FOCUS ON SOCIAL NEUROSCIENCE

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Social influences on neuroplasticity: stress and interventions to promote well-being

Richard J Davidson1 & Bruce S McEwen2
Experiential factors shape the neural circuits underlying social and emotional behavior from the prenatal period to the end of life. These factors include both incidental influences, such as early adversity, and intentional influences that can be produced in humans through specific interventions designed to promote prosocial behavior and well-being. Here we review important extant evidence in animal models and humans. Although the precise mechanisms of plasticity are still not fully understood, moderate to severe stress appears to increase the growth of several sectors of the amygdala, whereas the effects in the hippocampus and prefrontal cortex tend to be opposite. Structural and functional changes in the brain have been observed with cognitive therapy and certain forms of meditation and lead to the suggestion that well-being and other prosocial characteristics might be enhanced through training. Social influences are among the influences on brain structure and function that are most powerful in inducing plastic change. The vertebrate brain appears to be particularly sensitive to social influences and this sensitivity may be especially acute in primates1. The brain is constantly being shaped, wittingly and unwittingly, by environmental forces that impinge on organisms. The circuitry that has been implicated in social and emotional behavior appears to be importantly shaped by experience, and early experience in these domains is likely involved in governing differences among individuals in their vulnerability or resilience to future adversity. Studies in both animal models and humans provide a foundation for understanding how explicit interventions designed to promote prosocial behavior and well-being might induce plasticity-related changes in the brain. There is a growing corpus of evidence that suggests that interventions ranging from regular moderate physical exercise2 to cognitive therapy3,4 to interventions derived from ancient contemplative practices5 induce plasticity-related alterations in the brain and support a range of positive behavioral outcomes. There are many different mechanisms of plasticity and, at the human level, there are methodological constraints that limit the mechanisms that can be directly studied. Most human work has focused on alterations in different indices of brain structure that can be measured with modern magnetic resonance imaging (MRI). Enduring functional alterations can also be assessed using functional MRI (fMRI) and related techniques. Experience-dependent influences on particular features of cognitive function, such as language learning, appear to have a robust sensitive period6. However, even a competence as clearly cognitive as language acquisition is influenced by social context and social interaction (see ref. 6 for a review). The social deprivation of orphanages for abandoned children in Bucharest, Romania has been found to produce profound
1Waisman Laboratory for Brain Imaging and Behavior and Center for Investigating Healthy Minds, University of WisconsinMadison, Madison, Wisconsin, USA. 2Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York, USA. Correspondence should be addressed to R.J.D. ([email protected]) or B.S.M. ([email protected]).

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Published online 15 April 2012; doi:10.1038/nn.3093

cognitive impairment that can be partially remediated by early placement in foster care7. The earlier the age of foster care placement and removal from the orphanage, the less severe was the observed cognitive deficit. The extent of such sensitive periods in the realms of social and emotional behavior is not yet known. However, there are some hints; for example, there is recent evidence in a rodent model that amygdala circuits are kept in an immature state in an infant by the presence of the mother, but can be stimulated to mature by corticosterone to promote maturation to allow aversive learning8. Once a developmental event has occurred, can it be reversed? Research on recovery of vision in adult amblyopic subjects suggests mechanisms that might be used to remove the brakes on adult plasticity, such as the use of behavioral interventions9. Whether similar mechanisms might be present to facilitate adult plasticity of social behavior has not been studied. We do know that early stressful and nurturing environments have robust effects on the developing brain, some of which persist for the life of the organism. The effects of stress are the most well-characterized, and we review key findings at the animal level below. Research at the human level that has focused on the experiencedependent effects of stressful life events has taken advantage of largely unintended environmental circumstances, such as child maltreatment or exposure to early stress. In addition to this corpus, there is now a growing literature on the effect of interventions explicitly designed to promote positive outcomes, such as physical exercise2, cognitive therapy3,4, social service programs for older individuals10 and meditation5,11. There are also a growing number of interventions designed to promote prosocial behavior in children that include social-emotional learning12 and executive function training13. The evidence for their efficacy is mostly behavioral at this point in time, and the mechanisms by which such interventions operate have not been systematically examined, although it is likely that some features of neuroplasticity will be important for at least some of the behavioral effects that have been described. Here we review some key findings at the animal level that establish experience-induced structural plasticity in response to social influences. Although most of the findings have focused on stressful environmental influences, there are some data on specific environmental influences
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that appear to promote positive social and emotional behavior. We also review experience-induced plasticity in humans arising from both unintended influences, such as early life stress, and explicit intervention strategies that are designed to promote more effective coping with stress and salubrious social and emotional behavior. Some of these interventions are derived from ancient contemplative practices, whereas others have emerged from the modern research context. One important idea that we present is the notion that, just as we as a society are learning to take more responsibility for our physical health by engaging in regular physical exercise, we can also take more responsibility for our minds and brains by engaging in certain mental exercises that can induce plastic changes in the brain and that may have enduring beneficial consequences for social and emotional behavior. This also invites the perspective that qualities such as well-being ought to be viewed, at least in part, as a product of trainable skills and that interventions explicitly designed to promote well-being may have beneficial behavioral and biological effects. Although well-being and other similar constructs exhibit moderate stability in the absence of either unwitting or intentional influences, the evidence suggests that change can occur in the presence of such factors. Basic research at the animal level Evidence that the healthy mature animal brain is capable of structural plasticity can be traced to the so-called enriched environment studies14, which were in turn based on findings of enhanced problem solving behavior in rats living as pets in a complex environment15. Rats that lived for weeks in an environment filled with toys that were changed daily in a larger and more complex living space showed increased thickness of cerebral cortical areas. This was also true of aging rats16. Subsequent studies found that cortical neurons showed increased dendritic branching and complexity in such an environment compared with normal laboratory cages, as well as increased numbers of glial cells and increased blood supply17. More recent investigations have shown that both acute and chronic stress alter spine density and dendritic length and branching in brain regions, such as hippocampus, prefrontal cortex and amygdala18. Measured by conventional neuroanatomical methods, the time course of these changes were found to occur over days and are largely reversible, at least in young adult animals18,19. However, a recent study using transcranial two-photon microscopy to track the formation and elimination of dendritic spines in vivo after treatment with glucocorticoids in developing and adult mice revealed spine turnover in several hours that was higher in the developing barrel cortex, but was still very much present in the adult, and similar changes occurred in multiple cortical areas, suggesting a generalized effect that may occur in many brain regions20. Mechanisms for such dendritic and synaptic remodeling involve not only glucocorticoids, but also excitatory amino acids and other cellular mediators18,21. Sex hormones also promote structural plasticity in hippocampus, cerebral cortex, hypothalamus and other brain regions22,23. For example, ovarian hormones promote cyclic changes in spine density in the hippocampus, as well as in the primary sensory-motor cortex and prefrontal cortex of rodents and monkeys24,25. Mechanisms for these changes involve not only estradiol and progesterone, but also excitatory amino acids and other cellular mediators22. A major breakthrough in brain plasticity came with the rediscovery of neurogenesis in the adult dentate gyrus2629. Dentate gyrus neurogenesis is stimulated by physical activity and environmental enrichment30 and is inhibited by chronic physical and social stressors18. Regular physical activity also increases human hippocampal volume, possibly via stimulating neurogenesis2. Structural plasticity in the adult brain involving not only neurogenesis, but also dendritic and synaptic turnover, can be related to social
690 Control Control

