally, environmental factors and AL interacted to influence all-cause mortality. Future studies should focus on interventions at the neighborhood and individual level to address socioeconomically based disparities in breast cancer.

Choroid Plexus Enlargement and Allostatic Load in Schizophrenia.

Although schizophrenia is a brain disorder, increasing evidence suggests that there may be body-wide involvement in this illness. However, direct evidence of brain structures involved in the presumed peripheral-central interaction in schizophrenia is still unclear. Seventy-nine previously treatment-naïve first-episode schizophrenia patients who were within 2-week antipsychotics initial stabilization, and 41 age- and sex-matched healthy controls were enrolled in the study. Group differences in subcortical brain regional structures measured by MRI and the subclinical cardiovascular, metabolic, immune, and neuroendocrine biomarkers as indexed by allostatic load, and their associations were explored. Compared with controls, patients with schizophrenia had significantly higher allostatic load (P = .001). Lateral ventricle (P < .001), choroid plexus (P < .001), and thalamus volumes (P < .001) were significantly larger, whereas amygdala volume (P = .001) was significantly smaller in patients. The choroid plexus alone was significantly correlated with higher allostatic load after age, sex, education level, and the total intracranial volume were taken into account (t = 3.60, P < .001). Allostatic load was also significantly correlated with PANSS positive (r = 0.28, P = .016) and negative (r = -0.31, P = .008) symptoms, but in opposite directions. The peripheral multisystemic and central nervous system abnormalities in schizophrenia may interact through the choroid plexus during the early stage of the illness. The choroid plexus might provide a sensitive structural biomarker to study the treatment and prevention of brain-periphery interaction abnormalities in schizophrenia.

Allostasis: A Brain-Centered, Predictive Mode of Physiological Regulation.

Although the concept of allostasis was proposed some 30 years ago, doubts persist about its precise meaning and whether it is useful. Here we review the concept in the context of recent studies as a strategy to efficiently regulate physiology and behavior. The brain, sensing the internal and external milieu, and consulting its database, predicts what is likely to be needed; then, it computes the best response. The brain rewards a better-than-predicted result with a pulse of dopamine, thereby encouraging the organism to learn effective regulatory behaviors. The brain, by prioritizing behaviors and dynamically adjusting the flows of energy and nutrients, reduces costly errors and exploits more opportunities. Despite significant costs of computation, allostasis pays off and can now be recognized as a core principle of organismal design.

From serendipity to clinical relevance: How clinical psychology and neuroscience converged to illuminate psychoneuroendocrinology.

Dirk Hellhammer and his colleagues have played a major role in creating the field of psychoneuroendocrinology from their roots in psychology. In this review, using examples from the history of the McEwen laboratory and neuroscience and neuroendocrinology colleagues, I summarize my own perspective as to how the fields of neuroscience and neuroendocrinology have contributed to psychoneuroendocrinology and how they converged with the contributions from Dirk Hellhammer and his colleagues.

Psychological Stress and Mitochondria: A Conceptual Framework.

BACKGROUND: The integration of biological, psychological, and social factors in medicine has benefited from increasingly precise stress response biomarkers. Mitochondria, a subcellular organelle with its own genome, produce the energy required for life and generate signals that enable stress adaptation. An emerging concept proposes that mitochondria sense, integrate, and transduce psychosocial and behavioral factors into cellular and molecular modifications. Mitochondrial signaling might in turn contribute to the biological embedding of psychological states. METHODS: A narrative literature review was conducted to evaluate evidence supporting this model implicating mitochondria in the stress response, and its implementation in behavioral and psychosomatic medicine. RESULTS: Chronically, psychological stress induces metabolic and neuroendocrine mediators that cause structural and functional recalibrations of mitochondria, which constitutes mitochondrial allostatic load. Clinically, primary mitochondrial defects affect the brain, the endocrine system, and the immune systems that play a role in psychosomatic processes, suggesting a shared underlying mechanistic basis. Mitochondrial function and dysfunction also contribute to systemic physiological regulation through the release of mitokines and other metabolites. At the cellular level, mitochondrial signaling influences gene expression and epigenetic modifications, and modulates the rate of cellular aging. CONCLUSIONS: This evidence suggests that mitochondrial allostatic load represents a potential subcellular mechanism for transducing psychosocial experiences and the resulting emotional responses-both adverse and positive-into clinically meaningful biological and physiological changes. The associated article in this issue of Psychosomatic Medicine presents a systematic review of the effects of psychological stress on mitochondria. Integrating mitochondria into biobehavioral and psychosomatic research opens new possibilities to investigate how psychosocial factors influence human health and well-being across the life-span.

