What does a student’Stress and the psyche–brain–immune network in psychiatric diseases based on psychoneuroendocrineimmunology: a concise review
Contents
1. Stress, allostasis, and the brain
2. The mutual link between stress and inflammation
3. Focus on mental health and stress management: clinical effectiveness of psychotherapy and min…
4. Focus on mental health and stress management: biological effects on brain, inflammation, and…
5. Conclusions and perspectives
6. Acknowledgment
7. Author contributions
8. Competing interests
9. Footnotes
10. References
Full Text
In the last decades, psychoneuroendocrineimmunology research has made relevant contributions to the fields of neuroscience, psychobiology, epigenetics, molecular biology, and clinical research by studying the effect of stress on human health and highlighting the close interrelations between psyche, brain, and bodily systems. It is now well recognized that chronic stress can alter the physiological cross‐talk between brain and biological systems, leading to long‐lasting maladaptive effects (allostatic overload) on the nervous, immune, endocrine, and metabolic systems, which compromises stress resiliency and health. Stressful conditions in early life have been associated with profound alterations in cortical and subcortical brain regions involved in emotion regulation and the salience network, showing relevant overlap with different psychiatric conditions. This paper provides a summary of the available literature concerning the notable effects of stress on the brain and immune system. We highlight the role of epigenetics as a mechanistic pathway mediating the influences of the social and physical environment on brain structure and connectivity, the immune system, and psycho‐physical health in psychiatric diseases. We also summarize the evidence regarding the effects of stress management techniques (mainly psychotherapy and meditation practice) on clinical outcomes, brain neurocircuitry, and immune‐inflammatory network in major psychiatric diseases.
In the last decades, Psychoneuroendocrineimmunology research has made relevant contributions to the fields of neuroscience, psychobiology, epigenetics, molecular biology and clinical research by studying the effect of stress on human health and highlighting the close interrelations between psyche, brain, and bodily systems. This paper provides a summary of the available literature concerning the notable effects of stress on the brain and immune system.
Keywords: psychoneuroendocrineimmunology; stress; allostasis; epigenetics; mind‐body therapies; NF‐κB
The immune system is under neuroendocrine control; conversely, products of immune cells can affect central and peripheral nervous activity.[ 1] Brain‐immune cross‐talk is deeply influenced by mental states and psychosocial factors. The study of the complex interrelations between psyche, brain, and biological systems is the specific aim of psychoneuroendocrineimmunology (PNEI), a paradigm that proposes a systemic multidimensional approach to human health, by integrating scientific knowledge derived from both psychological and biological sciences.[[ 2]] More than 40 years ago, Ader and Cohen reproduced an experimental behavior‐conditioned immunosuppression in rats,[ 4] providing the first in vivo indirect evidence of communication between the central nervous system (CNS) and the immune system. In the early 1980s, Besedovsky et al. detected changes in the activity of two main neuroendocrine axes, namely, the hypothalamic–pituitary–adrenal gland (HPA) and hypothalamic–pituitary–thyroid gland, triggered by interleukin‐1 (IL‐1)‐mediated immune response,[[ 5]] This demonstrated that the activity of HPA neuroendocrine branch of the stress response can be enhanced by inflammatory signals produced by immune cells. In 1989, Blalock discovered the production of peptide hormones by peripheral leukocytes and different types of neuroendocrine‐derived cytokines and chemokines, establishing the “molecular basis for bidirectional communication between the immune and neuroendocrine systems.”[ 7] Since 1990, subsequent experimental studies found cytokine expression in CNS both in physiological and pathological conditions and provided the evidence that peripheral immune system can affect the cytokine balance in the brain, thereby altering mood and behavior, as observed in clinical studies conducted on patients exposed to cytokine therapies for cancer or chronic viral hepatitis.[ 8]
A major factor that can profoundly affect the psycho‐neuro‐endocrine‐immune network is stress (see below). Stress is the physiological response of the body to any demand: biological, emotional, and cognitive.[ 9] Whereas acute stress may induce dynamic adaptation to different demands, chronic stress can have long‐lasting maladaptive effects, with pathologic consequences on nervous, immune, endocrine, and metabolic systems.[10] Many psychosocial conditions entailing high levels of chronic stress, that is, poor socioeconomic state, adverse life events, loneliness, experiences of trauma and/or abuse, have been associated with network dysregulation and are thought to be relevant clinical risk factors. Just to mention a few pertinent examples, healthy individuals with a history of childhood trauma showed signs of enhanced inflammation assessed through serum C‐reactive protein (CRP), leukocytes count, and fibrinogen; higher levels of inflammation markers were found among subjects with current depression in addition to a history of trauma.[11] Moreover, recent studies have detected increased levels of inflammation in schizophrenia and other mental disorders.[[12]]
In this brief review, we have recognized the role of stress on the brain and immune system, highlighting the importance of epigenetics as a mechanistic pathway mediating the deep influences of the social and physical environment on brain structure and functions, the immune system, and mental and physical health.