Chronic stress

Chronic stress

Prefrontal cortex and hippocampus

Amygdala and orbitofrontal cortex

Figure 1 Chronic stress causes neurons to shrink or grow, but not necessarily to die. Representation of the chronic stress effects detected in animal models on growth or retraction of dendrites in the basolateral amygdala and orbitofrontal cortex (growth) and in the CA3 hippocampus, dentate gyrus and medial prefrontal cortex (shrinkage). These effects are largely reversible in young adult animals, although aging appears to compromise resilience and medial prefrontal cortex recovery21.

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interactions in the visible burrow system for rats31 and in the tree shrew. In the tree shrew, a resident-intruder protocol shows the powerful effect on the intruder in terms of reduced neurogenesis and dendritic shrinkage in the hippocampus32,33. Although the hippocampus shows impaired neurogenesis and atrophy of dendritic trees after chronic stress, the same stressor causes dendritic growth in the basolateral amygdala, along with increased anxiety (Fig. 1) and aggression, whereas neurons in the medial prefrontal cortex shrink and those in the orbitofrontal cortex grow18,34,35. These are largely reversible changes, at least in young adult animals, although aging compromises the reversibility of neuronal atrophy in the medial prefrontal cortex19. Stress-induced changes in the circuitry of these brain regions alters the balance between different neural systems that are activated by experiences18,36. For example, low self esteem in humans has been associated with a smaller hippocampus, impulsiveness and poor executive function have been associated with a defective prefrontal cortex, and aggression and anxiety have been associated with an overactive amygdala36. Early life experiences are potent in this regard37. In both animal models and humans, experiences, good and bad, shape these circuits and their connectivity, and experiences can trigger adaptive or maladaptive responses depending on the health and balance of those interconnections. In animals, early life events related to maternal care, as well as parental care in humans, have a powerful role in later mental and physical health, as demonstrated by the adverse childhood experiences study38. Prenatal stress impairs hippocampal development in rats, as does stress in adolescence39. Abusive maternal care in rodents and the surprising attachment shown by infant rats to their abusive mothers appears to involve an immature amygdala40, the activation of which by glucocorticoids causes aversive conditioning response to emerge. Maternal anxiety in the variable foraging demand model in rhesus monkeys leads to chronic anxiety in the offspring, as well as signs of metabolic syndrome41,42. There is also structural plasticity in the mesolimbic reward system that is affected by social defeat and leads animals to increased drug self-administration. As a result, medium spiny neurons in the nucleus accumbens show altered dendritic spine formation43. Social defeat, along with maternal separation in infancy, increases vulnerability to substance self-administration44. Drugs of abuse alter the morphology of many brain regions45, which may or may not drive addictive behavior or reflect compensatory changes46. Notably, there
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is cross-sensitization of appetitive stimuli in that induction of need-free salt appetite leads Group differences in OFC volume to altered dendritic morphology in the shell of the nucleus accumbens and sensitizes the animal to amphetamine self-administration47. In addition to findings that underscore the deleterious effect of early life stress on later development, some animal studies have found protective effects of nurturing environments, as well as resilience-enhancing effects of exposure to mild stress early in life. Animal models have contributed enormously to our Typically developing Physically abused understanding of how the brain and body are Correlation for physically abused children Correlation for physically abused children affected48,49. Epigenetic, transgenerational r = 0.504, P = 0.005 r = 0.516, P = 0.005 effects transmitted by maternal care are central to these findings. Beside the amount of maternal care, the consistency over time of that care and the exposure to novelty are also very important, not only in rodents50,51, but also in monkeys52. A recent study found that the rat pups who received high levels of licking and grooming during the first week of postnatal life had higher levels of glucocorti coid mRNA expression in the hippocampus as Poorer academic functioning Poorer family functioning young adults and enhanced induction of synaptic plasticity in the dentate gyrus in vitro53. Brain-behavior correlations Beneficial effects of early exposure to mild Figure 2 Physically abused children show alterations in orbitofrontal (OFC) volume compared with stress have been observed in squirrel mon- typically developing children, and volume shrinkage in this region is related to measures of family keys. After exposure to mild stress from stress. Top, physically abused children show reductions in orbitofrontal cortex compared with typically postnatal weeks 1727, the mildly stressed developing controls. Bottom, among physically abused children, those showing poorer academic animals displayed decreased anxiety as young function and poorer family functioning (greater family stress) exhibit less volume in orbitofrontal 68 adults, as measured by decreased maternal cortex . Note that because the voxel-wise analysis was a between-groups comparison and the correlational analysis was conducted with the abused children only, this does not suffer from the clinging, enhanced exploratory behavior and double-dipping problem. increased food consumption. Moreover, animals exposed to early mild stress had lower basal plasma adrenocorticotropic hormone and cortisol, and lower diverse treatments ranging from antidepressant drugs, such as fluoxetine, cortisol following stress exposure54. Animals exposed to early mild to regular physical activity may be a key feature of treatment60. In addistress exhibited enhanced prefrontally dependent response inhibition as tion, there are other potential applications, such as the recently reported young adults, suggesting that the early exposure to mild stress enhances ability of fluoxetine to enhance recovery from stroke61. An important prefrontal regulatory mechanisms that facilitate stress inoculation55. aspect of this new view62 is that the drug is opening a window of opporIn this same squirrel monkey model, mild stress exposure early in life tunity that may be capitalized by a positive behavioral intervention; for results in increased ventromedial prefrontal cortex (vmPFC) volume example, behavioral therapy in the case of depression or intensive physduring the peripubertal period56. The increased vmPFC volume reflects iotherapy to promote neuroplasticity to counteract the effects of a stroke. surface area expansion of this PFC zone rather than