Psychosocial Stress, Inflammation, and Adhesion Molecules

I have been re-reading a book by Joseph LeDoux (NYU), Synaptic Self: How Our Brains Become Who We Are (2002), in which he argues that synapses in the brain are the foundation of personality, the basis of our sense of self:

My notion of personality is pretty simple: it‟s that your “self,” the essence of who you are, reflects patterns of interconnectivity between neurons in your brain. Connections between neurons, known as synapses, are the main channels of information flow and storage in the brain. Most of what the brain does is accomplished by synaptic transmission between neurons, and by calling upon the information encoded by past transmission across synapses. (p. 3-4)

This is relevant to some of the work I have been doing for Dr. Cress at the University of Arizona Cancer Center. Dr. Cress has been working for many years on the function of integrins in cancer metastasis, specifically in prostate cancer.

Here is how integrins are defined at Wikipedia, which is as precise as any you will find.

Integrins are transmembrane receptors that are the bridges for cell-cell and cell-extracellular matrix (ECM) interactions. When triggered, integrins in turn trigger chemical pathways to the interior (signal transduction), such as the chemical composition and mechanical status of the ECM, which results in a response (activation of transcription) such as regulation of the cell cycle, cell shape, and/or motility; or new receptors being added to the cell membrane. This allows rapid and flexible responses to events at the cell surface, for example to signal platelets to initiate an interaction with coagulation factors.

There are several types of integrins, and a cell may have several types on its surface. Integrins are found in all metazoa.^[3]

Integrins work alongside other receptors such as cadherins, the immunoglobulin superfamily cell adhesion molecules, selectins and syndecans to mediate cell–cell and cell–matrix interaction. Ligands for integrins include fibronectin, vitronectin, collagen, and laminin.

Integrins are heterdimic adhesion receptors, meaning they have two different parts, the α (alpha) and β (beta) subunits. There are at least 18 α and eight β subunits are known in humans and other vertebrates (Takada, Ye, & Simon, 2007).

Dr. Cress has been work with the A6B4 integrin (alpha 6 beta 4) and its role in metastatic prostate cancer. A6 is one of three laminin-binding molecules in humans (the others are A3 and A7), although other researchers suggest there are five laminin-binding integrins, A1, A2, A3, A6, A7 (Alberts, Johnson, & Lewis; 2007; Molecular Biology of the Cell. 5th edition). This graphic explains the functions of the different integrins and their combinations.

Integrins are also expressed in the brain, especially in synapses and in the lamination of axons, which allows information to more quickly and efficiently through the brain (and through neural cells throughout the body). Schwann cells in peripheral nerves interact with axons and extracellular matrix (ECM) as part of their work in ensheathing and myelinating axons and they express B4 (beta 4 integrin) [Feltri, et al, 1994], and specifically A6B4. 

In digging around for additional information on synapses and brain function, I found a related article by LeDoux - this is the abstract (crucial section is in bold):

STRUCTURAL PLASTICITY AND MEMORY
Raphael Lamprecht and Joseph LeDoux

Much evidence indicates that, after learning, memories are created by alterations in glutamate-dependent excitatory synaptic transmission. These modifications are then actively stabilized, over hours or days, by structural changes at postsynaptic sites on dendritic spines. The mechanisms of this structural plasticity are poorly understood, but recent findings are beginning to provide clues. The changes in synaptic transmission are initiated by elevations in intracellular calcium and consequent activation of second messenger signalling pathways in the postsynaptic neuron. These pathways involve intracellular kinases and GTPases, downstream from glutamate receptors, that regulate and coordinate both cytoskeletal and adhesion remodelling, leading to new synaptic connections. Rapid changes in cytoskeletal and adhesion molecules after learning contribute to short-term plasticity and memory, whereas later changes, which depend on de novo protein synthesis as well as the early modifications, seem to be required for the persistence of long-term memory.

Source: Nature Reviews Neuroscience; January 2004; 5(1):45-54. doi:10.1038/nrn1301 

Rho GTPaseas mediate extracellular stimulation-induced actin cytoskeleton rearrangements. Stimulation of the postsynaptic neuron leads to actin-dependent morphological changes mediated by Rho GTPases105–108. 1) Activation of adhesion molecules, such as integrin or cadherin, which have been shown to be involved in synaptic plasticity, regulates Rho GTPase inactivation by RhoGAPs. 2) Calcium influx through membrane channels can induce activation of tyrosine kinases (TKs), such as the cell adhesion kinase-β/proline-rich tyrosine kinase 2 (CAKβ/Pyk2), that in turn activate Src. The later modulates p190 RhoGAP activity and thereby controls Rho GTPase inactivation. 3) On the other hand, Rho GTPase activators, RhoGEFs, are also regulated by extracellular stimulation. Ephrin A activates, through the receptor tyrosine kinase EphA, a Rho GEF called ephexin. EphA has been implicated in memory formation133. 4) Rho GTPase controls actin polymerization through downstream effectors such as Rho-associated kinase (ROCK). ROCK activates LIM-domain-containing protein kinase (LIMK), which in turn inhibits the actin depolymerizing factor cofilin. This event can contribute to actin polymerization. ROCK, LIMK and cofilin have been shown to be involved in synaptic plasticity. 5) Cdc42 and Rac, other members of the Rho GTPase family, induce actin polymerization by regulating downstream effectors. GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; N-WASP, neuronal Wiskott-Aldrich syndrome; SCAR, suppressor of cAR.

The text above is the caption for the image. Here is another quote from near the end of the paper, which is minimal and could be the topic of an entire paper:

Adhesion molecules and synaptic plasticity 

The formation of new synaptic contacts is a dynamic process that involves ongoing morphological alterations and modulation of adhesion between the pre- and postsynaptic neurons [115,116]. These processes require coordinated activity between molecules that regulate cytoskeletal rearrangements and morphology, and those that control adhesion between the pre- and postsynaptic membranes.Adhesion molecules, mostly integrins, cadherins, neurexin and the immunoglobulin superfamily, are membrane-bound molecules that have hetero- or homophilic interactions with proteins in the extracellular matrix and synaptic membranes to control the adhesion between the pre- and postsynaptic membranes. Adhesion molecules, which also have an intracellular component, can initiate signalling pathways that couple the dynamics of extracellular connectivity with intracellular events that control morphology. For example, cadherin regulates dendritic spine morphogenesis and function. Blockade of cadherin function leads to elongation of the spine, bifurcation of its head structure and alterations in the distribution of postsynaptic proteins [117]. Moreover, neuronal activity induces the movement of β-catenin (which mediates the interaction of cadherin with the actin cytoskeleton) from dendritic shafts into spines to become associated with cadherin and to influence synaptic size and strength [118]. Adhesion molecules such as cadherin also associate with molecules that regulate cytoskeletal rearrangements, such as proteins that control the Rho GTPase pathway [119].

Adhesion molecules could therefore contribute to the morphological alteration and stabilization of connectivity between neurons, a process that is hypothesized to underlie memory consolidation. Consistent with this hypothesis is the role of adhesion molecules in the formation and stabilization of LTP and LTM. Integrin-mediated adhesion helps to stabilize early-phase LTP (E-LTP) into late-phase LTP (L-LTP). For example, inhibition of integrin with a peptide that contains the integrin recognition sequence 10 min before, immediately after and 10 min after LTP induction caused a gradual decay of synaptic strength over 40 min [120]. The peptide had no effect when applied 25 min after LTP initiation, indicating that integrin has a role in stabilization of synaptic connectivity. Furthermore, N-cadherin is synthesized and internalized to new assembled synapses during the induction of L-LTP, and blocking N-cadherin adhesion prevents the induction of L-LTP but not E-LTP [121]. This event depends on glutamate receptor activity. In chicks, memory is impaired 24 h after a visual categorization task when antibodies against the cell adhesion molecule L1 are injected before, 5.5 h or 15–18 h after training (but not later) [122]. In addition, intraventricular injection of antibodies against neural cell adhesion molecule (NCAM) in rats 6–8 h after passive avoidance training, but not later, impaired retention of the avoidance response [123]. These observations indicate that adhesion molecules are essential for memory consolidation during a period of hours after acquisition.

The level and distribution of adhesion molecules is also correlated with synaptic plasticity and learning. In Aplysia, repeated application of 5-hydroxytryptamine (serotonin; 5-HT), which leads to long-term facilitation of the sensory–motor connection, induces the internalization of the adhesion molecule apCAM (Aplysia cell adhesion molecule) [43]. This could destabilize the interaction between sensory neurons, permitting the growth of new sensory axons.ApCAM could be redistributed to the area where new synapses are formed. In rats, N-cadherin is induced in the piriform cortex and hypothalamus 2 h after fear conditioning [124]. N-cadherin was not induced in control animals that were presented with the conditioned stimulus and unconditioned stimulus in a non-associative manner.

On the whole, these observations indicate that adhesion molecules have a central role in mediating neuronal connectivity and morphogenesis, and in the progressive stabilization of synaptic connectivity that leads to memory consolidation. (LeDoux, 2004, pages 50-51)

I did some more digging and found that A3, A5, A8, and B1 (McGeachie, Cingolani, & Godaare, 2011) are all expressed in synaptic formation and function and in the growth and activity of dendrites. If the alpha versions of the integrins are not functioning properly, learning and memory are inhibited, but there are differences for each of the alpha integrins and for the beta integrin:

Interestingly, behavioural tests revealed specific deficits in hippocampal-dependent working memory, while spatial memory was unaffected. Although ITGβ1 is likely to be the major subunit for ITGα3, ITGα5 and ITGα8 in the hippocampus (Hynes, 2002), ITGα3/+;ITGα5/+;ITGα8/+ mice showed behavioural deficits (see above) that are different from those of ITGβ1 conditional knockout mice. Such divergent results may reflect the differences arising from global reduction in ITGα3, ITGα5 and ITGα8 versus a more specific ablation of ITGβ1 mainly in CA1 pyramidal neurons.

[In the quote above, ITGα3, and so on, is used to represent integrin (ITG) alpha 3.] 

