Neuroscience and Biobehavioral Reviews 143 (2022) 104920

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Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Childhood adversity and vagal regulation: A systematic review and

meta-analysis
Christiane Wesarg a, b, *, Alithe L. Van den Akker a, c, Nicole Y.L. Oei a, b, d, Reinout W. Wiers a, b, d, e,
Janneke Staaks f, Julian F. Thayer g, DeWayne P. Williams g, Machteld Hoeve a, c
a
Research Priority Area (RPA) Yield, University of Amsterdam, Amsterdam, the Netherlands
b
Developmental psychology (Addiction Development and Psychopathology ADAPT-lab), University of Amsterdam, Amsterdam, the Netherlands
c
Research Institute of Child Development and Education, University of Amsterdam, Amsterdam, the Netherlands
d
Amsterdam Brain and Cognition (ABC), University of Amsterdam, Amsterdam, the Netherlands
e
Centre for Urban Mental Health, University of Amsterdam, Amsterdam, the Netherlands
f
University library, University of Amsterdam, Amsterdam, the Netherlands
g
Department of Psychological Science, University of California, Irvine, Irvine, CA, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Childhood adversity (CA) is associated with increased risk for physical and mental health problems, with al­
Childhood adversity terations in vagal regulation (an aspect of autonomic functioning indexed by vagally-mediated heart rate vari­
Early adversity ability [vmHRV]) implicated as a mechanism. Three-level meta-analyses were conducted to synthesize research
Maltreatment
on the relationship between CA and 1) baseline vagal activity, and 2) vagal reactivity to challenges including
Heart rate variability
Vagal activity
stress tests, emotion-eliciting tasks and cognitive tasks. No significant overall association was found between CA
Vagal reactivity and vagal activity (r = − .015; p = .11) or vagal reactivity (r = − .017; p = .13). However, analyses controlling for
moderator interrelatedness revealed an association between CA and lower baseline vagal activity in samples
including participants diagnosed with a psychiatric disorder, and for direct adversities such as maltreatment. For
vagal reactivity, CA was associated with lower reactivity if the adversity was experienced less recently, and for
studies operationalizing reactivity using task mean levels of vmHRV. These findings indicate that small alter­
ations in vagal functioning occur for specific CA subtypes and subgroups of individuals.

1. Introduction between childhood adversity and 1) baseline vagal activity and 2)

task-induced vagal reactivity to challenge. As not all individuals who
Childhood adversity, including exposure to abuse, neglect, poverty, have experienced adversity develop negative health outcomes, we also
and neighborhood violence, is among the most robust risk factors for the investigated the role of potential moderators in this association. In
development of chronic health problems and psychopathology (Carr addressing these questions, the present work aims to advance the un­
et al., 2013; Hughes et al., 2017; McLaughlin, 2016; Nemeroff, 2016; Oh derstanding of how and under which circumstances childhood adversity
et al., 2018). Extensive evidence suggests that exposure to childhood leads to psychopathology. This knowledge may further inform preven­
adversity is associated with alterations in the functioning of the auto­ tion and treatment approaches. After describing conceptual frameworks
nomic nervous system (ANS; Leitzke et al., 2015; Oosterman et al., 2010; for the study of vagal regulation in the context of childhood adversity
Propper and Holochwost, 2013; Voellmin et al., 2015), which may and the available evidence, we discuss how adversity and study char­
represent a key mechanism implicated in the pathway through which acteristics could moderate this association.
adversity increases risk for pathology (Koss and Gunnar, 2018;
Young-Southward et al., 2020). The present study sought to determine
1.1. Vagal regulation
whether childhood adversity relates to vagal regulation, a specific aspect
of ANS functioning indexed by vagally-mediated heart rate variability
Besides regulating several involuntary physiological processes
(vmHRV). Two meta-analyses were performed, testing associations
including digestion, respiration, body temperature, and sexual arousal,

* Correspondence to: University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, the Netherlands.
E-mail addresses: christiane.wesarg94@gmail.com, c.wesarg@uva.nl (C. Wesarg).

