Training in cognitive reappraisal normalizes whole-brain indices of emotion regulation in borderline personality disorder.

BACKGROUND: Borderline personality disorder is the prototypical disorder of emotion dysregulation. We have previously shown that borderline personality disorder patients are impaired in their capacity to engage cognitive reappraisal, a frequently-employed adaptive emotion regulation strategy. METHODS: Here we report on the efficacy of longitudinal training in cognitive reappraisal to enhance emotion regulation in borderline patients. Specifically, the training targeted psychological distancing, a reappraisal tactic whereby negative stimuli are viewed dispassionately as though experienced by an objective, impartial observer. At each of 5 sessions over 2 weeks, 22 borderline (14 Female) and 22 healthy control (13 Female) participants received training in psychological distancing and then completed a widely-used picture-based reappraisal task. Self-reported negative affect ratings and functional magnetic resonance imaging (fMRI) data were acquired at the first and fifth sessions. In addition to behavioral analyses, we performed whole-brain pattern expression analyses using independently-defined patterns for negative affect and cognitive reappraisal implementation for each session. RESULTS: Borderline patients showed a decrease in negative affect pattern expression following reappraisal training, reflecting a normalization in neural activity. They did not, however, show significant change in behavioral self-reports. CONCLUSIONS: To our knowledge, this study represents the first longitudinal fMRI examination of task-based cognitive reappraisal training. Using a brief, proof-of-concept design, the results suggest a potential role for reappraisal training in the treatment of borderline patients.

Social support and adaptive emotion regulation: Links between social network measures, emotion regulation strategy use, and health.

Social support, as perceived and experienced within one's social network, has been associated with greater well-being and favorable health outcomes. The transition to college marks a critical time in which social support not only strengthens interpersonal bonds, but also may help an individual discover and utilize various coping strategies to lower risks associated with negative emotions, which may result in better health and well-being. In the present study, we collected data from a large sample of undergraduate students (N = 376) and conducted preregistered analyses to examine links between students' perceived social support in residential college communities, patterns of emotion regulation strategy use, and multiple indicators of health and well-being. Overall, we found partial support for our hypotheses, with some associations between social support and patterns of emotion regulation strategy use, as well as associations between strategy use and health indicators. All results held when adjusting for participants' age and gender. Taken together, the present findings revealed reliable links between social network indicators, emotion regulation strategy use, and health. Future research can extend these findings by observing how these relationships unfold over time, to better understand how people manage their emotions by drawing on their personal networks. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Perceived stress moderates emotion regulation success in real-world contexts: an ecologically-valid multilevel investigation.

BACKGROUND: Emotion regulation plays a crucial role in well-being in everyday life. Effective emotion regulation depends upon adaptively matching a given strategy to a given situation. Recent research has begun to explore these interactions in the context of daily reports of perceived stress, affect, and emotion regulation strategy usage. To further understand these differences in strategy efficacy in an ecologically valid context, we examined responses to real world stressors in a young adult sample. METHODS: We surveyed a range of emotion regulation strategies, including two forms of cognitive reappraisal (i.e., reinterpretation, which involves cognitively reframing one's emotional responses, and psychological distancing, which involves adopting an objective, impartial perspective). Participants reported strategy usage, momentary perceived stress, and affect in response to multiple ecological momentary assessments over a period of 7 days. RESULTS: Analyses of links between strategy usage and affect revealed that rumination was significantly negatively associated with more positive affect ratings. Further, a significant interaction between momentary perceived stress and reinterpretation usage was observed on affect, such that reinterpretation was more adaptive during situations perceived as less stressful. CONCLUSION: These results provide further insight into the importance of situational context in determining the effectiveness of particular emotion regulation strategies.

Emotion regulation during encoding reduces negative and enhances neutral mnemonic discrimination in individuals with depressive symptoms.