Inflammation from Psychosocial Stress

We know that psychosocial stress causes inflammation. University of Arizona researcher/professor Charles Raison (2006) found that depressed patients have higher levels of proinflammatory cytokines, acute phase proteins, chemokines, and cellular adhesion molecules (an important finding for my thesis). It has also been shown that therapeutic administration of the cytokine interferon-α (a cancer treatment drug that inhibits tumor cell growth) leads to depression in up to 50% of patients (Bonaccorso, et al, 2002).

Stress appears to down-regulate immunity through at least three mechanisms:

(A) Stress hormones are influenced by negative events and negative emotions: catecholamines (adrenaline and noradrenaline), adrenocorticotropic hormone (ACTH), cortisol, growth hormone, and prolactin, as examples

(B) Immune modulation by these hormones proceeds through two pathways: 

1. Directly, through binding of the hormone to its cognate receptor at the surface of a cell 
2. Indirectly — for example, by inducing dysregulation of the production of cytokines, such as interferon-γ (IFN-γ), interleukin-1 (IL-1),IL-2,IL-6 and tumour-necrosis factor (TNF)

Cytokines such as IFN-γ have many functions and affect different target cells. Therefore, there are secondary effects of many stress hormones on the immune response

(C) Communication between the CNS and the immune system is bidirectional - examples: 

1. IL-1 influences the production of corticotropin-releasing hormone (CRH) by the hypothalamus. In turn, CRH can affect the HPA axis and thereby trigger increases in stress hormone levels, which results in dysregulation of immune function 
2. Lymphocytes can synthesize hormones such as ACTH, prolactin and growth hormone

Glaser, R., & Kiecolt-Glaser, J. K. (2005). Stress-induced immune dysfunction: implications for health. Nature Reviews Immunology, 5(3), 243-251.

Here is the abstract (edited for relevance) from an excellent review article: Psychosocial stress and inflammation in cancer by Powell, Tarr, and Sheridan (2013) that provides some useful information about how stress (i.e., trauma) can compromise the immune system. [Bold area is my emphasis.]

Stress-induced immune dysregulation results in significant health consequences for immune related disorders including viral infections, chronic autoimmune disease, and tumor growth and metastasis.  Both human and animal studies have shown the sympathetic and neuroendocrine responses to psychosocial stress significantly impacts cancer, in part, through regulation of inflammatory mediators. Psychosocial stressors stimulate neuroendocrine, sympathetic, and immune responses that result in the activation of the hypothalamic–pituitary–adrenal (HPA)-axis, sympathetic nervous system (SNS), and the subsequent regulation of inflammatory responses by immune cells. Social disruption (SDR) stress, a murine model of psychosocial stress and repeated social defeat, provides a novel and powerful tool to probe the mechanisms leading to stress-induced alterations in inflammation, tumor growth, progression, and metastasis.

The following is from the first section of the same paper and it provides an overview of the chemical pathways involved in stress-induced inflammation.

[S]tudies using a mouse model of repeated social defeat, termed social disruption (SDR) stress, have shown that stress alone can trigger the generation, egress, and trafficking of immature, inflammatory myeloid derived-cells that are glucocorticoid (GC) insensitive (Curry et al., 2010, Engler et al., 2004a and Engler et al., 2005). In addition, these GC insensitive cells produce high levels of IL-6 and other inflammatory cytokines and chemokines (Powell et al., 2009, Stark et al., 2002 and Wohleb et al., 2011). As a consequence, these stress-induced changes at the cellular level translate to significant immune (enhanced inflammatory responses and immunity to microbial, viral, and allergen challenge) and behavioral (prolonged anxiety-like behavior) changes (Bailey et al., 2007, Bailey et al., 2009b, Bailey et al., 2009a, Dong-Newsom et al., 2010, Kinsey et al., 2007, Mays et al., 2010, Mays et al., 2012, Powell et al., 2011 and Wohleb et al., 2011). Indicative of the important role of the SNS in stress-induced immune alteration, these changes are reversed by the blockade of sympathetic signaling prior to stressor exposure (Wohleb et al., 2011).

The stress response in vertebrates stems from internal or external stimuli that trigger the “fight or flight” and "defeat/withdrawal" responses expressed in sympathetic nervous system (SNS) and the hypothalamic–pituitary–adrenal (HPA)-axis activation. Years of research has shown that specific central nervous system (CNS) pathways function as translators of social stimuli into peripheral biological signals that regulate inflammatory responses.

For instance, stress activates neuroendocrine and autonomic pathways like the HPA axis, and the SNS resulting in the release of GC, catecholamines, and pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α. The release of these sympathetic, neuroendocrine, and immune factors has a profound influence on immunity, behavior, and physiology in both humans and rodents and triggers peripheral biological responses that, in turn, signal back to the CNS to complete a bi-directional communication circuit. This is evident in models of repeated social defeat, like SDR, that enhance immune responses to microbial, viral, and allergic challenges and promote and prolong anxiety-like behavior in rodents (Kinsey et al., 2007, Bailey et al., 2009a, Bailey et al., 2009b and Mays et al., 2010). Social disruption stress-induced prolonged anxiety-like behavior coincides with a unique pattern of c-Fos activation in brain regions associated with fear and threat appraisal. For example, repeated social defeat, termed social disruption (SDR) causes increased c-Fos activation in the prefrontal cortex, amygdala, hippocampus, paraventricular nucleus, bed nucleus of the stria terminalis and the lateral septum (Wohleb et al., 2011). [Powell, Tarr, and Sheridan, 2013, p. 3]

When the HPA and SNS circuitry are activated, the release of neurotransmitters and stress hormones generates compensatory physiologic changes that impact behavior and the function of the immune system. In humans, chronic or repeated exposure to stress appears to lead to increases in the expression of inflammatory biomarkers, worsened disease states, and affective/emotional disorders (Glaser and Kiecolt-Glaser, 2005; Gouin et al., 2012).

In several studies, stressed individuals exhibit reduced anti-inflammatory glucocorticoid regulation and increased inflammatory nuclear factor (NF)-κB signaling (Miller et al., 2008). In these situations, psychosocial stress represents a challenge to homeostasis that manifests as physiological alterations in the body (Glaser and Kiecolt-Glaser, 2005).

This may be something to look at in terms of how trauma impacts the brain and body, a microbiological model of traumatic stress, inflammation, and the alteration of adhesion molecules, all of which leads to impaired learning and impaired memory.

As of now, there are no known interventions at the cellular level for altering integrin function. However, the are many ways to control and eliminate inflammation. Among the most well-researched (I could provide citations for these, but it's late, so I might add them later):

1) Curcumin/turmeric
2) Resveratrol
3) Exercise
4) Stress-reduction techniques, such as meditation
5) Avoiding smoking, drinking, and processed foods

We have some control over how our bodies manage and adapt to stress. We are not merely victims of our biology.

The Restorative Power of Nature for Dealing with Psycho-Physiological Stress

The healing powers of nature can be very profound. The experience of calm, peace, or awe (subjective) no doubt contributes to the neurochemical changes in the brain (objective) that reduce anxiety and depression, as well as helping us cope better with stress.

Full Citation:
Berto, R. (2014, Oct 21). The Role of Nature in Coping with Psycho-Physiological Stress: A Literature Review on Restorativeness. Behavioral Sciences; 4(4), 394-409; doi:10.3390/bs4040394

The Role of Nature in Coping with Psycho-Physiological Stress: A Literature Review on Restorativeness

Rita Berto

(This article belongs to the Special Issue Advances in Environmental Psychology)

Abstract

Physical settings can play a role in coping with stress; in particular experimental research has found strong evidence between exposure to natural environments and recovery from physiological stress and mental fatigue, giving support to both Stress Recovery Theory and Attention Restoration Theory. In fact, exposure to natural environments protects people against the impact of environmental stressors and offer physiological, emotional and attention restoration more so than urban environments. Natural places that allow the renewal of personal adaptive resources to meet the demands of everyday life are called restorative environments. Natural environments elicit greater calming responses than urban environments, and in relation to their vision there is a general reduction of physiological symptoms of stress. Exposure to natural scenes mediates the negative effects of stress reducing the negative mood state and above all enhancing positive emotions. Moreover, one can recover the decrease of cognitive performance associated with stress, especially reflected in attention tasks, through the salutary effect of viewing nature. Giving the many benefits of contact with nature, plans for urban environments should attend to restorativeness.

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Introduction

This brief review attempts to draw greater attention to the role of the physical environment in stress recovery and psychological restoration processes. As people interact daily with physical settings, the physical environment can heighten stress or help people cope with it. “Stress” can be defined as the condition that results when person-environment transactions lead the individual to perceive a discrepancy (whether real or not) between the demands of a situation and the biological, psychological or social resources of the individual [1]. The negative effects of stress can be measured in various ways inside and out of the laboratory and these measures fall into three categories: those that rely on (1) neuro-physiological or bodily changes in the individual experiencing stress, (2) performance or behavioral changes and (3) self-report by individuals. The present paper updates and reviews the literature from each area, discussed separately.

In Psychology, most theoretical accounts of stress effects invoke some variation of the inverted U-hypothesis relating arousal to performance [2], with both high and low levels of arousal causing reduced performance. However, other theories account for effects of stress on cognition, specifically on attention allocation, with stress overloading attentional capacity for the deployment of attention itself and other resources [1]. Except for social support (operationalized primarily in terms of family, socio-cultural and economic conditions), Health Psychology has directed attention away from environmental factors that can be coping resources, whereas research and theories in Environmental Psychology point also to certain kind of environments that have the capacity to facilitate recovery of depleted resources. Environmental conditions are antecedent factors in stress-related mechanisms interceding between environment and health: they might operate as an environmental stressor, straining human adaptive capacities, or as a coping strategy, re-establishing some balance between environmental demands and personal resources. People rarely respond to stressful conditions passively, instead they use coping strategies. The physical environment can damage or ameliorate coping resources, thus heightening or reducing stress themselves. 