Stress, allostasis, and the brain
Stress is well explained within the conceptual framework of allostasis, a brain‐centered, predictive model of physiological and behavioral regulation.[14] Briefly stated, allostasis relates to the multiple systemic and neural processes that dynamically respond to novel and challenging situations, involving a complex network of nonlinearly and reciprocally interacting mediators (cortisol and catecholamines in primis, as well as the parasympathetic nervous system, cytokines, and metabolic hormones). The integrated action of these mediators is aimed at promoting fitness and adaptation to the ever‐changing environment. In fact, physical and psychosocial threats trigger brain‐driven, multisystemic stress responses that are apt to make the organism temporarily more fit to confront impending demands: An increase is seen in cortical arousal and sensory gating; cognitive and motivational resources are focused on the challenge; and mood shifts toward hypervigilance and anxiety in anticipation of danger. In parallel, endocrine and autonomic systems drive the emergency patterns of visceral activity and regulate inflammatory response. Adaptive in the short‐run, excessive and/or protracted stress responses may have long‐lasting maladaptive effects, with progressive and cumulative “wear and tear” effects on the physiological systems involved in allostasis (allostatic load and overload)[15] that adversely affect health trajectories over time. Moreover, to soothe stress‐related anxiety and depressive symptoms, individuals may indulge in unhealthy behaviors (smoking, compulsive drinking and eating, taking drugs, and social withdrawal), further worsening social stigma, self‐esteem, and allostatic load/overload.[15]
The cortico‐limbic structures involved in cognition and emotional processing (prefrontal cortex (PFC), anterior cingulate, amygdala, insula, hippocampus, and striatum) attribute valence and personal salience to stimuli―under the influence of a variety of moderating factors, such as social support, life experiences and habits, psychological traits, and genetics―and orchestrate behavioral and physiological response to the stressors. In turn, the same brain structures are major target of stress hormones and mediators. Stress‐induced neuronal remodeling (i.e., changes in dendritic extension and branching, spine density, and synapse turnover) is mainly due to the action of norepinephrine and glucocorticoids (GCs), along with other mediators, that is, glutamate and its receptors, brain‐derived neurotrophic factor (BDNF), corticotrophin‐releasing factor, cell surface molecules, protease tissue plasminogen activator, and endocannabinoids. This results in dynamic structural and functional changes in multiple brain areas, depending on nature, magnitude, timing, and persistence of stress exposure.[[16]]
Prolonged stress leads to gray matter reduction and hypofunction of the PFC, a structure critical for working memory, context appraisal, executive, and self‐regulatory functions.[[17]] Neurons of the hippocampus, which are crucial for memory and mood, are endangered by chronic stress through exposure to excess GCs;[17] in keeping with this, prospective reports of chronic life stress in humans have been shown to predict hippocampal volume.[19] Moreover, cumulative adverse life events correlate with gray matter reduction in many emotion‐related brain areas (medial prefrontal, anterior cingulate, and insular cortices).[20] Opposite stress‐related effects occur in the amygdala, including cellular hypertrophy and enlarged dendritic arborization,[21] with enhanced reactivity to adverse stimuli in humans reporting long‐term exposure to a disadvantaged psychosocial environment.[[15], [22]] Despite being generally adaptive in situations that require enhanced vigilance and rapid responses, these structural and functional changes may come, in vulnerable individuals, at the cost of anxiety, poor extinction of adverse memories, and reduced cognitive and behavioral flexibility. This enhances long‐term risks for psychopathology, such as depression, post‐traumatic stress disorder (PTSD), and addiction.[[23]] It is worth noting that structural remodeling of the hippocampus and PFC are common traits in psychiatric diseases and in conditions characterized by chronic stress accumulation (as in shift workers and caregivers) often associated with cognitive deficits, dysregulated cortisol secretion and metabolism, and immune disorders.[15]