an increase in cortical thickness. Moreover, increased white matter myelination in this Plasticity in human social brain Experience-induced effects of adversity and stress. The social and region was detected with diffusion tensor imaging56. One of the longest held notions of brain plasticity is that certain criti- emotional circuitry of the brain is continuously being shaped by forces cal periods or windows exist in development, during which circuitry that impinge on the nervous system during prenatal development and is laid down that lasts for the lifetime. However, a more recent set of throughout life. The fact that experience-induced plasticity has been findings suggests that developmentally induced plasticity, at least c ertain documented in the social brain in a variety of animal models provides kinds, can be reversed by re-opening those windows. For example, ocular the foundation for examining similar effects in humans. There is now a dominance imbalance resulting from early monocular deprivation can substantial body of evidence on the effect of stressful environments on be reversed by patterned light exposure in adulthood that can be facili- the developing human brain and associated behavior6267. For example, tated by fluoxetine57 and food restriction58, in which reducing inhibitory in a sample of 31 physically abused and 41 typically developing teenage neuronal activity appears to be important59. Investigations of underlying children who underwent structural MRI scanning using diffeomorphic mechanisms for the re-establishment of a new window of plasticity are image normalization and tensor-based morphometry, the abused children focusing on the balance between excitatory and inhibitory transmission had smaller orbitofrontal volumes and, furthermore, the smaller the orbitofrontal volume in the abused sample, the more severe the social stress and removing molecules that put the brakes on such plasticity9. Depression is more prevalent in individuals who have had adverse as reported by children and parents on a structured interview (Fig. 2)68. early life experiences38. Neurotrophic factors such as BDNF may be an Early life stress modulates the hypothalamic-pituitary-adrenal axis, particularly cortisol as an output measure of this system, although the important feature of the depressive state, and elevation of such factors by
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effects on this system are complex and depend a b 0.0032 0.0071 on the chronicity and timing of the stress69. Comparison to 0.0031 0.0069 Evidence that child abuse is associated with early adopted 0.003 0.0067 alterations in the epigenetic regulation of the Early adopted 0.0029 0.0065 glucocorticoid receptor was obtained in a study 0.0028 0.0063 Comparison to of postmortem tissue extracted from the hiplater adopted 0.0027 0.0061 pocampus of suicide victims with a history Later adopted 0.0026 0.0059 of child abuse and those with no abuse history along with controls70. In hippocampus, decreased levels of glucocorticoid receptor Amygdala Hippocampus Caudate mRNA were observed, as well as mRNA tranFigure 3 Anatomically segmented amygdala volumes are larger in later-adopted post-institutionalized scripts bearing the glucocorticoid receptor 1F children. (a) Anatomical segmentation of the amygdala. (b) Later-adopted post-institutionalized splice variant and increased cytosine methyla- children show larger amygdala volume compared with both early adopted children and with typically tion of an NR3C1 promoter70. developing controls. No differences among groups were found in hippocampus or caudate 71. Asterisk One study capitalized on unfortunate circum- indicates that the later adopted group exhibited significantly larger amygdala volume compared with stances and examined 38 post- institutionalized each of the comparison groups. children who were raised in impoverished orphanages in either Eastern Europe or Asia and 40 non-institutionalized children71. At the time of testing, the chil- dysfunctions and/or structural abnormalities in their interconnections dren were 8.59.5 years and were institutionalized, on average, at 2.5 have been implicated in psychopathology8183. months of age. Using an automated segmentation algorithm, the authors Prosocial intervention and training. An important question replete specifically looked at volumetric measures of the amygdala, hippocam- with both theoretical and practical relevance is whether explicit intervenpus and caudate. When the post-institutionalized sample was compared tions or training designed to foster prosocial behavior and well-being, or with controls, no overall differences between groups were found for any more naturally occurring forms of positive social interaction and social of the three structures examined. However, they also divided the post- support, can induce neuroplastic changes in the brain. A study examininstitutionalized sample into those who were adopted at an early age versus ing the effect of holding the hand of ones spouse found a significant those adopted later on (<15 months versus >15 months at age of adop- attenuation of the neural response to the threat of shock in several threattion, respectively). When participants were divided in this way, the later sensitive brain regions, including the anterior insula and ventral anterior adopted post- institutionalized children were found to have significantly cingulate cortex, in women when they were holding their spouses hand larger amygdale than those adopted early on and their control counter- compared with controls that included holding a strangers hand and an parts. There were no significant differences among any of the groups in the alone condition84. As this and other similar studies examined the effect of volumes of the hippocampus or caudate (Fig. 3). When examined contin- an acute manipulation, the effects are likely to be phasic and short-lived, uously, the authors found that the age at adoption was positively correlated but they raise the question of whether cumulative exposure to social with amygdala volume, such that those adopted at a later age had larger support would induce beneficial plastic changes85. Other forms of social amygdala volumes. Higher parental ratings of internalizing behavior and support, such as maternal care, appear to modulate the effect of prenatal anxiety were also correlated with larger amygdala volume. A similar pat- risk on hippocampal volume, at least in women86. tern of results was obtained from a sample of 10-year-old children, some There is a growing literature documenting functional and structural of whom were continuously exposed to maternal depressive symptoms changes in the brain with specific interventions and training regimes. from birth and others who had no exposure to maternal depressive symp- The behavioral evidence in support of such interventions and training toms72. At 10 years of age, children who had been continuously exposed provides a reasonable foundation for the exploration of neural changes to maternal depressive symptoms from birth had significantly larger left that support