2. The Mechanisms and Theoretical Approaches Underlying the Phenomenon

Experimental research has found evidence that restoration from stress and from mental fatigue relates to exposure to nature [3,4]. Natural environments protect people against the impact of environmental stressors and offer physiological, emotional and attention restoration more so than do urban environments. Natural places that allow a shift towards more positively-toned emotional states, positive changes in physiological activity levels, and in behavior and cognitive functioning are called restorative environments [5,6]. For pragmatic and theoretical reasons [7] nature scenes dominated by green vegetation have been the most frequently studied among restorative environments, with a relatively high success rate [8]. Exposure to nature is a coping strategy, which has positive effects on both arousal/activation level and cognitive overload. Arousal theories [9,10] imply that recuperation from excessive arousal should occur more rapidly in settings having low levels of arousal. Since natural settings tend to have lower levels of arousal properties, such as complexity, intensity and movement than urban environments [11], they should have comparatively restorative influences on stress. The alternative overload perspectives provide a different explanation of why recuperation following a stressor may be more rapid when external stimulation is comparatively low. High complexity and other increasing-stimulation properties typical of urban settings, place taxing processing demands [12] and elicit more sustained attention than nature settings; accordingly restoration from cognitive overload is hampered.

Research on restorative environments has developed within two complementary theoretical positions: the Stress Recovery Theory (SRT) [13] and the Attention Restoration Theory (ART) [6]; the former is a psycho-evolutionary theory, while the latter a psycho-functionalist. The evolutionary perspective contends that because humans evolved over a long period in natural environments, people are to some extent physiologically and perhaps psychologically adapted to natural, as opposed to urban settings [4]. To functionalist, humans have an unlearned predisposition to pay attention and respond positively to natural content (e.g., vegetation, water) and to configurations characteristic of settings that were favorable to survival during evolution [5,13,14,15]. Although in both theories natural environments are more restorative than urban or artificial environments, they differ in what drives individuals toward a restorative place: In SRT it is physiological stress, whereas in ART it is mental fatigue. These theories complement one another, in that the elevated physiological arousal and negative affect characteristic of stress (SRT) can occur in absence of mental fatigue. Conversely elevated arousal or negative affect do not always accompany attentional fatigue (ART); attentional fatigue can be considered a stress aftereffect and treated as a condition that increases vulnerability to stress [3,4,6,12,16].

Research related to these two theories agrees on two findings: (1) Environmental preference is affected by people’s need to get restoration [17,18,19,20,21,22]; (2) Environments perceived as natural tend to be more restorative than environments perceived to be urban or artificial e.g., [3,23,24,25,26,27,28]. In fact, research shows restoration related to environmental preference, but the direction of the effect remains unclear; however the positive linear correlation between the perception of place restorative qualities and environmental preference may suggest that the general preference for natural environment can be explained by individual conviction that “psycho-physiological” restoration occurs easier in natural environments. In practice people prefer natural environments because those places allow maintaining or enhancing psycho-physiological wellbeing.

Mental fatigue gives higher preference for the natural over the urban environment [22]. Nature is especially conducive to our involuntary attention engagement; on the contrary built content captures attention dramatically, requiring attention to be overcome [6,8,24]. In the ART this attention-drawing quality of natural settings is referred to as “soft fascination” [6]. When nature captures people’s attention, the executive system that regulates directed attention gets to rest, pessimistic thoughts are blocked, and negative emotions are replaced by positive ones [29]. In addition to fascination, nature is characterized also by other properties called restorative factors, which work together with fascination. Actually, the renewal of a depleted capacity also occurs with a physical and/or psychological “being-away” from demands on directed attention, a sense of “extent”, i.e., being in a large enough world where “coherence” and “scope” are perceived in the environment, and “compatibility” between one’s inclinations and the environmental demands, for more details see [6,21,23].

The research does not claim that the restorative experience can occur only in natural environments, nor does it state that all urban environments lack restorative qualities [30,31]. For example, some natural environments would not likely be restorative because they are perceived as dangerous [32,33], and some urban environments, such historical environments [18], museums [34], or monasteries [35], can sustain restoration because they have to some extent restorative qualities, are easily approachable and so compatible with the little free time of the majority of the inhabitants of the city [36,37]. Accordingly the involuntary attentive process might be activated also by the vision of urban environments [31], but only if environmental information is fascinating, i.e., doesn’t overload the attentive system [38], as nature does. ART claims that fascination is a restorative characteristic of an environment related to information processing, therefore suitable urban-artificial solutions can sometime fill the gap due to the lack of nature [30,31,39]. 

3. The Direct and Indirect Effects of Natural Environments

Central to the recovery from psycho-physiological stress are positive changes in emotional states. Exposure to natural environments produce positive mood chances, actually exposure to natural stimuli can mediate the negative effect of stress reducing the negative mood state and at the same time enhancing positive emotions. In particular, natural settings have restorative influences on three affective dimensions: positive affects, anger/aggression, and fear [4,40,41]. Moreover, people report more positive emotions (such as friendliness) and fewer negative emotions (such as sadness) when viewing urban scenes with trees than when viewing the same scenes with inanimate objects [42]. In contrast, exposure to environments lacking of natural elements can produce anxiety, anger, frustration and sadness [43,44]. The association between environment and emotions leads people to assess natural environment on the opportunity they offer to regulate mood, in practice preference for natural environments arises from the favourable effects on mood of such environments [45].

The positive emotional states elicited by viewing natural stimuli are part of the mechanism underlying the landmark Ulrich’s [46] finding that hospital patients had more favorable recovery (shorter post-operative hospital stays, lower scores post-surgical complications, fewer negative comments in nurses’ notes, fewer strong analgesic intake) if their windows overlooked trees rather than a brick building wall. Exposure to nature can reduce anxiety, improve pain control and patients’ satisfaction with the procedure [47,48]. One study found that the exposure to natural environments (pleasant stimuli) effectively distracted patients from stressful or painful conditions [47]. Another study found that heart-rates and self-reports of emotional state of patients in dental clinics improved with exposure to natural environments [49]; patients felt calmer on days when a mural depicting a natural scene was on the wall then on days when the wall was blank. To this end, Diette et al. [47] recommended the routine clinical use of nature sights and sounds of sights. The use of nature scenes was shown to be an effective tool for “distraction”, i.e., patient’s attention is focused on a pleasant stimulus and away from a stressful or painful condition. Research in prisons has shown that prisoners whose cell windows offered views of farmland and trees had lower frequencies of stress symptoms such as digestive illness and headaches, and fewer sick calls than prisoners whose cell windows offered views of the prison courtyard [50,51].

The negative effects of psycho-physiological stress can also manifest with significant decreases of cognitive performance. However, people can recover cognitive efficiency simply taking advantage of the beneficial effect deriving from exposure to nature. For example, children playing in highly natural school playgrounds showed fewer attention and concentration problems, and improved cognitive and physical functioning than children playing in less natural school playgrounds, for a review [52]. At workplace, a view of natural elements was found to buffer the negative impact of job stress, intention to quit and it had a positive effect on general wellbeing and cognitive functioning [53,54]. The most significant understanding of nature’s salutary effect on cognition comes through studies of attention. Research has shown that natural settings might have restorative effects that include increased performance on task requiring attention and cognitive processing [5,23,55,56,57]. Cognitive restoration following visual exposure to the natural environment, as reflected in improved performance on attentional tasks, has been established in a variety of experimental studies involving either the use of videos [17] or actual field trips [3,58,59], or image slideshows of natural scenes [23,55]. Kaplan’s ART [6] gives a convincing explanation of what makes up the so-called “psychological restoration.” The theory originated when it was noticed that people preferred scenes depicting natural than urban environments, and exposure to natural environments had a profound restorative effect on the ability to focus, in practice people’s attention was easily and almost effortlessly held. The tenets of this theory state that a person can engage two types of attention: involuntary and voluntary, for more details see [60]. The former is a rather effortless form of attention, in contrast the latter, otherwise called directed attention, requires a good deal of focus and effort that leads inevitably to mental fatigue. The mental fatigue state increases the probability that an individual experiences the stress response due to the cognitive overload, and the concomitant reduction of the cognitive resources necessary to address daily requests. Mental/attentional fatigue manifests itself in negative emotions, irritability, impulsiveness, impatience, reduced tolerance for frustration, insensitivity to interpersonal cues, decrease altruistic behaviors, reduced performance, increased likelihood of taking risks [58,61,62,63,64], generally speaking in reduced competence and/or decreased effectiveness in functioning [58,63]. In practice, the inability to renew the attentional capacity aggravates the mental fatigue state and can also damage mood, work performance and interpersonal relationships.

Nature may not only have direct effects on stress recovery and mental fatigue restoration, but it may also have indirect effects by serving as a buffer against the health impacts of stressful events [65]. Many people seek out nature in time for stress. Unfortunately due to increasing urbanization, modern people’s homes have become more removed from green environments [65]. Restricted access to green spaces may increase people’s vulnerability to the impact of stressful life events and environmental stressors affecting physical and psychological wellbeing. Higher accessibility to park/forest-like area correlates with higher happiness, lower stress, anger, depression and tension, improved mood and concentration [17]. In particular, the amount of green space within a radius of 1–3 km relates to perceived general health [66].

Thus, urban green besides making our cities more appealing, gives relief from stressful life, and an opportunity to recover cognitive resources and restore the optimal level of physiological activation [5,13,44,67]. This can have positive effects on sense of control, privacy, encouraging personal relationships and physical exercise, and offering natural fascinating distractions that promotes positive emotions and mood. Loss of control and the lack of privacy can aggravate the stress condition and threaten individual’s capacity to cope with stressful situations [68]. Exposure to nature offers the opportunity to display control through a “temporary being-away” or “temporary escape” from reality. Estrangement from habits/routines means to go away from the source of stress. ]Regarding social support. Outdoor spaces and gardens can promote social relationships and enhance the sense of community. Mental health services engage nature-related programs (horticulture, gardening) to provide opportunities that enhance multiple aspects of health and wellbeing, increase constructive interpersonal relationships that enhance social inclusion, and support the destigmatization of mental illnesses [69,70]. Participants benefit from the increase of positive emotions, expand healthy relationships with peers and staff, improve physical activity, have greater involvement in familiarity within the community and exhibit skills that enable acceptance in the community and the perception of being part of the community [71]. Active participation in nature has additionally been found to reduce mental distress, enhance self-confidence and improve physical health of the participants [72].