Epigenetic mechanisms are regarded as potential mechanistic pathways mediating the transduction of environmental inputs into ever‐changing patterns of gene expression. Stress has been associated with changes in DNA methylation and histone alterations in many stress‐sensitive brain regions,[25] with gene expression changes showing relevant overlap with those found in psychiatric conditions, such as depression.[17] Prenatal and early‐life stressful experiences (ELSs) affect the ontogenetic origin of individual diversities in vulnerability to stress throughout life, producing persistent neuroplastic changes.[26] Seminal studies conducted in rats revealed that low levels of maternal behavior when nurturing pups, that is, poor licking and grooming or arch‐backed nursing, have permanent epigenetic consequences in offspring, such as hypermethylation of the promoter region of GC receptor (GR) gene, thereby reducing hippocampal GR expression and blunting inhibitory control on HPA response.[27] Similar epigenetic changes are reported in humans who have experienced childhood abuse.[[28]] Growing literature confirms that ELS results in neurobiological and cognitive alterations that reflect system‐level adjustments to risky environments, generally promoting avoidance versus approach‐oriented behaviors. Maltreated children display enhanced reactivity and stronger functional interconnectivity of brain areas (amygdala and insula) in the “salience network” involved in threat detection and pain anticipation.[30] Moreover, ELS is associated with disrupted emotional regulation, reduced top‐down control over amygdala reactivity,[[31]] and reduced thickness in many cortical regions involved in emotional processing (medial and lateral PFC and orbitofrontal cortex).[33] Reward system development is also affected: adolescents exposed to emotional neglect show blunted activation of ventral striatum to positive stimuli, which predicts depressive symptoms in later life.[34]
Importantly, stress‐related neuroplastic changes seem to be largely reversible. Weakened functional connectivity in a neural circuit including PFC and reduced cognitive flexibility were found in students tested during a stressful period of examinations; alterations disappeared after a vacation period.[35] However, rather than complete reversal, resilience means achieving a new state and new reaction capabilities.[36] In the rat brain, some of the gene expression changes induced by chronic stress fail to return to prestress levels of transcription after extended recovery, despite a normalization of anxiety‐related behavior.[37] In addition, morphological studies show that after stress abates, dendrites re‐expand and spines/synapses regrow. However, these are more often proximal dendrites than apical ones, thus changing the global morphology (and the connectivity) of neurons.[38]
The mutual link between stress and inflammation
The bidirectional link between stress and the immune system has been well documented for decades, both in animal models and humans. Studies on murine models of repeated social defeat (RSD) reveal that chronic stress and social isolation trigger neuroendocrine and behavioral changes through the activation of HPA pathway together with behavioral adaptation (anxiety). This triggering produces microglial activation and CNS inflammation via GR‐mediated pathways, with increased in situ neuro‐inflammatory cytokine production.[39]At the same time, RSD‐induced stimulation activates the autonomic nervous system (ANS) branch of stress response, which increases sympathetic firing and induces synthesis, activation, and trafficking of peripheral monocytes, irrespective of GR‐mediated pattern.[40] In line with evidence from animal models, human studies have shown that chronically stressed individuals, as in the case of caregivers, display increased blood CRP levels and higher NF‐κB–mediated transcription products in circulating monocytes.[40] In this regard, seminal studies by Irwin and Cole established that life’s adversities and chronic psychosocial distress are typically associated with a concert of epigenetic modifications in the immune cells, including hyperactivation of several proinflammatory transcription factors (i.e., NF‐κB/Rel and GATA‐family), suppression of genes involved in innate immunity (interferon (IFN) response factors), and impairment of GR expression (thereby altering stress response).[[41]] This “conserved transcriptional response to adversity,” which is characterized by increased expression of proinflammatory genes and decreased expression of antiviral‐ and antibody‐related genes, has been found across a diverse array of adverse life circumstances: low socioeconomic status,[43] social isolation,[44] diagnosis and treatment of chronic diseases with higher psycho‐emotional load, breast cancer recurrence,[45] and PTSD.[46]