Individuals with depression exhibit dysfunctional emotion regulation, general episodic memory deficits, and a negativity bias, where negative experiences are better remembered. Recent work suggests that the negativity bias in depression may be driven by enhanced mnemonic discrimination, a memory measure that relies on hippocampal pattern separation - a computation that processes experiences with overlapping features as unique. Previously, we found that individuals with depressive symptoms show enhanced negative and impaired neutral mnemonic discrimination. The current study aimed to investigate emotion regulation as an approach toward modifying memory encoding of negative and neutral events in individuals with depressive symptoms. Here we show that applying psychological distancing (a cognitive reappraisal strategy characterized by taking a third-person perspective toward negative events) during encoding was associated with reduced negative and enhanced neutral mnemonic discrimination during retrieval in individuals with depressive symptoms. These results suggest that applying emotion regulation techniques during encoding may provide an effective approach toward altering dysfunctional memory in those with depressive symptoms. Given that pharmacological treatments often fail to treat depression, emotion regulation provides a powerful and practical approach toward modifying cognitive and emotional processes. Future neuroimaging studies will be important to determine how emotion regulation impacts the neural mechanisms underlying these findings.

Unpacking reappraisal: a systematic review of fMRI studies of distancing and reinterpretation.

In recent decades, a substantial volume of work has examined the neural mechanisms of cognitive reappraisal. Distancing and reinterpretation are two frequently used tactics through which reappraisal can be implemented. Theoretical frameworks and prior evidence have suggested that the specific tactic through which one employs reappraisal entails differential neural and psychological mechanisms. Thus, we were motivated to assess the neural mechanisms of this distinction by examining the overlap and differentiation exhibited by the neural correlates of distancing (specifically via objective appraisal) and reinterpretation. We analyzed 32 published functional magnetic resonance imaging (fMRI) studies in healthy adults using multilevel kernel density analysis. Results showed that distancing relative to reinterpretation uniquely recruited right bilateral dorsolateral PFC (DLPFC) and left posterior parietal cortex, previously associated with mentalizing, selective attention and working memory. Reinterpretation relative to distancing uniquely recruited left bilateral ventrolateral PFC (VLPFC), previously associated with response selection and inhibition. Further, distancing relative to reinterpretation was associated with greater prevalence of bilateral amygdala attenuation during reappraisal. Finally, a behavioral meta-analysis showed efficacy for both reappraisal tactics. These results are consistent with prior theoretical models for the functional neural architecture of reappraisal via distancing and reinterpretation and suggest potential future applications in region-of-interest specification and neural network analysis in studies focusing on specific reappraisal tactics.

Predicting real-world emotion and health from spontaneously assessed linguistic distancing using novel scalable technology.

Individuals who are better at regulating their emotions have been shown to have better physical and mental health outcomes. One promising emotion regulation strategy is psychological distancing, which involves appraising a stimulus with objectivity or spatial/temporal distance. Language-based psychological distancing (linguistic distancing [LD]) refers to the degree to which one implements psychological distancing naturally via language. A crucial, underexamined mechanism that may account for real-world emotion and health self-reports is spontaneous (i.e., implicit) LD. Using HealthSense, a novel, scalable, mobile health assessment application, we collected lexical transcriptions for personally specific negative and positive events as well as emotion and health-relevant data over 14 days (data collected in 2021) and examined how implicit LD during negative and positive events relates to well-being over time. Primary analyses revealed that higher LD during negative events was associated with lower levels of stress as well as greater emotional and physical well-being within persons. LD during positive events on 1 day predicted greater reports of happiness 2 days later within persons. LD during positive events was associated with fewer symptoms of depression and LD during negative events was associated with greater physical well-being among persons. Exploratory analyses revealed that average depression, rumination, and perceived stress across the 2 weeks were significantly negatively associated with LD during negative events between persons. The present results expand understanding of the relationship between LD and mental and physical health risks and motivate future research on low-burden, scalable interventions involving LD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Lexical markers of cognitive reappraisal, bereavement, and proinflammatory cytokine production.