The recognition of nature’s health benefits has brought to broader discussion on public health and also inspired practical applications. In particular psychologists have begun to study whether technology can salvage some of nature’s healthful properties [73]. Although virtual nature may not replace actual nature, people who are not able to go outside can benefit from exposure to virtual nature [74]. When real nature is not at hand, surrogate (artificial plants, potted plants) or simulation (pictures of nature, films, slides) of nature are accepted at work, in hospitals or institutions providing restorative effects such as improved affect and decreased physiological stress [17,75]. In particular, the immersion in a virtual computer-generated nature setting has been found to be a valid therapeutic aid in treatment of anxiety disorders and an effective tool in stress management and relaxation [76,77]. Virtual settings are enriched with a variety of positive visual and auditory stimulation that affect self-efficacy and mood; the virtual reality (VR) scenario-experience is vivid and real and induces a high sense of “presence” that affects relaxation and the emotional response. 

4. How to Measure the Effects of Natural Environments

4.1. Physiological Effects

Though their concern was not to compare the effects of natural vs. urban settings, back in 1963 Wadeson et al. [78] found evidence that exposure to natural environments had a direct influence on urine and blood levels of cortisol, a stress-related hormone. More recently, literature has shown that independently from the type of exposure: plants, poster, slides, video, VR settings or views of natural environments/stimuli, people experience a general reduction of symptoms related to psycho-physiological stress. Natural environments elicit greater calming physiological and psychological responses than urban environments. The SRT [13] proposes exactly that perceiving particular qualities and contents in a place can support recovery from physiological stress. Using a paradigm in which stressed individuals were exposed to simulations of either natural or urban environments, Ulrich encompassed the range of restorative effects of the natural environments on human beings [4,13,46,79]. Research showed different rates of recovery from stress depending upon the type of environmental exposure. Physiological measures of stress (e.g., electromyography, skin conductance response, pulse transit time, cardiac response, partial thromboplastin time) indicated that recovery was quicker and more complete in the natural environment exposure conditions, even when recovery was measured over a 10-minute period only [79]. In the initial minutes of recovery the parasympathetic component response was recorded to the natural environments, whereas there was no evidence of the parasympathetic involvement in response to the urban settings. The parasympathetic system, often called “relax and renew,” is the branch of the Autonomic Nervous System (ANS) responsible for recuperating and returning to a balanced state (homeostasis) after experiencing a stressful situation; it reacts to return the body to a state of equilibrium by slowing down heart rate, dilating blood vessels, activating digestion, and storing energy. In contrast, the sympathetic system, the other branch of the ANS, activates in response to stressors; it is also known as the “fight or flight” response [80], because its activation is central in the taxing mobilization involved in responding to unexpected stressful events.

The relaxing effect of nature is supported by electroencephalogram (EEG) data as well. EEG measures are sensitive to conditions such as fatigue and sleep deprivation. If so, perhaps neuro-physiological measures, such as the EEG or functional magnetic resonance imaging (fMRI), might be used to differentiate stress states of the organism from normal or restored states. Unstressed subjects who viewed slides of natural landscapes and urban scenes [79], or single natural elements such as plants with flowers and pots without plants [81], or who were seated in an outdoor setting watching greenery or a concrete block fence [82] had greater brain electrical activity in the alpha frequency range. High alpha amplitude is associated with lower level of physiological arousal as well as feeling of wakeful relaxation [79]. Generally, feeling of anxiety are related to high arousal and accordingly to low alpha amplitude. All these results suggest that subjects are less aroused physiologically and more relaxed but wakeful, during exposure to natural stimuli. EEG studies identify tranquility as an outcome of viewing natural settings [83]. Recently, Korean researchers used the fMRI to investigate brain activation patterns in participants viewing nature vs. urban scenes [84]. The urban scenes showed enhanced activity in the amygdala, which is linked to impulsivity, anxiety and increased stress. By contrast, the natural scenes promoted activity in the anterior cingulate and the insula – where increased activity is associated with heightened empathy and altruistic behavior. 

4.2. Behavioral Effects

A logical extension of attention restoration theory is that people deprived of nature will display behaviors caused by weary minds: inhibition is essential to delay and reflection, lacking this capability an individual behaves in a less adaptive and appropriate fashion [6]. Moreover, without the patience and endurance necessary to carry out difficult or unpleasant tasks, performance becomes more oriented to the short term. In fact, directed attention fatigue not only leads to the inability to focus, but it has also several unfortunate consequences, including performance errors, inability to plan, social incivility and irritability [6]. Taylor, Kuo and Sullivan [85] found also a relationship between exposure to nature and self-control; in studying a group of girls living in the same housing complex, the researchers found that those with greener views scored higher than those deprived of nature on several tasks related to discipline, higher concentration, inhibited impulsivity and ability to delay gratification. Regarding social behavior, which also depends upon inhibition, it becomes less appropriate and there is also a greater inclination to be impulsive, to take unnecessary risks, and to act in an impatient and hasty manner. Kuo and Sullivan [86] reported significantly lower levels of aggression and violence in residents with apartments near nature than in those who looked onto barren lands; the researchers suggested that if fatigued attention is related to irritability, and irritability leads to impulsivity and aggression, then perhaps people deprived of nature’s restorative qualities would be overly aggressive. In general, exposure to nature enhances sense of attachment, social life, mental and physical health, quality of life and the occurrence of activities and events that enhance wellbeing. In particular, green vegetation in neighborhood common spaces correlates with stronger ties, higher sense of safety and adjustment [87], less aggressive behavior, and fewer property and violent crimes reported to the police than areas without greenery [86].

Views of nature affect driving as well. Comparing the physiological responses of subjects who watched a video driving through nature with those who watched a drive through more built-up environments, Parsons et al. [88] found that the nature-group displayed lower levels of stress and recovered more quickly from the stress they experienced. Views of dense vegetation (vs. sparse and mixed) enhance in fact drivers’ ability to tolerate frustration [89]. 

4.3. Self-Report Measures

Quantifiable measures of restoration are the key to understand how restorative mechanisms work, and research on the buffering effects of nature among stressed or mentally fatigued individuals has mostly relied on physiological and cognitive measures as outcome variables. However, together with physiological, behavioral and performance measurements there are also self-report measures aimed to assess the restorative value of real places/pictures, i.e., the degree of perceived restorativeness of a setting. To this aim, the majority of the studies have used the Perceived Restorativeness Scale (PRS). The scale based on the ART, which appeared in 1997 [25,26], aimed to measure the presence of the four theoretical restorative factors (being-away, fascination, extent, compatibility) in the environment. From then on, the PRS has been widely used not only to compare the restorative value of natural and urban settings, but also to measure perceived restorativeness of outdoor activities [90,91], vacation destination [92], zoo and small public parks [93,94,95], and it has appeared with different names, e.g., Restorative Outcome Scale [96], Revised Perceived Restorativeness Scale [97], Perceived Restorative Characteristics Questionnaire [94], PRS-short version [23], but questions about the scale validity/reliability remain.

Since the PRS appearance researchers have differed on the number of items making up the scale and on its factorial structure [97,98]. However, research has confirmed, through the PRS, both the positive correlation between environmental preference and perceived restorativeness, and the lack of correlation between familiarity on perceived restorativeness [21,99]. Furthermore, research using the PRS found that the higher restorative value of natural versus urban or artificial settings did not differ with gender or age [100]. Primary school children can discriminate the restorative value of environments varying in their degree of naturalness [101], and assess natural environment more restorative than school environments and playground [102].

Regarding the PRS factorial structure, Pasini et al. [103] have shed light on the psychometric characteristics of the scale. After a detailed understanding of the meaning of PRS individual items with the method of cognitive interviews, which is the proper starting point for the development of a self-rating scale, Pasini et al. [103] ended up in an 11-item. Using Confirmatory Factor Analysis to compare five models based on previously published research and underlying theory, the researchers found that a four-factor model that mirrored the four factors of ART, had the best fit to the data. The resulting 11-item PRS was also invariant across nationality and gender.

The PRS-11 is less concerned with people’s environmental preference. Instead, it addresses the perceived “cognitive” supportiveness of the environment in relation to individual’s psychological wellbeing. It assesses aspects of purposive behaviors to avoid mental fatigue, and the cognitive fit between person and environment is indicative of a “no-mental fatigue” state in relation to the environment, and not only of how an environment is restorative. For this reason the PRS-11 can help researchers and community planners who can both rely on a valid, reliable, brief and easy to comprehend instrument. In fact, for people interested in people’s wellbeing, it is the subjective fit which is essential, i.e., the perceived supportiveness of the environment in connection with the personal goal to recover from mental fatigue.

The PRS-11 assumes that people’s subjective appraisal of their environments provides a reasonable, straightforward index of the quality of their psychological restoration experiences in those settings. However the complex psycho-physiological pathways of stress make measurement via one single measure insufficient. Moreover the issue of which type of measure (behavioral, self-report or neuro-physiological) is the better or more appropriate measure of stress effects is far from settled. Stress impacts physical and mental health and a number of inter-personal differences have been found to impact on the ways we experience and interact with green space, they are gender [104], age [105], culture/ethnicity [106], interests/expertise [107] and it is a matter of fact that different “extraneous” variables are associated with restorative experiences in favorite settings [96]. Nevertheless, the relationship between perceived restorativeness and stress measures has not been firmly established. To this end, considering the different kinds of measures (self-report, physiological, behavioral, task performance) a multi-method multi trait study (MMMTS) would allow assessing the adequacy, namely if the PRS-11 fits with other measures of stress or recovery. However, the conceptual formulation of the trait “perceived cognitive supportiveness/perceived restorativeness” implicitly includes the proposition that this trait can be meaningfully differentiated by other traits. 