Clinical, hemispheric, and autonomic changes associated with use of closed-loop, allostatic neurotechnology by a case series of individuals with self-reported symptoms of post-traumatic stress.

BACKGROUND: The objective of this pilot study was to explore the use of a closed-loop, allostatic, acoustic stimulation neurotechnology for individuals with self-reported symptoms of post-traumatic stress, as a potential means to impact symptomatology, temporal lobe high frequency asymmetry, heart rate variability (HRV), and baroreflex sensitivity (BRS). METHODS: From a cohort of individuals participating in a naturalistic study to evaluate use of allostatic neurotechnology for diverse clinical conditions, a subset was identified who reported high scores on the Posttraumatic Stress Disorder Checklist (PCL). The intervention entailed a series of sessions wherein brain electrical activity was monitored noninvasively at high spectral resolutions, with software algorithms translating selected brain frequencies into acoustic stimuli (audible tones) that were delivered back to the user in real time, to support auto-calibration of neural oscillations. Participants completed symptom inventories before and after the intervention, and a subset underwent short-term blood pressure recordings for HRV and BRS. Changes in temporal lobe high frequency asymmetry were analyzed from baseline assessment through the first four sessions, and for the last four sessions. RESULTS: Nineteen individuals (mean age 47, 11 women) were enrolled, and the majority also reported symptom scores that exceeded inventory thresholds for depression. They undertook a median of 16 sessions over 16.5 days, and 18 completed the number of sessions recommended. After the intervention, 89% of the completers reported clinically significant decreases in post-traumatic stress symptoms, indicated by a change of at least 10 points on the PCL. At a group level, individuals with either rightward (n = 7) or leftward (n = 7) dominant baseline asymmetry in temporal lobe high frequency (23-36 Hz) activity demonstrated statistically significant reductions in their asymmetry scores over the course of their first four sessions. For 12 individuals who underwent short-term blood pressure recordings, there were statistically significant increases in HRV in the time domain and BRS (Sequence Up). There were no adverse events. CONCLUSION: Closed-loop, allostatic neurotechnology for auto-calibration of neural oscillations appears promising as an innovative therapeutic strategy for individuals with symptoms of post-traumatic stress. TRIALS REGISTRATION: ClinicalTrials.gov #NCT02709369 , retrospectively registered on March 4, 2016.

Allostatic load: a useful concept for advancing nursing research.

AIMS AND OBJECTIVES: To elucidate the historical development of the allostatic load concept, alongside its use in nursing research, and to explore how allostatic load has been investigated among two stress-vulnerable populations. BACKGROUND: 'Stress' is a prominent term in understanding the development of disease. Allostatic load is among several approaches undertaken to quantify the magnitude of stress and understand how stress can affect health. METHOD: We explored the advent of allostatic load including its antecedents, and consequences. We used an exemplar case to apply the concept. We reviewed studies that used allostatic load among workers and women of childbearing age. RESULTS: There remains a need to consolidate a common definition and operationalisation of allostatic load. Despite this need for further work, allostatic load is a good fit for nursing science which focuses on the client, environment and health. Only 12 studies explored allostatic load among workers (n = 6) and women of childbearing age (n = 6). In some studies, allostatic load was used as a predictor while in others it was used as an outcome. None of the studies considered it as a mediator. CONCLUSIONS: The concept of allostatic load holds promise for nursing researchers to operationalise a holistic view of multiple stressors and to quantify their effects on health. Studies are needed to affirm the role of allostatic load as a potential mediator between multiple stressors and outcomes. Longitudinal studies are also needed to demonstrate a causal pathway from stressor exposure to tertiary outcomes such as chronic conditions and morbidity. RELEVANCE TO CLINICAL PRACTICE: Allostatic load is a useful concept for nurses working with stress-vulnerable populations. With the use of an interpretable allostatic load index, nurses will be able to intervene at various stages of the allostasis-adaptation process (stress-response) and adjust interventions accordingly.