OBJECTIVE: The loss of a spouse is considered one of the most significant life change-related stressors. Bereaved spouses have significantly increased risk of chronic inflammation, and ultimately greater morbidity and mortality. High levels of proinflammatory cytokines are related to negative health outcomes. In bereavement, the ability to successfully regulate emotion is a vital skill for healthy coping and may represent a key psychological mechanism accounting for varying degrees of resilience. Psychological distancing is a frequently adaptive emotion regulation strategy in which an individual appraises a negative situation by taking a step back and distancing oneself, and coolly evaluates what is happening. The objective of the present work was to investigate whether psychological distancing, implemented implicitly via natural language use (i.e., linguistic distancing [LD]), is related to inflammation and bereavement-related health indicators. METHOD: Participants (N = 144) underwent a blood draw for the inflammation assay, completed questionnaire measures evaluating grief symptoms and health, and completed an oral task describing their relationship with their deceased spouse, which was used for the lexical analyses. RESULTS: We found that LD was significantly associated with a panel of a priori proinflammatory stimulated cytokines (TNF-α, IL-6, IFN-γ, IL-17A, and IL-2), bereavement-related health indices, and the relationship between grief symptoms and inflammation varied depending on the participants' implementation of LD. CONCLUSIONS: LD may have a buffering effect for this vulnerable population. This work elucidates novel dependencies among language, emotion, and health. This work identifies resilience factors and probes the translational value of LD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Psychological Distancing Usage Uniquely Predicts Reduced Perceived Stress During the COVID-19 Pandemic.

Social distancing during the COVID-19 pandemic has presented millions of people with extraordinary challenges that are associated with significant amounts of stress. Emotion regulation is crucial during this crisis as people seek to mitigate the stress and uncertainty of the present moment. In this study, we surveyed a nationally representative sample of 297 adults from the United States on their levels of perceived stress related to the COVID-19 pandemic as well as their level of engagement of different emotion regulation strategies during the pandemic. We performed multiple linear regression analyses to assess which regulation strategies were associated with individual differences in perceived stress. Among all emotion regulation strategies, psychological distancing, which involves thinking about stressful circumstances in an objective, impartial way, was uniquely associated with reductions in perceived stress due to COVID-19 across individuals. This effect was not moderated by age, gender, socioeconomic status, race/ethnicity, or trait-related difficulty in regulating emotion. Conversely, situation modification was associated with significantly greater perceived stress overall. These results suggest the broad applicability and utility of psychological distancing during pandemic-related social distancing as part of an adaptive emotion regulation toolkit and motivate the investigation of interventions involving psychological distancing in this context.

Spousal caregiving, widowhood, and cognition: A systematic review and a biopsychosocial framework for understanding the relationship between interpersonal losses and dementia risk in older adulthood.

Accumulating research suggests that stressful life events, especially those that threaten close intimate bonds, are associated with an increased risk of dementia. Grieving the loss of a spouse, whether in the form of caregiving or after the death, ranks among 'life's most significant stressors', evoking intense psychological and physiological distress. Despite numerous studies reporting elevated dementia risk or poorer cognition among spousal caregivers and widow(er)s compared to controls, no review has summarized findings across cognitive outcomes (i.e., dementia incidence, cognitive impairment rates, cognitive performance) or proposed a theoretical model for understanding the links between partner loss and abnormal cognitive decline. The current systematic review summarizes findings across 64 empirical studies. Overall, both cross-sectional and longitudinal studies revealed an adverse association between partner loss and cognitive outcomes. In turn, we propose a biopsychosocial model of cognitive decline that explains how caregiving and bereavement may position some to develop cognitive impairment or Alzheimer's disease and related dementias. More longitudinal studies that focus on the biopsychosocial context of caregivers and widow(er)s are needed.

Novel computational algorithms to index lexical markers of psychological distancing and their relationship to emotion regulation efficacy over time.

The degree to which one employs an objective or spatially/temporally distant perspective via language, i.e., linguistic distancing, has previously been shown to be positively associated with well-being. We sought to further elucidate relationships among language and emotion over time as a function of the implementation of sub-tactics of psychological distancing. In Study 1, we developed novel deep machine learning algorithms to identify the degree to which linguistic patterns reflect two types of psychological distancing, namely objective (OBJ) and spatial/temporal (FAR) distancing. In Study 2, in an expressive writing-based longitudinal emotion regulation training task, participants transcribed their thoughts while viewing negative or neutral stimuli over 5 sessions in one of three ways: by implementing objective language (Objective group), by implementing spatially/temporally distant language (Far group), or by responding naturally. We found that the OBJ and FAR algorithms significantly predicted changes in task-based self-reported negative affect in the Objective group and found no significant associations in the Far group. The relationship between the algorithm scores and self-reported negative affect was stronger in the Objective group compared to the Far group. These findings describe sensitive linguistic distancing algorithms that are capable of tracking changes in self-reported negative affect. These results may be useful in developing novel, unobtrusive emotion regulation assessments and interventions that utilize natural language processing.