5. Conclusions

Given the many benefits from contact with nature, plans for urban settings should consider the human need for restoration. For this, research must offer practical guidelines for the accessibility and quality of urban green areas. A well-designed urban landscape can contribute to creating a less stressful day [108] and to providing an opportunity for physical, cognitive and emotional restoration [36]. Thus, research can help integrate natural elements and structural features into built environments [109] in order to plan urban environments that are “cognitive sustainable” and restorative from mental fatigue and the stresses of urban life [30,110].

Empirical evidence on the stress reduction from exposure to natural settings agrees with both SRT and ART. However, the findings are unclear about whether active or passive involvement with nature is preferable for restorative benefits, and whether restorative outcomes (both physiological and cognitive) vary with the length of exposure to natural stimuli. According to adaptation level theory [111,112] people adapt (or get accustomed) to their environments. If that applies to exposure to natural environments, then people surrounded by nature might require a higher dose (a sort of threshold) to recover from stress and mental fatigue than would people surrounded by buildings. On the other hand, their long-term exposure may inoculate them from stress. Research could also consider effects related to different kinds and form of nature, as well as individual and cultural differences in the perception of restorativeness and the restoration process.

Another important issue concerns the relation between biophilic design and psychological wellbeing, i.e., whether the presence of natural features (such as curvilinear forms, gradations of colors, blending of textures) and elements (water, plants) in buildings can have real benefits on human emotional wellbeing, stress reduction, cognitive efficiency, learning and healing processes.

Research on restorative environments has included both field and laboratory studies using primarily the transversal design, or to a lesser extent the pre-post design [113]. These studies miss a longer-term question. Successful coping strategies can mask the negative effects of a stressor. Studies have not determined whether long-term exposure to nature helps one adapt to or recover from stress/mental fatigue. To answer that question, we need longitudinal studies. 

Acknowledgments

I wish to express special thanks to Jack Nasar, Editor of this special issue, for his patience and invaluable assistance in the arrangement of this manuscript. I gratefully acknowledge the anonymous reviewers for their valuable comments.

Conflicts of Interest

The author declares no conflict of interest.

References at the Behavioral Sciences site

Dante Cicchetti - Resilience Under Conditions of Extreme Stress: A Multilevel Perspective

This image is from a different article, "Neuroimaging resilience to stress: A review," Front. Behav. Neurosci., 07 May 2013 | doi: 10.3389/fnbeh.2013.00039.

Resilience has become a buzzword in the health and psychology press, a word generally defined as an individual's ability to adapt to stress or adversity in healthy ways. But it is a much more complex issue than that.

The article below employs a relational developmental systems model to understanding how resilience is formed. Most previous research has focused on the behavioral and psychosocial aspects of resilience. Dante Cicchetti, in the article below, adopts a much more comprehensive model.

The pathway to either psychopathology or resilience is influenced by a complex matrix of the individual’s level of biological and psychological organization, current experiences, active choices, the social context, timing of the adverse event(s) and experiences, and the developmental history of the individual.

In seeking to understand how resilience occurs, or doesn't occur, Cicchetti looked at maltreated children using a multilevel analysis to make sense of why some children develop resilience and others develop psychopathology.

Full Citation:
Cicchetti, D. (2010, Oct). Resilience under conditions of extreme stress: A multilevel perspective. World Psychiatry; 9(3): 145–154.

Resilience under conditions of extreme stress: A multilevel perspective

DANTE CICCHETTI

 

Abstract

Resilience has been conceptualized as a dynamic developmental process encompassing the attainment of positive adaptation within the context of significant threat, severe adversity, or trauma. Until the past decade, the empirical study of resilience predominantly focused on behavioral and psychosocial correlates of, and contributors to, the phenomenon and did not examine neurobiological or genetic correlates of and contributors to resilience. Technological advances in molecular genetics and neuroimaging, and in measuring other biological aspects of behavior, have made it more feasible to begin to conduct research on pathways to resilient functioning from a multilevel perspective. Child maltreatment constitutes a profound immersion in severe stress that challenges and frequently impairs development across diverse domains of biological and psychological functioning. Research on the determinants of resilience in maltreated children is presented as an illustration of empirical work that is moving from single-level to multilevel investigations of competent functioning in the face of adversity and trauma. These include studies of personality, neural, neuroendocrine, and molecular genetic contributors to resilient adaptation. Analogous to neural plasticity that takes place in response to brain injury, it is conjectured that it may be possible to conceptualize resilience as the ability of individuals to recover functioning after exposure to extreme stress. Multilevel randomized control prevention and intervention trials have substantial potential for facilitating the promotion of resilient functioning in diverse high-risk populations that have experienced significant adversity. Determining the multiple levels at which change is engendered through randomized control trials will provide insight into the mechanisms of change, the extent to which neural plasticity may be promoted, and the interrelations between biological and psychological processes in the development of maladaptation, psychopathology, and resilience.

 

* * * *

 

From the perspective of developmental psychopathology, maladaptation and mental disorder are viewed as evolving from progressive liabilities in the organization of biological and psychological systems, resulting in the undermining of the individual’s efforts to adapt effectively to stressful and adverse experiences 1,2. The dynamic interplay between risk and protective forces is conceived as influencing the developmental course through the impact it has on the quality of the organization of biological and psychological systems as the individual develops 3. 

Developmental psychopathologists stress that there is multifinality in developmental processes such that the manner in which persons respond to and interact with vulnerability and protective factors at each level of the ecology (i.e., culture, community, family, and their transactions) allows for diversity in developmental outcomes 4,5. Individuals may begin on the same major developmental trajectory, yet exhibit very different patterns of maladaptation or adaptation. The pathway to either psychopathology or resilience is influenced by a complex matrix of the individual’s level of biological and psychological organization, current experiences, active choices, the social context, timing of the adverse event(s) and experiences, and the developmental history of the individual 5.

Understanding the dynamic transactions between risk and protective factors plays a central role in building developmentally informed models of prevention. Through increasing the relative balance of protective processes over risk factors, the potential for righting the developmental course, attaining adaptive developmental pathways, and reducing the emergence of psychopathology may be achieved 4,6. 

Just as deviations from the average expectable environment potentiate some individuals toward the development of maladaptation, others demonstrate adaptation in the face of the same challenges 7,8,9. Thus, it is equally important to comprehend the mechanisms that promote adaptation among individuals experiencing significant adversity as it is to investigate the developmental trajectories toward maladaptation. Research conducted on biological, as well as psychological, protective factors is critically important for discovering mechanisms and processes that contribute to the development of either the recovery of function or resilient adaptation in the face of significant adversity 10,11,12. 

DEFINITION AND HISTORICAL CONTEXT

Resilience is conceived as a dynamic developmental process encompassing the attainment of positive adaptation within the context of significant adversity 8,13,14. There are two critical conditions that are implicit within this conceptualization of resilience: a) exposure to significant threat, severe adversity, or trauma; and b) the achievement of positive adaptation despite major assaults on the developmental process 8,14.

For four decades, researchers interested in children who develop well in the context of significant adversity have endeavored to enhance understanding of the diverse pathways to psychopathology, to elucidate the processes that eventuate in normal development, and to inform preventive interventions and social policies that could improve the lives of vulnerable children and families 7,15,16,17,18. Investigations in the area of risk and resilience have led scientists to rethink their prior assumptions about the causes and course of psychopathology and have resulted in a reformulation of the deficit etiological models that characterized earlier viewpoints about the development of children who have experienced disadvantage and great adversity 9,19,20.

Studies conducted on individuals at high risk for psychopathology and on persons with mental disorders frequently portrayed the developmental course as deterministic, inevitably resulting in maladaptive and pathological outcomes. Investigations focusing on genetic and biological predispositions to psychopathology, assaults on development associated with inadequate caregiving, and traumatic occurrences within the home – such as child maltreatment and domestic violence, exposure to community violence, chronic illness, and catastrophic life events – graphically convey the multiplicity of risks that can eventuate in disordered outcomes. As researchers discovered that not all high-risk children manifested the dire consequences that extant theories of psychopathology predicted, comprehending the processes through which children at risk did not develop psychopathology became viewed as important for informing theories on the development of maladaptation and pathology.

Before investigations on resilience could be initiated, a significant and illustrious history of research detailing the precursors to, as well as the contemporary patterns of, stress resistance had to take place (e.g., 8,21). In many of these early studies, researchers had discovered evidence of adaptive behavior; however, the nomenclature for labeling these results as indicative of resilience had not yet emerged.

The historical roots of resilience can be traced to early programs of research on individuals with schizophrenia and on persons exposed to parental mental illness, extreme stress and poverty, as well as on the functioning of individuals who experienced traumatic occurrences earlier in their lives 7,15,22,23. Early investigations of severely disordered schizophrenic patients were focused primarily on understanding maladaptive behavior, and the subset of patients who showed relatively adaptive patterns were considered atypical and afforded little attention. By the middle of the 20th century, researchers had discovered that people with schizophrenia with the least severe courses of illness were characterized by a premorbid history of a relative competence at work, good social relations, marriage and the capacity to fulfill responsibility (see 23). In a parallel fashion, studies of children of mothers with schizophrenia played a crucial role in the emergence of childhood resilience as a major theoretical and empirical topic 16,19,24.

Additionally, Werner’s longitudinal study 17,18, that systematically searched for protective forces that differentiated children with healthy adaptation profiles from those who were comparatively less well adjusted, was a groundbreaking investigation. Evidence that many of these children experiencing great adversity thrived despite their high-risk status led to increasing empirical efforts to understand individual variations in response to adversity. Early empirical efforts were primarily focused on the personal qualities of “resilient children”, such as autonomy or high self-esteem 25. As work in the area evolved, however, researchers increasingly acknowledged that resilience may often derive from factors external to the child 8. Subsequent research led to the delineation of these sets of factors implicated in the development of resilience: (a) attributes of the children themselves; (b) aspects of their families; and (c) characteristics of their wider social environments 8,25.