these behavioral outcomes. For example, interventions and right amygdale than children with no such exposure. There were no designed to promote prosocial behavior, such as effective emotion regusignificant differences in hippocampal volume between these groups. The lation, have been developed for incorporation in school curricula to supmean depression score of the mother computed over 7 years predicted port the development of more positive social and emotional trajectories amygdala volume of her child at age 10 such that mothers with higher in K-12 school children. A recent meta-analysis of 213 programs involvlevels of depressive symptoms had children with larger amygdala volume. ing more than 270,000 school children found that, compared with conThese findings are consistent with the idea that early life stress trols, participants in social emotional learning programs demonstrated induces structural changes in the developing brain. The two most significant gains in social and emotional skills and performed, on averprominent structural findings from human research suggest that age, 11% better on standardized measures of academic achievement12. amygdala volume is increased and that sectors of the prefrontal cortex Other evidence suggests that cognitive therapy for depression4, as well are decreased. Some caution regarding these findings in the amygdala as well-being therapy87, specifically helps to improve positive affect. is warranted because of methodological complications resulting from A recent review presented evidence consistent with the view that automated segmentation algorithms with subcortical structures such cognitive therapy enhances prefrontal function and via this enhanced as the amygdala73. Moreover, the precise ages at which these effects prefrontal activation, amygdala activation is inhibited88. A recent study occur needs to be carefully studied, as, particularly for the amygdala, examined the effect of cognitive therapy on patients with chronic early hypertrophy and enlargement may occur in response to adver- fatigue syndrome in a short-term longitudinal study89. At baseline, sity, and, perhaps in part because of excitotoxic processes, premature these patients showed decreased gray matter volume compared with volume reduction may be produced74. Such a developmental pattern in healthy controls. Patients then underwent 16 1-h sessions of cognitive the amygdala has been suggested to occur in the autistic brain75,76. The therapy and were rescanned following treatment. Increases in lateral amygdala and prefrontal cortex and their interconnections have been prefrontal volume were found in the patients following treatment that strongly implicated in emotion regulation7779 and well-being80, and were correlated with improvements in digit symbol substitution and in
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a choice reaction time task89. Unfortunately, changes in mood or social behavior were not reported. The effect of secular training derived from meditation traditions that emphasize the cultivation of positive affect, such as compassion and kindness, has received increased empirical attention. A recent review concluded that such exercises, which are oriented toward enhancing the positive emotions compassion and kindness, do indeed increase positive affect and decrease negative affect90. It has been shown that 1 d of compassion meditation training increases prosocial behavior in a virtual game compared with a 1 d of memory training control condition88. Collectively, these findings raise the possibility that such interventions and training programs designed to explicitly decrease stress and enhance certain forms of positive emotion may produce specific plasticity-related alterations in brain function and structure. A recent study of functional brain alterations with compassion meditation in expert practitioners who have been meditating for more than 10,000 h over the course of their lifetime, compared with novices who were just learning to meditate, found that, during a mental practice explicitly designed to enhance compassion, the practitioners showed enhanced gamma oscillations and gamma synchrony compared with controls91. Enhanced BOLD signal was detected with fMRI in response to emotional sounds in brain regions, including the insula and temporoparietal junction, that have been implicated in previous studies of empathy92. The increase in gamma oscillations and gamma synchrony might reflect its role in synaptic plasticity93 and suggest a general enhancement of synaptic plasticity through this form of mental practice. Other research suggests that mindfulness meditation may operate via a distinct neural mode of self-referencing that favors momentary nonjudgmental present-moment experience over narrative self-focused mentation. This form of mental training has been found to decrease anxiety and increase positive affect94. A study tested this idea by comparing novices and participants who attended an 8-week course in mindfulness meditation (mindfulness-based stress reduction, MBSR). fMRI was measured in response to a task that contrasted an experiential focus to a narrative self-focused condition in response to trait adjectives. The MBSR participants exhibited reductions in medial prefrontal activation and increased activation of the insula and lateral prefrontal cortices during the experiential versus narrative conditions95. Consistent findings using a different methodological strategy were obtained in a recent study comparing experienced mindfulness meditation practitioners to novices. The experienced practitioners showed decreased medial prefrontal activity in the baseline default BOLD signal compared with the novices96. Other findings indicate that activation of the medial prefrontal cortex at baseline is associated with mind-wandering97 and that mind wandering is associated with unhappiness98. A major limitation of all of the studies described above on is that they relied on between group comparisons of a meditation group compared with a control group. To more firmly establish that differences are the results of meditation training per se and not of self-selection and other factors that might confound between group comparisons, longitudinal investigations of changes over the course of meditation training are needed. Such a design was used to examine whether certain forms of meditation may operate via effects that are opposite to those produced by stress. As we noted above, early life stress increases amygdala volume. In a longitudinal study of 26 participants undergoing an 8-week training in MBSR, MRI scans were obtained before and after the 8 weeks of training. Reductions in perceived stress following MBSR were correlated with reductions in gray matter volume in the right basolateral amygdala that were obtained from MRI scans performed before and after the 8 weeks of training (Fig. 4)11. These findings suggest that the plasticity-related alterations in brain regions
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Gray matter concentration change (%) in cluster in the right amygdala