Allostatic load and biological anthropology.

Multiple stressors affect developing and adult organisms, thereby partly structuring their phenotypes. Determining how stressors influence health, well-being, and longevity in human and nonhuman primate populations are major foci within biological anthropology. Although much effort has been devoted to examining responses to multiple environmental and sociocultural stressors, no holistic metric to measure stress-related physiological dysfunction has been widely applied within biological anthropology. Researchers from disciplines outside anthropology are using allostatic load indices (ALIs) to estimate such dysregulation and examine life-long outcomes of stressor exposures, including morbidity and mortality. Following allostasis theory, allostatic load represents accumulated physiological and somatic damage secondary to stressors and senescent processes experienced over the lifespan. ALIs estimate this wear-and-tear using a composite of biomarkers representing neuroendocrine, cardiovascular, metabolic, and immune systems. Across samples, ALIs are associated significantly with multiple individual characteristics (e.g., age, sex, education, DNA variation) of interest within biological anthropology. They also predict future outcomes, including aspects of life history variation (e.g., survival, lifespan), mental and physical health, morbidity and mortality, and likely health disparities between groups, by stressor exposures, ethnicity, occupations, and degree of departure from local indigenous life ways and integration into external and commodified ones. ALIs also may be applied to similar stress-related research areas among nonhuman primates. Given the reports from multiple research endeavors, here we propose ALIs may be useful for assessing stressors, stress responses, and stress-related dysfunction, current and long-term cognitive function, health and well-being, and risk of early mortality across many research programs within biological anthropology.

Use of an allostatic neurotechnology by adolescents with postural orthostatic tachycardia syndrome (POTS) is associated with improvements in heart rate variability and changes in temporal lobe electrical activity.

Autonomic dysregulation and heterogeneous symptoms characterize postural orthostatic tachycardia syndrome (POTS). This study evaluated the effect of high-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM(®)), a noninvasive, allostatic neurotechnology for relaxation and auto-calibration of neural oscillations, on heart rate variability, brain asymmetry, and autonomic symptoms, in adolescents with POTS. Seven subjects with POTS (three males, ages 15-18) underwent a median of 14 (10-16) HIRREM sessions over 13 (8-17) days. Autonomic function was assessed from 10-min continuous heart rate and blood pressure recordings, pre- and post-HIRREM. One-minute epochs of temporal high-frequency (23-36 Hz) brain electrical activity data (T3 and T4, eyes closed) were analyzed from baseline HIRREM assessment and subsequent sessions. Subjects rated autonomic symptoms before and after HIRREM. Four of seven were on fludrocortisone, which was stopped before or during their sessions. Heart rate variability in the time domain (standard deviation of the beat-to-beat interval) increased post-HIRREM (mean increase 51%, range 10-143, p = 0.03), as did baroreflex sensitivity (mean increase in high-frequency alpha 65%, range -6 to 180, p = 0.05). Baseline temporal electrical asymmetry negatively correlated with change in asymmetry from assessment to the final HIRREM session (p = 0.01). Summed high-frequency amplitudes at left and right temporal lobes decreased a median of 3.8 µV (p = 0.02). There was a trend for improvements in self-reported symptoms related to the autonomic nervous system. Use of HIRREM was associated with reduced sympathetic bias in autonomic cardiovascular regulation, greater symmetry and reduced amplitudes in temporal lobe high-frequency electrical activity, and a trend for reduced autonomic symptoms. Data suggest the potential for allostatic neurotechnology to facilitate increased flexibility in autonomic cardiovascular regulation, possibly through more balanced activity at regions of the neocortex responsible for autonomic management. Clinical trial registry "Tilt Table with Suspected postural orthostatic tachycardia syndrome (POTS) Subjects," Protocol Record: WFUBAHA01.