Getting better over time: A framework for examining the impact of emotion regulation training.

Effective emotion regulation is indispensable for mental and physical health. Recent decades have seen exponential growth in research into the psychological mechanisms underlying emotion regulation. Much of the foundational research investigating emotion regulation processes has assessed changes in emotion during single laboratory-based sessions. One relatively underexplored topic is the assessment of whether and how the ability to regulate emotion effectively using particular strategies can change over time within an individual (e.g., through training). The goal of this review is to examine existing research into this topic in healthy as well as clinical populations. I will provide a framework for the design of future longitudinal emotion regulation intervention studies that may further address this topic, with factors including the strategy or strategies trained; situation factors including the number, frequency, and delivery modality of intervention sessions as well as the ecological validity of the stimuli experienced at each time point; and person factors including training recipient individual differences, within and across healthy and clinical populations. Thorough, theoretically motivated examination of these factors will be important in the development of novel, evidence-based, and increasingly personalized longitudinal interventions to improve emotion regulation efficacy. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Neural predictors and effects of cognitive behavioral therapy for depression: the role of emotional reactivity and regulation.

BACKGROUND: Cognitive behavioral therapy (CBT) is an effective treatment for many patients suffering from major depressive disorder (MDD), but predictors of treatment outcome are lacking, and little is known about its neural mechanisms. We recently identified longitudinal changes in neural correlates of conscious emotion regulation that scaled with clinical responses to CBT for MDD, using a negative autobiographical memory-based task. METHODS: We now examine the neural correlates of emotional reactivity and emotion regulation during viewing of emotionally salient images as predictors of treatment outcome with CBT for MDD, and the relationship between longitudinal change in functional magnetic resonance imaging (fMRI) responses and clinical outcomes. Thirty-two participants with current MDD underwent baseline MRI scanning followed by 14 sessions of CBT. The fMRI task measured emotional reactivity and emotion regulation on separate trials using standardized images from the International Affective Pictures System. Twenty-one participants completed post-treatment scanning. Last observation carried forward was used to estimate clinical outcome for non-completers. RESULTS: Pre-treatment emotional reactivity Blood Oxygen Level-Dependent (BOLD) signal within hippocampus including CA1 predicted worse treatment outcome. In contrast, better treatment outcome was associated with increased down-regulation of BOLD activity during emotion regulation from time 1 to time 2 in precuneus, occipital cortex, and middle frontal gyrus. CONCLUSIONS: CBT may modulate the neural circuitry of emotion regulation. The neural correlates of emotional reactivity may be more strongly predictive of CBT outcome. The finding that treatment outcome was predicted by BOLD signal in CA1 may suggest overgeneralized memory as a negative prognostic factor in CBT outcome.

Emotion Regulation and Immune Functioning During Grief: Testing the Role of Expressive Suppression and Cognitive Reappraisal in Inflammation Among Recently Bereaved Spouses.

OBJECTIVE: Losing a spouse is a distressing life event that can negatively affect both mental and physical health. Stress-induced health consequences often include increased risk of cardiovascular disease and altered immune system functioning marked by increased inflammation. Here, we sought to identify individual difference factors that covary with problematic inflammatory outcomes. METHOD: We measured recently bereaved spouses' (n = 99) propensity to use emotion regulation strategies and peripheral inflammation, as measured by levels of proinflammatory cytokines after ex vivo stimulation of peripheral leukocytes with T-cell agonists. Specifically, we measured participants' use of cognitive reappraisal, an adaptive emotion regulation strategy in many contexts, and expressive suppression, a less adaptive emotion regulation strategy that involves actively inhibiting emotions after already experiencing them. RESULTS: Bereaved spouses who self-reported frequently using expressive suppression as an emotion regulation strategy tended to have a more pronounced inflammatory response, as indexed by higher levels of a composite cytokine index consisting of interleukin (IL) 17A, IL-2, IL-6, tumor necrosis factor α, and interferon-γ (b = 0.042), as well as tumor necrosis factor α (b = 0.083) and interferon-γ (b = 0.098) when analyzed individually. Notably, these associations were observed in both unadjusted and adjusted models, with the latter including known covariates of inflammation and other potential confounding variables. CONCLUSIONS: These findings suggest that bereaved spouses' use of emotion regulation strategies is associated with altered immune functioning, and such a link may be an important biological pathway by which interventions targeting affect may improve immune system-related health outcomes.