In recent decades, there has been a shift in the focus of empirical investigations; rather than searching for protective factors, researchers are increasingly striving to discover the mechanisms underlying resilient functioning 8. This focus on processes as opposed to identifying factors has enabled scientists to design prevention and intervention strategies that are developmentally sensitive for promoting resilience in persons experiencing significant adversity or trauma 26,27,28. Knowledge of the processes contributing to resilient functioning can enable prevention and intervention scientists to capitalize on periods of developmental change and transitions as unique opportunities for promoting positive adaptation during significant adversity or trauma 27,29. As S. Luthar asserted, “it is far more prudent to promote the development of resilient functioning early in the course of development rather than to implement treatments to repair disorders once they are already crystallized” 7. Randomized control trial (RCT) preventive interventions may be conceptualized as true experiments in altering the course of development 30, thereby presenting opportunities to test existing developmental theories as well as to provide insights into the etiology and course of positive adaptational outcomes in individuals experiencing significant adversity 8,31. 

As research on resilience has evolved and transformed over the years, it has become clear that the attainment of positive adaptation in the face of significant adversity involves a developmental progression; new vulnerabilities and challenges and/or strengths and opportunities often emerge with changing circumstances over the life course 8. Resilience is not something an individual “has” – it is a multiply determined developmental process that is not fixed or immutable. Hence, it is important to conduct longitudinal studies of the determinants of resilient functioning. In this regard, longitudinal studies on resilience should focus not only on assessing the stability of the construct over developmental time, but also on the ability of formerly resilient individuals to “bounce back” or to recover positive functioning after experiencing difficult periods and achieve their prior resilient adaptation 32. Moreover, since resilient adaptation may be achieved at any point in the life cycle, there is a need for research on the achievement of positive outcomes at different points in development, including in adulthood and in later life 8.

A MULTILEVEL PERSPECTIVE ON RESILIENCE

Until the past decade, the empirical study of resilience predominantly focused on behavioral and psychosocial correlates of, and contributors to, the phenomenon and did not examine biological correlates or contributors 8,10,11. These studies were undertaken prior to the inception of modern techniques for examining the molecular genetic, neural, and biological correlates of human behavior and development.

Evidence from earlier variable-oriented and person-oriented investigations of resilience converge on a short list of attributes of child and environment that turn out to be well-established general correlates of competent adaptation and psychopathology. Although there were methodological flaws and limitations in the early studies 14, more contemporary investigations nonetheless continue to corroborate the factors associated with resilient functioning: (a) close relationships with competent and caring adults in the family and community; (b) self-regulation abilities; (c) positive views of self; (d) motivation to be effective in the environment (i.e., self-efficacy and self-determination); and e) friendships and romantic attachments with prosocial and well-regulated peers 12. Problem-solving skills, foresight in planning, and a future orientation (all linked to executive functions), active coping strategies, and the capacity to confront fears directly, minimizing denial, disengagement, and avoidant coping have all been associated with resilient functioning 7,12,14. Moreover, optimism, positive emotionality, perceiving stressful occurrences in less threatening ways and the ability to reframe adverse experiences in a positive vein, spirituality, and being able to find meaning amidst trauma have each been linked to resilience 33.

Undoubtedly, the relative neglect of biology as relevant to developmental theorizing on the unfolding of adaptive behavioral outcomes in the face of adversity was primarily due to the paucity of information that existed about the structural and functional organization of the brain 34,35,36. There simply was not enough knowledge about brain development and function to articulate their role in the genesis and epigenesis of normal and deviant mental processes, let alone in their contribution to the development of resilient adaptation 33.

Most of what is known about the causes, correlates, course, and consequences of resilient functioning in the face of adversity have been gleaned from investigations that focused on relatively narrow domains of variables 7,8. Yet it is apparent from the questions addressed by developmental psychopathologists that progress toward a process-level understanding of resilient adaptation will require the implementation of research designs and strategies that call for the simultaneous assessment of multiple domains of variables both within and outside of the developing person 11.

In the past decade, a number of scientists have urged researchers to incorporate neurobiological and molecular genetic assessments into their investigations of the developmental pathways to resilient functioning 10,11,37. Technological advances in molecular genetics, neuroimaging, magnetoencephalography, electroencephalographic (EEG) recording, and hormonal assay techniques have made it more feasible to conduct research on the development of resilience from a multilevel perspective 11,12.

In addition, the advent of modern neuroscience, along with its many associated subdisciplines, represents an unprecedented opportunity to augment current conceptual and methodological approaches to the study of resilience. Regardless, it is critically important to keep in mind that biological domains do not function independently; rather, more commonly the functioning of one system influences the functional properties of one or more other systems, through a developmental cascade of bidirectionally influenced processes 38. Given this increasing recognition of the importance of considering many levels of interdependent processes simultaneously, in order to advance the understanding of a multifaceted phenomenon such as resilience, it is incumbent upon resilience researchers to meet the challenge of simultaneously incorporating multiple levels of analysis both across and within systems 39. Biological and psychological domains are both essential to include in basic research on resilience and in resilience-promoting interventions. Each level both informs and constrains all other levels of analysis. Moreover, the influence of levels on one another is almost always bidirectional.

Because different levels of analysis constrain other levels, as scientists learn more about multiple levels of analysis, resilience researchers conducting their work at each level will need to develop theories that are consistent across all levels. When disciplines function in isolation, they run the risk of creating theories that ultimately will be incorrect, because vital information from other disciplines has either been ignored or is unknown. Just as is the case in systems neuroscience 40, it is critical that there be an integrative framework that incorporates all levels of analysis about complex systems in the development of resilience 11,36.

Resilience in maltreated children: from single-level to multilevel investigation

Growing up under conditions of child maltreatment constitutes a profound immersion in severe stress that challenges and frequently impairs development across diverse domains of biological and psychological functioning 41. The ecological conditions associated with maltreatment represent a severe deviation from the average expectable environment. Maltreated children are likely to manifest atypicalities in neurobiological processes, physiological responsiveness, emotion recognition and emotion regulation, attachment relationships, self-system development, representational processes, social information processing, peer relationships, school functioning, and romantic relationships 41. Accordingly, maltreated children are likely to develop a profile of relatively enduring vulnerability factors, placing them at great risk for future maladaptation and psychopathology.

Nonetheless, not all individuals who have been abused and neglected succumb to the extreme adversity in their lives. Investigation of how some maltreated individuals cope adaptively despite experiencing significant stress and trauma offers an opportunity to discover processes at multiple levels of analysis that are likely to be germane to effective coping in the face of adversity, yet less readily detectable under more normative stress exposure 42. Discovering how maltreated children develop and function resiliently despite experiencing a multitude of stressors offers considerable promise for elucidating developmental theories of coping and for prevention and intervention.

In a longitudinal investigation of the pathways to resilience in maltreated children, we sought to ascertain if there were different pathways to resilient functioning in maltreated and non-maltreated children (both from comparable low socioeconomic backgrounds) and to explore whether there were differences between these groups in resilience, recovery of function, or decline in functioning over the 3-year period of the study 32. Maltreated children demonstrated greater dysfunction than non-maltreated children on several indicators of resilient functioning (e.g., competence with peers, behavior problems, school functioning, relationships with adult caregivers). Moreover, many of these deficits persisted across 2 or 3 consecutive years of assessment. Furthermore, across each of the 3 years, maltreated children exhibited a lower level of resilient functioning than did the non-maltreated children. Additionally, the continuity of maladaptive functioning displayed by maltreated children across the course of this longitudinal study was substantial. Taken together, these findings underscore the deleterious impact that maltreatment experiences exert on competent functioning and attest to the non-transient nature of their influence.

In this study, we also constructed pattern groups based on the three consecutive yearly assessments of resilient functioning in maltreated and non-maltreated children. Inspection of these pattern groups revealed that there was a significantly greater percentage of maltreated children than non-maltreated children in the low resilient functioning pattern group (40.6% vs. 20%). Furthermore, a greater percentage of maltreated (9.8%) than non-maltreated children (1.3%) displayed zero competence indicators, thereby reflecting an absence of resilient strivings across the 3 year study period. Garmezy 16,24 consistently emphasized that most children maintain the ability to display some resilience strivings in the presence of chronic and serious adversity. The complete absence of resilient strivings in nearly 10% of the maltreated children is cause for great concern, as self-righting tendencies are vital characteristics of all living organisms. The consistent absence of such strivings throughout the duration of the investigation is quite aberrant and alarming.

We also examined factors that contributed to the development of resilient functioning in the groups of disadvantaged maltreated and non-maltreated children. For the maltreated children, the major predictors of resilient functioning were the personality characteristics of ego overcontrol (i.e., the ability to monitor and control impulses and regulate affect) and ego resiliency (i.e., the degree of relative flexibility in regulating affect and behavior to meet situational demands), and positive self-esteem. In contrast, for the non-maltreated children, positive relationships with their mother and other adult caregivers and ego resiliency played prominent roles in the prediction of adaptive functioning. Given the high percentage of insecure and disorganized attachments in maltreated youngsters 43, it makes sense that relationship factors would be more vital to the attainment of resilience in the disadvantaged non-maltreated children. 

Personality characteristics and self-system processes were more important in achieving resilient adaptation in maltreated children. Specifically, the self-system variables of self-reliance and self-confidence, in concert with interpersonal reserve (i.e., ego overcontrol), appear to bode well for the development of resilient adaptation in maltreated children. Through adopting a more reserved, controlled, and rational way of interacting and relating (i.e., resilient overcontrol), maltreated children who function in a resilient fashion may be more attuned to what is necessary for successful adaptation in their adverse home environments. It is conceivable that their more overcontrolled style may protect them from being targets of continued maltreatment incidents. In contrast, the more affectively expressive style of resilient undercontrollers may not be well suited for successful adaptation in maltreating environments, because such styles may provoke attention and reaction from others that could result in greater risk for maltreatment 44.

Following the completion of this longitudinal investigation of the psychosocial processes underlying resilience in maltreated children, we initiated two multilevel studies. The ecological-transactional perspective that undergirds this research inherently takes into account multiple levels of analysis, and allows for combining biological and psychological mechanisms within the same framework 3,4. This perspective does not ascribe ascendancy to any level of analysis over another, and it encourages loosening of conceptual boundaries between nature and nurture and biology and psychology 45,46,47. This theoretical perspective thus provides a ready-made structure for the integration of a multilevel perspective into resilience.