Mental health consequences of stress and trauma: allostatic load markers for practice and policy with a focus on Indigenous health.

OBJECTIVE: Mental health, well-being, and social life are intimately related as is evident from the higher incidence of psychiatric illness in individuals exposed to social stress and adversity. Several biological pathways linking social adversity to health outcomes are heavily investigated in the aims of facilitating early identification and prevention of adverse health outcomes. We provide a practice-orientated overview of the allostatic load model and how it relates to metabolic and cardiovascular comorbidity in psychiatric disorders. CONCLUSIONS: Allostatic load brings together a set of neuroendocrine, metabolic, immune and cardiovascular biomarkers that are elevated in individuals with adverse early life experiences and are predictive of cardiovascular and metabolic risk in psychiatric illness of critical importance for Indigenous Australians.

Effects of yoga on the autonomic nervous system, gamma-aminobutyric-acid, and allostasis in epilepsy, depression, and post-traumatic stress disorder.

A theory is proposed to explain the benefits of yoga practices in diverse, frequently comorbid medical conditions based on the concept that yoga practices reduce allostatic load in stress response systems such that optimal homeostasis is restored. It is hypothesized that stress induces (1) imbalance of the autonomic nervous system (ANS) with decreased parasympathetic nervous system (PNS) and increased sympathetic nervous system (SNS) activity, (2) underactivity of the gamma amino-butyric acid (GABA) system, the primary inhibitory neurotransmitter system, and (3) increased allostatic load. It is further hypothesized that yoga-based practices (4) correct underactivity of the PNS and GABA systems in part through stimulation of the vagus nerves, the main peripheral pathway of the PNS, and (5) reduce allostatic load. Depression, epilepsy, post traumatic stress disorder (PTSD), and chronic pain exemplify medical conditions that are exacerbated by stress, have low heart rate variability (HRV) and low GABAergic activity, respond to pharmacologic agents that increase activity of the GABA system, and show symptom improvement in response to yoga-based interventions. The observation that treatment resistant cases of epilepsy and depression respond to vagal nerve stimulation corroborates the need to correct PNS underactivity as part of a successful treatment plan in some cases. According to the proposed theory, the decreased PNS and GABAergic activity that underlies stress-related disorders can be corrected by yoga practices resulting in amelioration of disease symptoms. This has far-reaching implications for the integration of yoga-based practices in the treatment of a broad array of disorders exacerbated by stress.

Hypocortisolism as a potential marker of allostatic load in children: associations with family risk and internalizing disorders.

Although the majority of research attention to the hypothalamic-pituitary-adrenal (HPA) axis in stress-related disorders and as a marker of allostatic load has focused on overactivation of this stress system, theory and data clearly indicate that underactivation is also an important type of dysregulation. In the current study we focused on low cortisol, exploring a constellation of risk factors including stress exposure, maternal depression, and attenuated basal and stress reactive cortisol in two samples of children. The first sample was comprised of 110 preschoolers living in high-stress environments. Cortisol was assessed across the day at home and at child care as well as across two stress paradigms. These data were used to classify whether children's HPA axis activity was attenuated. Serious family financial strain, maternal depression, and attenuated cortisol all made unique contributions in models predicting current clinical levels of internalizing symptoms as rated by mothers and teachers. The second sample was 166 third, sixth, and ninth graders studied five times across a 1-year period. Maternal and child depression were determined through structured clinical interviews, and stress exposure was assessed via checklist and interview techniques with the child and parent. Cortisol was assessed multiple times across a lab visit at Time 1, and these data were combined into a single continuous measure. Cortisol concentrations across the lab visit interacted with stress exposure across the year such that children with lower average cortisol at Time 1 and increased stress across the 12 months showed elevated levels of internalizing symptoms. Based on these and related data we propose that prior to puberty low cortisol may be an important marker of allostatic load, particularly for risk of depression and anxiety.

Poor self-rated health is not associated with a high total allostatic load in type 2 diabetic patients--but high blood pressure is.