Connecting cognition, cardiology, and chromosomes: Cognitive reappraisal impacts the relationship between heart rate variability and telomere length in CD8+CD28- cells.

Individuals who poorly regulate emotion exhibit premature aging and worse general health. Telomere shortening, a prognostic biomarker of physical health, is related to aging, poor immunocompetence and autonomic nervous system functioning. Cognitive reappraisal is one type of emotion regulation strategy, which involves changing one's appraisal of an aversive situation to modify its emotional impact. Heart rate variability (HRV; i.e., oscillations in heart rate) relates to emotion regulatory processes, such that higher HRV typically reflects greater regulatory capacity. Previous research has identified a positive association between HRV and telomere length. Importantly, the association between HRV and telomere length may change depending on how often an individual uses cognitive reappraisal. One hundred and thirty-seven healthy participants completed measures of cognitive reappraisal frequency, HRV, and underwent blood draws to measure telomere length (computed with the relative ratio of telomere repeat copy number to single copy gene number) in the T cell effector population, CD8+CD28-. Cognitive reappraisal moderated the relationship between telomere length and HRV such that individuals with high cognitive reappraisal frequency had a significant positive association between HRV and telomere length, while individuals with average and less than average frequency did not exhibit this relationship. The results suggest that frequent usage of cognitive reappraisal enhances the already positive influence of HRV on chromosomal integrity in CD8+CD28- T lymphocytes. Although future research is needed to test these effects causally, these findings suggest that regularly using emotion regulation techniques may buffer the relationship between autonomic nervous system functioning and chromosomal integrity in immune cells.

Predicting emotional health indicators from linguistic evidence of psychological distancing.

Psychological distancing, a form of cognitive reappraisal, involves construal of emotionally valenced stimuli in an objective manner, or with perceived spatial and temporal distance. Prior work suggests that in appropriate contexts, reappraisal broadly, and distancing specifically, is related to adaptive mental and physical health outcomes. Additionally, recent research suggests that shifting language to be more distant (i.e., linguistic distancing [LD]) can have adaptive emotion regulatory effects. The present study addressed whether LD is also associated with adaptive health indicators. Participants transcribed their thoughts while viewing negative or neutral stimuli in one of three ways: (a) by implementing objective language, (b) by implementing spatially and/or temporally far away language, or (c) by responding naturally. Across psychological distancing groups, LD was associated with lower negative affectivity (lower perceived stress and depression symptoms), better general well-being (better emotional well-being and energy and vitality), and better emotion regulation (ER; greater reappraisal frequency and fewer difficulties in implementing ER). Participants who used more LD in the objective group had lower negative affectivity, better general well-being, and better ER, and those in the far group had better ER. The results reveal linguistic mechanisms underlying ER and its relationship to health indicators, suggesting future examination of LD interventions.

Implicit reappraisal as an emotional buffer: Reappraisal-related neural activity moderates the relationship between inattention and perceived stress during exposure to negative stimuli.

Emotion regulation often is an adaptive option in the face of elevated perceived stress. Perceived stress has been shown to have negative consequences for physical and mental health, including cognitive deficits and difficulties controlling attention. Cognitive reappraisal is an emotion regulation strategy that involves changing one's cognitive construal of an emotionally evocative stimulus to alter its emotional impact. Reappraisal can be implemented explicitly or implicitly (i.e., with or without conscious awareness). The objective of the present study was to examine whether implicit cognitive reappraisal during exposure to negative stimuli moderates the relationship between inattention and perceived stress. We found, as expected, that inattention problems are associated with increased perceived stress, but also found that one's spontaneous propensity to engage in cognitive reappraisal-as indexed by correspondence with a reliable thresholded whole-brain pattern of reappraisal implementation-moderated the relationship between inattention and perceived stress. Overall, the current study provides evidence that spontaneous reappraisal recruitment has a buffering effect on the relationship between inattention and perceived stress.

Neural mechanisms of emotion regulation and their role in endocrine and immune functioning: A review with implications for treatment of affective disorders.