In the first multilevel investigation of resilience, emotion regulation, and hemispheric EEG asymmetry in maltreated and nonmaltreated children from high-stress low socioeconomic backgrounds, we hypothesized that the positive emotionality and increased emotion regulatory ability associated with resilient functioning would be associated with relatively greater left frontal EEG activity 48. A large body of literature concerning the meaning and correlates of hemispheric asymmetries in EEG activity has suggested that this ubiquitous phenomenon indexes a neural system that has emotion-specific influences whereby the two hemispheres of the cerebral cortex have been found to be differentially involved in emotion 48. Specifically, the left hemisphere is associated with positive emotions/approach behavior and the right hemisphere is linked with negative emotions/withdrawal behavior. Emotions, and in particular positive emotion and good emotion regulatory abilities, have consistently been associated with resilient adaptation 18,49,50. Thus, the potential connection of hemispheric EEG asymmetry with resilience lies in their common linkages with emotion and emotion regulation.

EEG asymmetry across central cortical regions distinguished between children with high and low resilient functioning, such that left hemisphere activity characterized those maltreated children who were adapting resiliently based on our competence composite index (e.g., good peer relations, adapting successfully to school, low levels of depressive symptomatology, low externalizing and internalizing psychopathology) 51. Moreover, a behavioral measure of emotion regulation, based on 35 hours of observation of the children, significantly contributed to the prediction of resilience in maltreated and non-maltreated children.

The investigation of a neural-level phenomenon such as hemispheric EEG asymmetry in the context of resilient adaptation reminds us that there is certainly no one single characteristic that will be ascendant in the process of resilience over the course of development. Resilience is a dynamic, interactive process between multiple levels across time, none of which holds primary importance at any given moment. However, viewed across development, the relative importance of various biological and psychological processes, although inevitably interrelated, may also vary across development.

In another multilevel investigation conducted in our laboratory, resilient functioning in maltreated and non-maltreated low-income children in relation to the regulation of two stress-responsive adrenal steroid hormones, cortisol and dehydroepiandrosterone (DHEA), as well as the personality constructs of ego resiliency and ego control, was examined 52. The steroid hormones we chose to investigate as potential predictors of resilience are the two primary adrenocortical products of secretory activity of the hypothalamic-pituitary-adrenal (HPA) axis. The capacity of individuals to elevate cortisol levels in response to exposure to acute trauma is important for survival 2. DHEA exerts an impact upon a diverse array of biological actions, including effects on the immune, cardiovascular, endocrine, metabolic, and central nervous systems 53.

As in the previous single- and multilevel research on the pathways to resilient adaptation described above, we utilized a composite measure of resilience that included multi-method, multi-informant assessments of competent peer relations, school success, and low levels of internalizing and externalizing symptomatology. We found that ego resiliency and ego overcontrol and the adrenal steroid hormones associated with stress (i.e., cortisol and DHEA) made independent and non-interactive contributions to resilience. Although operating at different levels of analysis, behavioral/psychological and biological factors each made unique contributions to resilience.

Prolonged stress, as is often the case in child maltreatment, can lead to allostatic load, characterized by cumulative physiological dysregulation across multiple biological systems, through a cascade of causes and sequelae that can change the brain, organ systems, and the neurochemical balance that undergirds cognition, emotion, mood, personality, and behavior 54,55. Allostatic load is thought to occur when the adaptation to stress necessitates that the responses must be maintained over sustained time periods. Allostasis and allostatic load can be conceived as embodying a general biological principle – namely that the systems that help the body adapt to stress, and serve a protective function in the short term, also may take part in the development of pathophysiological processes when overused or managed ineffectively.

We found that higher morning levels of cortisol were related to lower levels of resilient strivings for the non-maltreated children. High basal cortisol may indicate that non-maltreated children are experiencing greater stress exposure and, consequently, are constrained in their ability to adapt competently. Within the group of maltreated children, differences in cortisol regulation were found as a function of the subtype(s) of maltreatment experienced. Physically abused children with high morning cortisol had higher resilient functioning than physically abused children with lower levels of morning cortisol. The positive role of increased cortisol for physically abused children is divergent from the more general pattern of higher cortisol being related to lower resilient functioning as we discovered in the non-maltreated and sexually abused children in this study.

Prior research on neuroendocrine regulation has indicated that physically abused children generally exhibit lower levels of morning cortisol secretion 56. It may be that the subgroup of physically abused children who were able to elevate cortisol to cope with the life stressors was demonstrating a greater striving for resilient adaptation. In contrast, the larger subgroup of physically abused children with lower levels of morning cortisol may have developed hypocortisolism over time in response to chronic stress exposure (i.e., allostatic load) 57. As a result, for these children there may be a diminished capacity to mobilize the HPA axis to promote positive adaptation under conditions of ongoing stress. Additionally, we found that the very low level of resilience among sexually abused children with high basal cortisol may be a product of their different traumatic experiences and consequences of chronic excessive vigilance and preoccupation, with commensurate HPA axis hyperarousal 52.

Finally, we also discovered that maltreated children with high resilient functioning exhibited a unique atypical pattern of a relative DHEA diurnal increase. Maltreated children who have the capacity to elevate DHEA over the course of the day may be better equipped to cope with the demands of high chronic exposure to stress and to adapt competently. In contrast, the non-maltreated children who functioned resiliently did not exhibit the pattern of diurnal DHEA increase; instead they displayed the lowest levels of DHEA across the day.

Gene-environment interaction and the molecular mechanisms that promote resilient functioning in maltreated children

Recent years have witnessed a renascence of interest in investigating the interaction between genes and environmental pathogens in the development of psychopathology and resilience 58,59,60. From a genetic perspective, resilience can be conceptualized as the extent to which persons at genetic risk for maladaptation and mental disorder are not affected 61. Additionally, there may be genetic contributors to resilient adaptation that protect some individuals in families where there is a high genetic loading for developing maladaptation and mental disorder from succumbing to these deleterious outcomes 58. Moreover, genes are likely to serve a protective function against environmental insults for some individuals. Thus, it is apparent that genetic influences on maladaptation and psychopathology operate in a probabilistic and not in a deterministic manner.

In gene-environment interaction (GxE), environmental experiences moderate genetic effects (or vice versa) on normal, psychopathological, and resilient developmental outcomes. For example, genetic effects on functioning outcomes may be observed only under certain environmental contexts or in conjunction with particular histories of experience; conversely, experience may only relate to outcomes among persons with specific genetic characteristics 62.

The majority of GxE studies have investigated polymorphisms in monoamine oxidase A (MAOA) and serotonin transporter (5-HTT), two of the primary genes implicated in the maturation of the early developing brain and in mood, behavior, and responsiveness to stress 58. The variability exhibited in children’s responses to the environmental hazard of child maltreatment suggests that this heterogeneity may be within the hemisphere of genetic influence 59. The experience of child maltreatment has proven to be a strong environmental pathogen that has generated a number of provocative findings which have contributed to engendering interest in research on GxE (59,60; for meta-analyses, see 65,66).

Caspi and colleagues 62,63 demonstrated GxE effects in a large sample of adults who had experienced severe early child maltreatment. Specifically, Caspi et al 58 found that adult males who were maltreated early in development and who possessed the low activity allelic variant of the MAOA gene evidenced higher levels of antisocial and aggressive symptomatology than did those individuals who were maltreated early and who had the high activity variant of MAOA. The latter group demonstrated lower levels of antisocial and aggressive symptoms 62 than did maltreated adults with the low activity variant of MAOA. In a subsequent investigation, Caspi et al 63 discovered that adults who experienced severe maltreatment in childhood and who possessed the short (s/s) variant of the 5-HTT gene exhibited higher levels of depressive symptoms than did adults who had the long variant (l/l) of the 5-HTT gene and had been maltreated as children. In contrast, adults in the latter group had significantly fewer depressive symptoms than did maltreated adults with the short allele variants 63. Thus, it is conceivable that the high activity MAOA gene polymorphism and the long variants of the 5-HTT gene may confer protection against antisocial disorder and depression to adults who have been severely maltreated in their childhood.

In our laboratory, we conducted a multigenic study examining the interaction between polymorphisms of 5-HTT and MAOA genes in a large sample of maltreated children in relation to depressive symptomatology 67. Adolescents from low socioeconomic backgrounds with a history of child maltreatment or no such history were administered a semi-structured diagnostic interview for mental disorders; moreover, these adolescents provided buccal cells for genetic analysis. Heightened depressive symptoms were found among extensively maltreated youth with low MAOA activity. Among comparably maltreated youths with high MAOA activity, self-coping strategies related to lower depressive symptoms. The finding that self-coping strategies and high MAOA activity were related to lower depressive symptoms calls to mind results from a number of our studies on resilience in maltreated children. Specifically, self-reliance and self-determination were found to be predictors of resilient functioning in maltreated children 32. It is conceivable that the maltreated children with positive self-system characteristics who functioned resiliently also may have possessed polymorphic variants of genes (such as high MAOA activity) that served a protective function against maladaptation.

Sexual abuse and the 5-HTT short/short genotype predicted higher depression, anxiety, and somatic symptoms. This GxE interaction was further moderated by MAOA activity level. Specifically, we found that sexually abused adolescents with one or two copies of the 5-HTT short allele had significantly reduced levels of internalizing symptoms if they also had the high activity version of the MAOA gene 67.

We also have begun to decipher co-actions across multiple levels of analysis through incorporating genetic and multiple physiological measures in our multilevel research on pathways to resilience in abused and neglected children. For example, in a longitudinal investigation that is currently underway in our laboratory, we are employing a multiple-levels-of-analysis approach to examining the course of trauma-related psychopathology in maltreated children, as well as the multilevel processes that contribute to resilient outcomes. In addition to genotyping relevant candidate genes, we have incorporated multiple measures of neurophysiological responses to classes of emotion stimuli, and hormonal, neurocognitive and behavioral functioning. The field can no longer afford to continue the artificial distinction among genetics, neurobiology, and behavior in research on the determinants of resilience. 