OBJECTIVE: Allostatic load has been linked to self-rated health (SRH), cardiovascular disease and mortality in non-diabetic individuals. The aim of this study was to construct an allostatic load score and to find any correlations with SRH. METHODS: The subjects included in the study came from a randomized, controlled trial of type 2 diabetes. Blood samples were drawn, urine was collected for 24h, and questionnaires, including SRH, were filled out on three occasions: at baseline; after the 10-week intervention; and at a follow-up 3 months after the intervention. Allostatic load was estimated using a wide range of variables, including systolic and diastolic blood pressure, pulse pressure, cortisol, catecholamines, HbA(1c), insulin, plasma glucose and waist circumference. RESULTS: There was no association between SRH and allostatic load. However, three other components were significantly correlated with allostatic load at the baseline investigation and the two follow-up investigations - namely, systolic blood pressure, diastolic blood pressure and HbA(1c). CONCLUSION: The absence of an association between allostatic load and SRH in diabetic individuals contrasts with previous findings in non-diabetic women, and shows that it is hazardous to apply findings in one population to another, especially diabetic and non-diabetic populations.

A program in contemplative self-healing: stress, allostasis, and learning in the Indo-Tibetan tradition.

This paper reviews current behavioral health interventions and introduces a self-healing program based on the Indo-Tibetan tradition. While most work on behavior change emphasizes cognition and motivation, this review highlights stress-reactivity as a rate-limiting resistance to learning. Surveying cognitive-behavioral theories, it finds these limited in modeling stress-reactivity. Reviewing current interventions that address stress by integrating relaxation, mindfulness, imagery, or movement with cognitive-behavioral education, it attributes their limited effectiveness to the limits of their model of stress and their strategy of eclectically mixing techniques. Next, the article explores the Indic model of stress-cessation and self-healing assumed by mindfulness practice, concluding that it more fully reflects current findings on stress and learning. It reviews the theory and practice of mindfulness and of two less known contemplative "vehicles" preserved in Tibet, using more advanced techniques and insights better suited to lay lifestyles and secular cultures. It suggests that the Tibetan tradition of integrating all three vehicles of contemplative insight and skill in one self-healing practice should maximize coherence and effectiveness while minimizing confounding variables caused by eclecticism. Finally, the paper introduces an intervention that integrates mindfulness with techniques of cognitive analysis, affect modulation, motivational imagery, and reinforcing breathing, tailored over centuries into a complete, threefold path of self-healing. A pilot study of this intervention in women treated for breast and other gynecologic cancers suggests that the whole spectrum of Indo-Tibetan mind/body practices can be readily mastered and effectively used by Westerners to reduce stress and enhance learning and quality of life.

Dorsal raphe nuclei integrate allostatic information evoked by depletion-induced sodium ingestion.

Structures of the lamina terminalis (LT) sense and integrate information reflecting the state of body water and sodium content. Output from the LT projects into a neural network that regulates body fluid balance. Serotonin (5-HT) and the dorsal raphe nuclei (DRN) have been implicated in the inhibitory control of salt intake (i.e., sodium appetite). Signals arriving from the LT evoked by fluid depletion-induced sodium ingestion interact with this inhibitory serotonergic system. We investigated the role of neurons along the LT that directly project to the DRN. We analyzed the pattern of immunoreactivity (ir) of LT cells double-labeled for Fos (a marker of neural activity) and Fluorogold (FG; a retrograde tracer) following sodium depletion-induced sodium intake. Seven days after injection of FG into the DRN, sodium appetite was induced by furosemide injection and overnight access to only a low sodium diet (Furo-LSD) and distilled water. Twenty-four hours later, access to 0.3 M NaCl was given to depleted or sham-depleted rats and sodium intake was measured over the following 60 min. Ninety minutes after the termination of the intake test, the animals were perfused and their brains were processed for immunohistochemical detection of Fos and FG. Compared to sham-depleted animals there was a significantly greater number of Fos-/FG-ir double-labeled cells in the subfornical organ, the organum vasculosum of the lamina terminalis and the median preoptic nucleus in rats that ingested NaCl. Projections from the LT cells may contribute to inhibitory mechanisms involving 5-HT neurons in the DRN that limit the intake of sodium and prevent excess volume expansion.