In the past century, medical progress has helped increase life expectancy and improve health outcomes more generally. Despite this progress, psychiatric disorders-especially affective disorders including depressive and anxiety disorders-are quite common and have been linked to dysfunction in endocrine and immune systems. In this review, we discuss neurobiological correlates of emotion regulation strategies and their effects on mental and physical health. Some of these correlates, namely sub-regions of prefrontal cortex, also play a key regulatory role in autonomic, endocrine, and immunological processes. Given this functional overlap, we propose a novel neuro-immuno-affective framework that targets improving emotion regulation, in order to: (1) reduce negative affect associated with depressive and/or anxiety disorders; and (2) alter endocrine and immune system functioning (e.g., reduce inflammation)-via changes in activity within (and connectivity between) brain systems that support (successful) emotion regulation. We conclude by arguing that such a framework can be adapted for psychiatric treatment protocols that holistically incorporate neural and immunological biomarkers to promote mental and physical health.

Cognitive reappraisal of low-calorie food predicts real-world craving and consumption of high- and low-calorie foods in daily life.

In an increasingly obesogenic environment, an individual's regulatory capacity to pursue nutrient-rich, low-calorie foods over palatable, energy-dense items is essential to maintaining a healthy weight and preventing the detrimental health risks of obesity. Cognitive reappraisal, the process by which one changes the meaning of a stimulus by altering its emotional impact (or in this case, its appetitive value) demonstrates promise as a regulatory strategy to decrease obesogenic food consumption, but little research has directly addressed the relationship between cognitive reappraisal of food cravings and real-world eating behaviors. Additionally, research examining self-regulation of eating has typically focused exclusively on diminishing cravings and consumption of unhealthy, high-calorie foods, rather than examining, in tandem, ways to strengthen (or, up-regulate) cravings for healthier, low-calorie alternatives. In the present study, fifty-seven college aged participants first completed a cognitive reappraisal task in the laboratory in which they practiced regulating their craving responses to high- and low-calorie food items by focusing on the long-term health consequences of repeatedly consuming the pictured foods. Next, for a week following the laboratory session, participants reported daily eating behaviors via ecological momentary assessment. Participants who reported greater up-regulatory success during the reappraisal task also reported increased craving strength for low-calorie foods as well as decreased consumption of high-calorie foods in their daily lives. Greater overall regulation success also predicted more frequent consumption of craved low-calorie foods. These findings substantiate the association between cognitive reappraisal ability and real-world appetitive behaviors, and suggest that future interventions may benefit from specifically targeting individuals' evaluations of low-calorie foods.

Sensitization of the Neural Salience Network to Repeated Emotional Stimuli Following Initial Habituation in Patients With Borderline Personality Disorder.

OBJECTIVE: Borderline personality disorder is the prototypical disorder of emotion reactivity and dysregulation, yet there remains limited understanding of its neurocognitive correlates. Two mechanisms that may underlie anomalous reactivity in response to negative stimuli among patients with borderline personality disorder are impairment in habituation and exaggerated sensitization of activity in the neural salience network, including the amygdala, anterior insula, and dorsal anterior cingulate cortex. The authors aimed to reveal the most plausible mechanism by examining the effect of repeated exposure to emotional images both within and across study sessions. METHOD: A total of 75 participants (patients with borderline personality disorder, N=26; patients with avoidant personality disorder included as a psychopathological control group, N=25; and healthy control subjects, N=24) were included in the study analyses. All participants viewed five presentations of the same set of negative and neutral images at each of two sessions, separated by approximately 3 days, while functional MRI data were acquired. Salience network activity, as measured by blood-oxygen-level-dependent signal in anatomically defined regions of interest across the salience network, was compared across the three groups for each presentation at each of the two study sessions. Self-reported negative affect was measured for each trial. RESULTS: Salience network activity showed a main effect of within-session habituation across all groups and sessions. However, a group-by-session interaction was present, such that only patients with borderline personality disorder showed increased salience network activity in response to the images reencountered at the second session, and this increased salience network sensitization predicted greater sensitization in self-reported negative affect. CONCLUSIONS: These results elucidate the neural mechanisms by which patients with borderline personality disorder appraise negative social situations as exaggeratedly salient and suggest potential neurocognitive intervention targets.