20 15 10 5 0 5 10 15 10 5 0 5 10 15 20 25

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Change in perceived stress scale score

Figure 4 Change in gray matter volume in the right basolateral amygdala from pre to post 8 weeks of MBSR was associated with decreases in perceived stress over this same time period. Individuals undergoing MBSR who showed the largest decreases in perceived stress also showed the largest decreases in basolateral amygdala gray matter volume11.

that have been implicated in stress can occur with as little as 8 weeks of mindfulness meditation training. Summary, conclusions and implications It has been known for more than a century that social and emotional behavior is modified by experience. Abundant evidence exists that stress and adversity, particularly early in life, can produce enduring alterations in behavior. It has also been claimed for thousands of years that specific forms of mental training can produce robust beneficial and enduring effects on behavior. The rigorous investigation of such effects and the neural mechanisms responsible for producing them has only recently become a serious focus of neuroscientific study. The findings that we discuss underscore the structural plasticity of emotional circuitry in response to both acute and chronic stress, particularly alterations of spine density and dendritic length and branching in hippocampus, amygdala and prefrontal cortex. Evidence at the animal level has identified several different mechanisms of plasticity, including dendritic and synaptic turnover and neurogenesis. The animal and human evidence is consistent in demonstrating that many forms of stress promote excessive growth in sectors of the amygdala, whereas effects in hippocampus tend to be opposite. Whether critical or sensitive periods exist for plasticity in response to social influences has not been thoroughly addressed and more systematic developmental studies are required. Moreover, the reversibility of structural changes following alterations in social and emotional conditions has not been systematically examined. At the human level, research is beginning to document the effect of explicit interventions designed to decrease stress and promote prosocial behavior and well-being on brain structure and function. These studies are consistent with basic research in demonstrating increases in specific sectors of prefrontal activation and decreases in amygdala activation. These functional alterations are accompanied by structural changes that show increases in prefrontal volume and decreases in amygdala volume. The precise differences among the various interventions that have been developed for this general purpose have not been systematically studied,
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nor has the relation between functional and structural changes been carefully documented. Moreover, it is apparent that both structural and functional connectivity between prefrontal regions and subcortical structures is extremely important for emotion regulation and that these connections represent important targets for plasticity-induced changes. This is likely to be an important focus of future studies. Finally, the studies on interventions explicitly designed to promote positive emotional qualities, such as kindness and mindfulness, imply that such qualities might best be regarded as the product of skills that can be enhanced through training, just as practice will improve musical performance and produce correlated regionally specific anatomical changes. Whether these interventions simply modulate the adverse effects of stress or whether they result in a profile of neurobehavioral functioning that is better than normal will require considerably more evidence, although the available evidence points toward the latter possibility. This perspective can lead to the view that social and emotional characteristics can be educated in ways that are not dissimilar from certain forms of cognitive learning. Many forms of meditation and cognitive therapy can enhance self-control or self-regulation99. Such improvements in self-control are particularly apparent in social and interpersonal contexts. It is in these contexts that attentionally demanding stimuli typically occur and where self-regulation is especially important. A recent study of a cohort of 1,000 participants assessed from birth to 32 years of age found that childhood measures of self-control predicted physical health, substance dependence, personal finances and criminal offending outcomes at 32 years of age100. The authors defined self-control as a family of processes that include delay of gratification, impulse and attentional control, executive function, and willpower. They suggest that early interventions that enhance selfcontrol might reduce a panoply of societal costs, save taxpayers money and promote prosperity. The mental training at the core of the techniques described above might constitute ideal interventions to promote early self-control and improve later adult prosocial outcomes. For example, mindfulness meditation has been found to strengthen selective and other aspects of attention and executive function5. Whether such interventions can produce changes that have lasting consequences is a possibility that requires extensive empirical investigation.
ACKNOWLEDGMENTS R.J.D. is supported by grants from the National Institute of Mental Health (R01-MH43454 and P50-MH084051), the National Center for Complementary and Alternative Medicine (P01-AT004952), the Fetzer Institute, the John Templeton Foundation, and gifts from Bryant Wangard and Ralph Robinson, Ann Down, Keith and Arlene Bronstein, and the John W. Kluge Foundation. B.S.M. is supported by US National Institutes of Health grants R01 MH41256 and 5P01 MH58911. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests.