If psychosocial stress is a powerful regulator of central and peripheral inflammation, then systemic inflammatory factors, in turn, can retroact on the CNS and increase the reactivity of many stress‐ and reward‐related cortical and subcortical structures. This reaction affects social cognition and behavior by enhancing the sensitivity to (thus the saliency of) threatening social experiences, while promoting a behavioral approach toward supportive figures (for a recent review see Ref. [47]). Stress and inflammation are thus inextricably linked and can influence each other. In otherwise healthy subjects, higher sensitivity to social disconnection (and thus to psychosocial stressful events) has been associated with larger increases in circulating cytokines and proinflammatory gene expression in response to endotoxin injection.[48]
These reciprocal interactions between stress‐related brain circuitry and the immune system have been proposed as important contributors to the pathogenesis of a variety of medical and mental diseases. These conditions are frequently comorbid and variably associated with inflammatory system dysregulation; they include anxiety and depression, and cardiovascular and metabolic diseases. Increased inflammatory biomarkers, such as IL‐1β, IL‐6, TNF‐α, CRP, and ICAM‐1, have been found in depression.[[49]] Moreover, inflammation can increase frequency and severity of depressive symptoms, as observed in patients suffering from several chronic pathologic conditions (i.e., inflammatory relapse in rheumatoid arthritis) or who underwent specific treatments, such as IFN therapy, which was initially used in the 1990s to treat patients affected by chronic viral hepatitis. Moreover, the higher prevalence of co‐occurrence of depression and inflammatory diseases was clearly observed in several studies conducted in the last two decades. Patients with type 1 and type 2 diabetes are more likely to have depression, with prevalence more than three times and nearly twice higher, respectively, compared to nondiabetics.[52] In addition, a meta‐analysis has recently shown that the prevalence of type 2 diabetes is consistently elevated among persons with severe psychiatric diseases (i.e., schizophrenia, bipolar, or major depressive disorders), including antipsychotic‐naive participants.[53]
Depression and anxiety are commonly diagnosed among patients with coronary heart failure (CHF). In CHF patients, depression worsens both primary and secondary outcomes: all‐cause and cardiac mortality rates, cardiac symptoms, hospitalization, and quality of life. A recent Danish nationwide study, despite the use of strict inclusion criteria for the diagnosis of depression, has drawn the following conclusions: “A history of depression was an adverse prognostic factor for all‐cause mortality in heart failure patients with left ventricular ejection fraction ≤35% but not for other heart failure patients.”[54] Mounting evidence indicates that patients diagnosed with depression exhibit autonomic and biochemical dysregulations comparable to those observed in patients with heart failure; these include decreased heart rate variability and increased elevated circulating levels of proinflammatory cytokines (i.e., TNF‐α and IL‐1), CRP, and platelet hyperactivity.[55] Interestingly, in response to a mental arithmetic task, patients with coronary artery disease have a greater increase of CRP and IL‐6 compared to healthy controls, with an observed positive relationship between stress intensity and strength of inflammatory response.[56]
In sum, psychosocial stress can boost inflammation, and inflammation can, in turn, cause or aggravate depression and other cardiovascular and metabolic disorders. Taken together, these findings show that adverse life events and chronic stress are “getting under the skin” and can influence lifelong health trajectories through physical and mental consequences.