Neural plasticity and resilience: some potential linkages

Experience-expectant and experience-dependent mechanisms of neural plasticity are integral to the very anatomical structure of cortical tissue and cause the formation of the brain to be an extended malleable process 65,66,67. Developmental psychopathologists and neuroscientists can utilize this knowledge as an avenue for understanding the vulnerability and protective processes of brain development as contributors to the genesis and epigenesis of psychopathology and resilience. Moreover, because the mechanisms of plasticity cause the brain’s anatomical differentiation to be dependent on stimulation from the environment, it is clear that the cytoarchitecture of the cerebral cortex is shaped by input from the social environment. Because the human cortex is only diffusely structured by the genetic plan, and because its eventual differentiation is highly reactive to the active coping strategies of the individual in a particular environment, it is highly likely that both normal, abnormal, and resilient outcomes of this process would encompass a diverse range of cortical network anatomies and individual personalities. 

Analogous to neural plasticity that takes place in response to brain injury 68,69,70,71, resilience can be viewed as the ability of an individual to recover after exposure to adversity or trauma 9,32. According to this view, adversity is thought to exert a damaging effect on one or more neural substrates, and mechanisms of neural plasticity bring about recovery in an individual. This might lead to the conclusion that certain individuals, classified as resilient, may have some increased innate capacity (i.e., plasticity), above and beyond normative levels, to recover from environmental insults that impact the brain. This view of resilience conceives of adversity in the environment as “bad” for the brain, with recovery as an innate property of the brain itself. This perspective, however, does not consider the impact of a positive environment (e.g., presence of social supports), or of the individual’s active attempts at coping, or of protective/plasticity genes, on such recovery.

Another conceptualization of resilience would be one of greater than normative resistance to the impact of environmental adversity on the brain, such that resilient individuals may not succumb to the potentially damaging effects that adversity may have on the brain and other biological systems. This view of brain-adversity interaction would not strictly be classified as involving neural plasticity. Thus, for these individuals, the term recovery of function may not apply, in that they did not “lose” function at all. 

The rapid growth in sophisticated techniques that permit imaging of the brain directly has resulted in the availability of a variety of methodologies to developmental psychopathology researchers; many of these methods could be utilized to examine neural plasticity, as well as brain structure and function, in detail. These new tools make it possible to now undertake empirical investigations of the relation between neural plasticity and resilience, perhaps enabling an examination of the direct linkage of these two processes. Questions about how neural plasticity may play a role in the development and maintenance of resilient functioning could be addressed, as well as whether the mechanisms of neural plasticity may operate differently in individuals classified as resilient.

Among the compelling questions about resilient adaptation that could potentially be addressed utilizing brain imaging methodologies are: (a) Is brain structure and function different in maltreated and non-maltreated children functioning resiliently, matched on experiences of adversity? (b) Is the brain structure and function of resilient individuals who have experienced adversity different from normal children reared in non-adverse environments? (c) Are particular areas of the brain more likely to be activated in resilient than in non-resilient functioning during challenging or stressful tasks? (d) What aspects of brain structure and function differentiate individuals who function resiliently, despite experiencing early adversity, from those who function in a non-resilient fashion and who encounter adversity early in life (i.e., what is the role of early experience?) e) Are there sensitive periods beyond which the achievement of resilience is improbable or is resilience possible to achieve across the life span? and f) Are there changes over time in brain structure and/or functioning in individuals classified as resilient that may reflect processes of neural plasticity? The inclusion of neuroimaging techniques to the existing predominantly psychological approaches to charting the pathways to resilience, along with the additional biological and molecular genetic methodologies discussed earlier in this paper, could result in many exciting discoveries about the complex processes that eventuate in competent outcomes despite the experience of significant adversity.

Aside from investigating the proximal relation between resilience and neural plasticity, there are several neurobiologically mediated processes (e.g., cognition, neuroendocrine functioning) that have a direct relation to resilient outcome 14,51. Although such processes exert an impact on resilient functioning, neural plasticity may, to some degree, be the common, underlying mechanism that mediates the relation between such processes and resilience. 

Resilience-promoting interventions: a multilevel perspective

Research on resilience has substantial potential to guide the development and implementation of interventions for facilitating the promotion of resilient functioning in diverse high-risk populations that have experienced significant adversity 27,72. Such interventions should target protective and vulnerability forces at multiple levels of influence – culture, community, family, and the individual.

Although several of the interventions that have been implemented have employed a multifaceted approach in order to ensure sensitivity to the diverse transactions between children and their environmental contexts, to our knowledge there have been very few interventions that have included biological assessments as part of the pre-post evaluation battery. Because one of the primary objectives of the field of prevention science is to intervene in the course of development to foster the recovery of function and to promote resilient adaptation in individuals at high risk for psychopathology 6, it is now essential to utilize a multiple-levels-of-analysis perspective ranging from DNA sequences to culture in research evaluations aimed at assessing the efficacy of RCT interventions whose goal is to foster the development of resilient adaptation.

There are at least two reasons for the dearth of attention to biological processes in the evaluation of preventive interventions with children and adolescents. This lack of attention may partly originate from a tradition in developmental psychology of measuring biological processes as indices of heritable, constitutional individual differences reflecting the neurobiological bases of temperament 73. This tradition encourages beliefs that biological processes are either not malleable or are more refractory to positive change as a result of experience. Because there are bidirectional relations between different levels of biological and psychological organization, it is essential to recognize that experience also influences biology 68,74. Evidence for neurobiological reorganization in response to alterations in the environment may be less apparent in normative populations where there likely is greater stability in supportive milieus; however, investigations of individuals reared in extreme environmental conditions should enable us to more clearly isolate the components of these diverse systems, thereby shedding light on the bidirectional effects of experience and neurobiology.

Random assignment to adversity or trauma is not possible, but random assignment to intervention is. If biological systems recover in response to the intervention, then this provides support for arguments that the systems under study are sensitive to environmental input during development. Furthermore, if randomized interventions alter neurobiological systems associated with disorders, and it can be shown that they mediate changes in psychosocial and behavioral functioning, then this fosters a better understanding of the neurobiological bases of the disorder. Moreover, preventive interventions may contribute to recovery or repair of biological sequelae in ways that have only begun to be understood. Improved comprehension of the neurobiological processes that increase risk of maladaptive development may also suggest novel targets for preventive intervention. Thus, it is important for prevention scientists to investigate the means by which changes in experience and psychological functioning resulting from preventive interventions may modify biological processes.

Now that animal studies have demonstrated that experience can exert impacts on the microstructure and biochemistry of the brain 75, a vital role for continuing neural plasticity throughout epigenesis in contributing to the recovery from various forms of maladaptation and mental disorder may be suggested. There is growing evidence in the animal literature that efficacious interventions modify not only maladaptive behavior, but also the cellular and physiological correlates of behavior 76,77. Successful preventive interventions may alter behavior and physiology through producing alterations in gene expression that create a new structural reorganization in the brain 76. One important goal of preventive intervention research is to identify periods of development when a specific intervention may be more efficacious so that the intervention can be targeted to that period. A goal of preventive intervention work that includes measures of neurobiological processes is to better identify sensitive periods for intervention 78.

Determining the multiple levels at which change is engendered through RCT prevention trials will provide more insights into the mechanisms of change, the extent to which neural plasticity may be promoted, and the interrelations between biological and psychological processes in maladaptation, psychopathology, and resilience 79. Moreover, preventive interventions with the most in-depth empirical support, based on integrative multilevel theories of normality, psychopathology, and resilience, can be implemented in effectiveness trials in community or real-world settings to reach the broadest number of people and prevent, alleviate, and ultimately cure, suffering from mental disorders 80. Furthermore, the inclusion of biological assessments in evaluations of interventions designed to foster resilience will enable scientists to discover whether the various components of multifaceted interventions each exert a differential impact on separate brain systems. It is thus possible to conceptualize successful resilience-promoting interventions as examples of experience-dependent neural plasticity.

Finally, although the consensus is that resilience is a dynamic developmental construct that, theoretically, is possible throughout the life course, it nonetheless is important to ascertain whether the timing of resilience-promoting interventions is a crucial variable that merits consideration. Specifically, it will be extremely important to know whether resilience-promoting interventions are more effective when implemented in the early years of life. Likewise, are such interventions more likely to achieve their goal of promoting resilience if they are instituted as closely as possible to the identification of the adverse event(s) or experience? The incorporation of a multiple-levels-of-analysis perspective will enable scientists to learn whether, for example, resilience-promoting interventions implemented in the early years of life are better for brain development and functioning, even if improvement occurs in individuals who receive resilience-facilitating interventions later in life or receive their interventions further removed in time from their adverse event(s) or traumatic experiences.

CONCLUSIONS

It is important to note that the call for a multilevel perspective in resilience research and resilience-promoting interventions − that includes the criticality of conducting genetic and neurobiological, as well as behavioral, assessments − does not reduce resilience to biology, let alone to a single biological variable. The inclusion of a multilevel perspective on resilience should not hearken scientists and clinicians back to the time when some espoused the view that they were “invulnerable” children. The incorporation of a multilevel perspective into research on resilience still requires adherence to a dynamic, transactional view that respects the importance of context.

We are in the midst of a truly exciting period for research on the pathways to resilient functioning in individuals who have experienced great adversity and trauma. The advances in genomics, epigenetics, brain imaging, and hormonal and immunological assay techniques will make important contributions to propelling increased knowledge about the developmental processes leading to resilience 11,12. Such enhanced understanding has great potential for the development and implementation of novel, perhaps even individualized, resilience-promoting interventions for high-risk children and adults who are not functioning well due to experiences of adversity and trauma. In order to comprehend fully how individuals achieve resilient functioning in the face of adversity, it is incumbent upon us to investigate it with a commensurate level of complexity.

Acknowledgements

Work on this article was supported by grants from the National Institute of Mental Health (MH083979) and the Spunk Fund, Inc.

References at the NCBI site