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1. 2. 3. 4. 5. 6. 7. 8. Adolphs, R. Conceptual challenges and directions for social neuroscience. Neuron 65, 752767 (2010). Erickson, K.I. et al. Exercise training increases size of hippocampus and improves memory. Proc. Natl. Acad. Sci. USA 108, 30173022 (2011). Disner, S.G., Beevers, C.G. & Haigh, E.A.P. & Beck, A.T. Neural mechanisms of the cognitive model of depression. Nat. Rev. Neurosci. 12, 467477 (2011). Clark, D.A. & Beck, A.T. Cognitive theory and therapy of anxiety and depression: convergence with neurobiological findings. Trends Cogn. Sci. 14, 418424 (2010). Lutz, A., Slagter, H., Dunne, J.D. & Davidson, R.J. Attention regulation and monitoring in meditation. Trends Cogn. Sci. 12, 163169 (2008). Kuhl, P.K. Brain mechanisms in early language acquisition. Neuron 67, 713727 (2010). Nelson, C.A. et al. Cognitive recovery in socially deprived young children: the Bucharest Early Intervention Project. Science 318, 19371940 (2007). Sullivan, R.M. & Holman, P.J. Transitions in sensitive period attachment learning in infancy: the role of corticosterone. Neurosci. Biobehav. Rev. 34, 835844 (2010). 9. Bavelier, D., Levi, D.M., Li, R.W., Dan, Y. & Hensch, T.K. Removing brakes on adult brain plasticity: from molecular to behavioral interventions. J. Neurosci. 30, 1496414971 (2010). Carlson, M.C. et al. Evidence for neurocognitive plasticity in at-risk older adults: the experience corps program. J. Gerontol. A Biol. Sci. Med. Sci. 64, 12751282 (2009). Hlzel, B.K. et al. Stress reduction correlates with structural changes in the amygdala. Soc. Cogn. Affect. Neurosci. 5, 1117 (2010). Durlak, J.A., Weissberg, R.P., Dymnicki, A.B., Taylor, R.D. & Schellinger, K.B. The impact of enhancing students social and emotional learning: a meta-analysis of school-based universal interventions. Child Dev. 82, 405432 (2011). Diamond, A. & Lee, K. Interventions shown to aid executive function development in children 4 to 12 years old. Science 333, 959964 (2011). Bennett, E.L., Diamond, M.C., Krech, D. & Rosenzweig, M.R. Chemical and anatomical plasticity of the brain. Science 146, 610619 (1964). Hebb, D.O. The Organization of Behavior: a Neuropsychological Theory (Wiley, New York, 1949). Diamond, M.C. The aging brain: some enlightening and optimistic results. Am. Sci. 66, 6671 (1978). Markham, J.A. & Greenough, W.T. Experience-driven brain plasticity: beyond the synapse. Neuron Glia Biol. 1, 351363 (2004). McEwen, B.S. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol. Rev. 87, 873904 (2007). Bloss, E.B., Janssen, W.G., McEwen, B.S. & Morrison, J.H. Interactive effects of stress and aging on structural plasticity in the prefrontal cortex. J. Neurosci. 30, 67266731 (2010). Liston, C. & Gan, W.-B. Glucocorticoids are critical regulators of dendritic spine development and plasticity in vivo. Proc. Natl. Acad. Sci. USA 108, 1607416079 (2011). Popoli, M., Yan, Z., McEwen, B.S. & Sanacora, G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat. Rev. Neurosci. 13, 2237 (2012). McEwen, B.S. & Milner, T.A. Hippocampal formation: shedding light on the influence of sex and stress on the brain. Brain Res. Rev. 55, 343355 (2007). McEwen, B.S. & Alves, S.E. Estrogen actions in the central nervous system. Endocr. Rev. 20, 279307 (1999). Dumitriu, D., Rapp, P.R., McEwen, B.S. & Morrison, J.H. Estrogen and the aging brain: an elixir for the weary cortical network. Ann. NY Acad. Sci. 1204, 104112 (2010). Chen, J.-R. et al. Gonadal hormones modulate the dendritic spine densities of primary cortical pyramidal neurons in adult female rat. Cereb. Cortex 19, 27192727 (2009). Cameron, H.A. & Gould, E. The control of neuronal birth and survival. in Receptor Dynamics in Neural Development (ed. C.A. Shaw) 141157 (CRC Press, 1996). Kaplan, M.S. Environment complexity stimulates visual cortex neurogenesis: death of a dogma and a research career. Trends Neurosci. 24, 617620 (2001). Altman, J. & Bayer, S.A. Mosaic organization of the hippocampal neuroepithelium and the multiple germinal sources of dentate granule cells. J. Comp. Neurol. 301, 325342 (1990). Nottebohm, F. From bird song to neurogenesis. Sci. Am. 260, 7479 (1989). Brown, J. et al. Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur. J. Neurosci. 17, 20422046 (2003). Kozorovitskiy, Y. & Gould, E. Dominance hierarchy influences adult neurogenesis in the dentate gyrus. J. Neurosci. 24, 67556759 (2004). Gould, E., McEwen, B.S., Tanapat, P., Galea, L.A. & Fuchs, E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J. Neurosci. 17, 24922498 (1997). Magarios, A.M., McEwen, B.S., Flgge, G. & Fuchs, E. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J. Neurosci. 16, 35343540 (1996). Vyas, A., Mitra, R., Shankaranarayana Rao, B.S. & Chattarji, S. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J. Neurosci. 22, 68106818 (2002). Liston, C. et al. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J. Neurosci. 26, 78707874 (2006). McEwen, B.S. & Gianaros, P.J. Stress- and allostasis-induced brain plasticity. Annu. Rev. Med. 62, 431445 (2011). Shonkoff, J.P., Boyce, W.T. & McEwen, B.S. Neuroscience, molecular biology and the childhood roots of health disparities: building a new framework for health promotion and disease prevention. J. Am. Med. Assoc. 301, 22522259 (2009). Anda, R.F., Butchart, A., Felitti, V.J. & Brown, D.W. Building a framework for global surveillance of the public health implications of adverse childhood experiences. Am. J. Prev. Med. 39, 9398 (2010). Isgor, C., Kabbaj, M., Akil, H. & Watson, S.J. Delayed effects of chronic variable stress during peripubertal-juvenile period on hippocampal morphology and on cognitive and stress axis functions in rats. Hippocampus 14, 636648 (2004). Moriceau, S. & Sullivan, R.M. Maternal presence serves as a switch between learning fear and attraction in infancy. Nat. Neurosci. 9, 10041006 (2006). Kaufman, D. et al. Early appearance of the metabolic syndrome in socially reared bonnet macaques. J. Clin. Endocrinol. Metab. 90, 404408 (2005). Coplan, J.D. et al. Variable foraging demand rearing: Sustained elevations in cisternal cerebrospinal fluid corticotropin-releasing factor concentrations in adult primates. Biol. Psychiatry 50, 200204 (2001).