Focus on mental health and stress management: clinical effectiveness of psychotherapy and min…
Despite huge investments in the development of several new classes of antidepressants, depressive disorders remain the most diagnosed psychiatric diseases in the world with global estimates of prevalence of 322 million of people.[57] Average response rates to antidepressant drugs are approximately 40–60%, and remission rates range from 30% to 40%.[58]
Thanks to their synergistic effects, current therapeutic approaches tend to combine pharmacological and nonpharmacological interventions to improve symptoms and ameliorate quality of life in patients affected by psychiatric disturbances. Evidence‐based psychotherapies[59] and mind‐body therapies (MBTs) have proven effective in reducing symptoms of anxiety and depression in both patients with primary mental disorders and patients with chronic diseases (i.e., cancer[60] and chronic pain[61]).
One of the first applications of psychotherapy in psychiatric diseases was targeted to treat mood disorders. Cognitive behavioral therapy (CBT) exhibits a convincing cost/effectiveness profile in the management of a wide range of psychiatric diseases, including anxiety and depression,[62] both when used alone and in combination with antidepressants.[63] CBT is currently recommended as the first‐line choice for ambulatory treatment of adult depressed patients[64] and as combined and/or sequential treatment to complement psychiatric drugs, in drug‐resistant[65] and relapsed major depression,[66] panic disorder, generalized anxiety disorder, and obsessive‐compulsive disorder.[64]
A multispecialist approach is also recommended in therapeutic management of PTSD to mitigate symptoms (i.e., disturbing thoughts and feelings, recurrent dreams, and trauma‐related distress) and reduce incidence of cognitive impairment, substance abuse, and suicidal behaviors. Despite limitations derived from the quality of the studies, Cochrane metanalyses show positive results for all types of psychotherapies among children and adolescents.[67] In adults with PTSD, individual trauma‐focused CBT, eye movement desensitization and reprocessing, and nontrauma‐focused CBT are the psychotherapeutic approaches that have shown the highest efficacy; this approach is also successful among high‐risk patients.[[68]]
Over the last decades, meditation practice has spread in Western countries as a safe and efficacious remedy to counteract distress. Evidence on the efficacy of mindfulness‐based interventions (MBIs) for management of psychological health, both in medical and psychiatric patients, as well as in healthy subjects,[70] has been growing. Mindfulness‐based cognitive therapy (MBCT), incorporating cognitive strategies into the theoretical and practical framework of mindfulness‐based stress reduction (MBSR), is recommended as an adjunctive treatment for unipolar depression, since it has been found effective in reducing current episodes of depression[[71]] and relapse of the disease.[73]
As adjuvant therapy to standard medical treatment, MBIs reduced symptoms of depression and anxiety among elderly women[74] and in mothers who suffered from postpartum depression.[75]
In an RCT that included older adults with depression and neurocognitive decline, the mindfulness group, compared to controls, showed significant improvements in memory functions and mood outcomes.[76] Some results suggest that both MBSR and MBCT are safe and efficacious interventions for anxiety symptoms.[77] Moreover, MBI group therapy was found to be noninferior to CBT when applied to patients with depressive, anxiety, or stress‐related disorders in primary care.[78] In patients diagnosed with substance‐use disorder, psychiatric disorder, and trauma exposures, MBIs have been associated with significant improvements in substance craving, relapse, and post‐traumatic stress disturbances compared to CBT or usual treatment.[79] MBSR also resulted in effective improvement of symptoms and psychological quality of life in veterans with PTSD.[80]
s personal stress look like (i.e., financial, school, work, relationships)? Using the results of the questionnaires, what are some ways to cope with stress? How does a student personally cope (i.e., diet, exercise, faith)?