10.

11. 12.

13. 14. 15. 16. 17. 18. 19.

20.

2012 Nature America, Inc. All rights reserved.

21.

22. 23. 24.

25. 26. 27. 28.

29. 30. 31. 32.

npg

33.

34.

35.

36. 37.

38.

39.

40. 41. 42.

694

volume 15 | number 5 | MAY 2012 nature neuroscience

review
43. Christoffel, D.J. et al. IkB kinase regulates social defeat stress-induced synaptic and behavioral plasticity. J.Neurosci. 31, 314321 (2011). 44. Miczek, K.A., Yap, J.J. & Covington, H.E. Social stress, therapeutics and drug abuse: preclinical models of escalated and depressed intake. Pharmacol. Ther. 120, 102 128 (2008). 45. Robinson, T.E. & Kolb, B. Structural plasticity associated with exposure to drugs of abuse. Neuropharmacology 47 Suppl 1, 3346 (2004). 46. Russo, S.J. et al. The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci. 33, 267276 (2010). 47. Roitman, M.F., Na, E., Anderson, G., Jones, T.A. & Bernstein, I.L. Induction of a salt appetite alters dendritic morphology in nucleus accumbens and sensitizes rats to amphetamine. J. Neurosci. 22, RC225 (2002). 48. Levine, S., Haltmeyer, G.C., Karas, G.G. & Denenberg, V.H. Physiological and behavioral effects of infantile stimulation. Physiol. Behav. 2, 5559 (1967). 49. Meaney, M.J. & Szyf, M. Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome. Dialogues Clin. Neurosci. 7, 103123 (2005). 50. Akers, K.G. et al. Social competitiveness and plasticity of neuroendocrine function in old age: influence of neonatal novelty exposure and maternal care reliability. PLoS ONE 3, e2840 (2008). 51. Tang, A.C., Akers, K.G., Reeb, B.C., Romeo, R.D. & McEwen, B.S. Programming social, cognitive and neuroendocrine development by early exposure to novelty. Proc. Natl. Acad. Sci. USA 103, 1571615721 (2006). 52. Parker, K.J. & Maestripieri, D. Identifying key features of early stressful experiences that produce stress vulnerability and resilience in primates. Neurosci. Biobehav. Rev. 35, 14661483 (2011). 53. van Hasselt, F.N. et al. Adult hippocampal glucocorticoid receptor expression and dentate synaptic plasticity correlate with maternal care received by individuals early in life. Hippocampus 22, 255266 (2011). 54. Parker, K.J., Buckmaster, C.L., Schatzberg, A.F. & Lyons, D.M. Prospective investigation of stress inoculation in young monkeys. Arch. Gen. Psychiatry 61, 933941 (2004). 55. Parker, K.J., Buckmaster, C.L., Justus, K.R., Schatzberg, A.F. & Lyons, D.M. Mild early life stress enhances prefrontal-dependent response inhibition in monkeys. Biol. Psychiatry 57, 848855 (2005). 56. Katz, M. et al. Prefrontal plasticity and stress inoculation-induced resilience. Dev. Neurosci. 31, 293299 (2009). 57. Maya Vetencourt, J.F. et al. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science 320, 385388 (2008). 58. Spolidoro, M. et al. Food restriction enhances visual cortex plasticity in adulthood. Nature Commun. 2, 320 (2011). 59. Southwell, D.G., Froemke, R.C., Alvarez-Buylla, A., Stryker, M.P. & Gandhi, S.P. Cortical plasticity induced by inhibitory neuron transplantation. Science 327, 11451148 (2010). 60. Duman, R.S. & Monteggia, L.M. A neurotrophic model for stress-related mood disorders. Biol. Psychiatry 59, 11161127 (2006). 61. Chollet, F. et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomized placebo-controlled trial. Lancet Neurol. 10, 123130 (2011). 62. Castrn, E. & Rantamki, T. The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev. Neurobiol. 70, 289297 (2010). 63. Shonkoff, J.P. & Garner, A.S. The lifelong effects of early childhood adversity and toxic stress. Pediatrics 129, 232246 (2012). 64. Shonkoff, J.P. Protecting brains, not simply stimulating minds. Science 333, 982 983 (2011). 65. Heim, C., Shugart, M., Craighead, W.E. & Nemeroff, C.B. Neurobiological and psychiatric consequences of child abuse and neglect. Dev. Psychobiol. 52, 671690 (2010). 66. Gould, F. et al. The effects of child abuse and neglect on cognitive functioning in adulthood. J. Psychiatr. Res. 46, 500506 (2012). 67. Choi, J., Jeong, B., Rohan, M.L., Polcari, A.M. & Teicher, M.H. Preliminary evidence for white matter tract abnormalities in young adults exposed to parental verbal abuse. Biol. Psychiatry 65, 227234 (2009). 68. Hanson, J.L. et al. Early stress is associated with alterations in the orbitofrontal cortex: a tensor-based morphometry investigation of brain structure and behavioral risk. J. Neurosci. 30, 74667472 (2010). 69. Loman, M.M. & Gunnar, M.R. Early experience and the development of stress reactivity and regulation in children. Neurosci. Biobehav. Rev. 34, 867876 (2010). 70. McGowan, P.O. et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat. Neurosci. 12, 342348 (2009). 71. Tottenham, N. et al. Prolonged institutional rearing is associated with atypically large amygdala volume and difficulties in emotion regulation. Dev. Sci. 13, 4661 (2010). 72. Lupien, S.J. et al. Larger amygdala but no change in hippocampal volume in 10-yearold children exposed to maternal depressive symptomatology since birth. Proc. Natl. Acad. Sci. USA 108, 1432414329 (2011). 73. Morey, R.A. et al. A comparison of automated segmentation and manual tracing for quantifying hippocampal and amygdala volumes. Neuroimage 45, 855866 (2009). 74. Tottenham, N. & Sheridan, M.A. A review of adversity, the amygdala and the hippocampus: a consideration of developmental timing. Front. Hum. Neurosci. 3, 68 (2009). 75. Nacewicz, B.M. et al. Amygdala volume and nonverbal social impairment in adolescent and adult males with autism. Arch. Gen. Psychiatry 63, 14171428 (2006). 76. Mosconi, M.W. et al. Longitudinal study of amygdala volume and joint attention in 2- to 4-year-old children with autism. Arch. Gen. Psychiatry 66, 509516 (2009). 77. Ochsner, K.N. & Gross, J.J. The cognitive control of emotion. Trends Cogn. Sci. 9, 242249 (2005). 78. Wager, T.D., Davidson, M.L., Hughes, B.L. & Lindquist, M.A. & Ochsner, K.N. Prefrontal-subcortical pathways mediating successful emotion regulation. Neuron 59, 10371050 (2008). 79. Urry, H.L. et al. Amygdala and ventromedial prefrontal cortex are inversely coupled during regulation of negative affect and predict the diurnal pattern of cortisol secretion among older adults. J. Neurosci. 26, 44154425 (2006). 80. Davidson, R.J. Well-being and affective style: neural substrates and biobehavioural correlates. Philos. Trans. R. Soc. Lond. B Biol. Sci. 359, 13951411 (2004). 81. Davidson, R.J., Putnam, K.M. & Larson, C.L. Dysfunction in the neural circuitry of emotion regulation: a possible prelude to violence. Science 289, 591594 (2000). 82. Johnstone, T., van Reekum, C.M., Urry, H.L., Kalin, N.H. & Davidson, R.J. Failure to regulate: counterproductive recruitment of top-down prefrontal-subcortical circuitry in major depression. J. Neurosci. 27, 88778884 (2007). 83. Kim, M.J. & Whalen, P.J. The structural integrity of an amygdala-prefrontal pathway predicts trait anxiety. J. Neurosci. 29, 116148 (2009). 84. Coan, J.A., Schaefer, H.S. & Davidson, R.J. Lending a hand: social regulation of the neural response to threat. Psychol. Sci. 17, 10321039 (2006). 85. Uchino, B.N., Cacioppo, J.T. & Kiecolt-Glaser, J.K. The relationship between social support and physiological processes: a review with emphasis on underlying mechanisms and implications for health. Psychol. Bull. 119, 488531 (1996). 86. Buss, C. et al. Maternal care modulates the relationship between prenatal risk and hippocampal volume in women but not in men. J. Neurosci. 27, 25925 (2007). 87. Fava, G.A., Rafanelli, C., Cazzaro, M., Conti, S. & Grandi, S. Well-being therapy. A novel psychotherapeutic approach for residual symptoms of affective disorders. Psychol. Med. 28, 475480 (1998). 88. DeRubeis, R.J., Siegle, G.J. & Hollon, S.D. Cognitive therapy versus medication for depression: treatment outcomes and neural mechanisms. Nat. Rev. Neurosci. 9, 788796 (2008). 89. de Lange, F.P. et al. Increase in prefrontal cortical volume following cognitive behavioural therapy in patients with chronic fatigue syndrome. Brain 131, 21722180 (2008). 90. Hofmann, S.G., Grossman, P. & Hinton, D.E. Loving-kindness and compassion meditation: potential for psychological interventions. Clin. Psychol. Rev. 31, 11261132 (2011). 91. Lutz, A., Greischar, L.L., Rawlings, N.B., Ricard, M. & Davidson, R.J. Long-term meditators self-induce high-amplitude gamma synchrony during mental practice. Proc. Natl. Acad. Sci. USA 101, 16369 (2004). 92. Lutz, A., Brefczynski-Lewis, J., Johnstone, T. & Davidson, R.J. Regulation of the neural circuitry of emotion by compassion meditation: effects of meditative expertise. PLoS One 3, e1897 (2008). 93. Uhlhaas, P.J., Roux, F., Rodriguez, E., Rotarska-Jagiela, A. & Singer, W. Neural synchrony and the development of cortical networks. Trends Cogn. Sci. 14, 7280 (2010). 94. Kemeny, M.E. et al. Contemplative/emotion training reduces negative emotional behavior and promotes prosocial responses. Emotion published online (12 December 2011). 95. Farb, N.A. et al. Attending to the present: mindfulness meditation reveals distinct neural modes of self-reference. Soc. Cogn. Affect. Neurosci. 2, 313322 (2007). 96. Brewer, J.A. et al. Meditation experience is associated with differences in default mode network activity and connectivity. Proc. Natl. Acad. Sci. USA 108, 16 (2011). 97. Christoff, K., Gordon, A.M., Smallwood, J., Smith, R. & Schooler, J.W. Experience sampling during fMRI reveals default network and executive system contributions to mind wandering. Proc. Natl. Acad. Sci. USA 106, 87198724 (2009). 98. Killingsworth, M.A. & Gilbert, D.T. A wandering mind is an unhappy mind. Science 330, 932 (2010). 99. Chambers, R., Gullone, E. & Allen, N.B. Mindful emotion regulation: an integrative review. Clin. Psychol. Rev. 29, 560572 (2009). 100. Moffitt, T.E. et al. A gradient of childhood self-control predicts health, wealth, and public safety. Proc. Natl. Acad. Sci. USA 108, 26932698 (2011).

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