https://doi.org/10.1016/j.neubiorev.2022.104920
Received 2 August 2022; Received in revised form 5 October 2022; Accepted 17 October 2022
Available online 19 October 2022
0149-7634/© 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
C. Wesarg et al. Neuroscience and Biobehavioral Reviews 143 (2022) 104920

the ANS is critically involved in cardiovascular functioning (Wax­ alterations in baseline vagal activity and vagal reactivity to challenge,
enbaum et al., 2019). Polyvagal Theory (Porges, 2003, 2007) describes findings are mixed, revealing lower or higher (re-)activity or no signif­
how a specific aspect of ANS functioning—vagal regulation—promotes icant association with childhood adversity (Busso et al., 2017; Dale
adaptive functioning in the context of changing environmental de­ et al., 2018; De Witte et al., 2016; Giuliano et al., 2018a; Hagan et al.,
mands. Vagal regulation refers to parasympathetic influences on the 2020). Until now, only two meta-analyses (Lavi et al., 2019; Sigrist et al.,
heart via the tenth cranial nerve, the vagus nerve (Porges, 1995). At rest, 2021) have computed an overall effect between vagal functioning and
the parasympathetic nervous system (PNS) exerts constant inhibitory childhood adversity, with both focusing on maltreatment. Based on 32
control over the heart, reducing heart rate (Porges, 1995, 2007). This studies, Sigrist and colleagues (2021) concluded that child maltreatment
inhibition varies cyclically at a frequency corresponding to respiration, was not associated with resting vagal activity per se, but that the rela­
resulting in a pattern of heart rate decreases (during inhalation) and tionship significantly varied as a function of both participants’ age and
increases (during exhalation) which is known as respiratory sinus the presence of psychopathology. Within the framework of a larger
arrhythmia (RSA; Berntson et al., 1997). Under challenging conditions, meta-analysis, Lavi and colleagues (2019) found no association between
vagal withdrawal enables increases in heart rate and arousal. In maltreatment and children’s vagal emotion reactivity based on five
contrast, vagal augmentation (i.e., PNS activation) generally leads to a studies.
reduction in heart rate and arousal (Porges, 1995, 2007). Measures of Given considerable heterogeneity in how childhood adversity has
resting vagal activity thus reflect an organism’s ability to maintain ho­ been defined and operationalized, and differences in study populations,
meostasis and a general level of responsiveness during steady states, inconsistent results on the association between childhood adversity and
whereas measures of vagal reactivity represent the organism’s ability to vagal regulation are not surprising. Further, childhood adversity has
flexibly engage with and disengage from the environment to meet been shown to have little predictive specificity across psychiatric dis­
changing situational demands (Appelhans and Luecken, 2006; Hamilton orders (Kessler et al., 2010), highlighting the need to study moderators
and Alloy, 2016). Generally speaking, higher levels of resting vagal that influence pathways from adversity to health outcomes. In the
activity and a moderate vagal withdrawal to challenge have been seen as following paragraphs, we discuss the role of adversity characteristics,
reflecting adaptive and effective regulatory processes (Gentzler et al., individual characteristics, and methodological aspects in moderating
2009; Ottaviani et al., 2019). the association between childhood adversity and vagal regulation.

1.2. Theoretical framework and evidence on the association between 1.3. Childhood adversity characteristics as potential moderators
childhood adversity and vagal regulation
1.3.1. Dimension of adversity
Childhood adversity has been defined as “experiences that are likely As childhood adversity is a rather broad construct, the nature of
to require significant adaptation by an average child and that represent a adversity may moderate the magnitude or direction of the association
deviation from the expectable environment” (McLaughlin, 2016, p. between childhood adversity and vagal regulation. As proposed in the
363). Theories have been brought forward suggesting that prolonged dimensional model of adversity (Sheridan and McLaughlin, 2014),
exposure to adversity during sensitive developmental periods can deprivation and threat may portray two orthogonal dimensions of early
modify the maturation of brain regions involved in stress regulation adverse experiences with distinct effects on the brain and biological
(Danese and McEwen, 2012; Gabard-Durnam and McLaughlin, 2019; systems. Deprivation reflects a lack of environmental inputs and a fail­
Heim et al., 2019; Koenig, 2020; Lupien et al., 2009). In individuals ure to meet a child’s needs (Hildyard and Wolfe, 2002), as is the case
exposed to childhood adversity, structural and functional alterations when children are emotionally and/or physically neglected by parents
pertaining but not limited to the orbitofrontal cortex, ventromedial or raised in low-quality institutions. In contrast, threat encompasses
prefrontal cortex and the amygdala have repeatedly been identified exposures to interpersonal violence that involve harm to the child, such
(Kraaijenvanger et al., 2020; McCrory et al., 2010; Monninger et al., as physical and sexual abuse (Sheridan and McLaughlin, 2014). Differ­
2020; Saarinen et al., 2021; Teicher et al., 2016). These structures are ential associations for threat and deprivation have been shown for
involved in the central autonomic network (CAN; Benarroch, 1993) that multiple outcomes, including functional threat reactivity (Hein et al.,
further comprises the anterior cingulate, the anterior and posterior 2020; Puetz et al., 2020; Young et al., 2022), brain structure (Baniha­
insula, and the hypothalamus (among others; Thayer and Lane, 2000). shemi et al., 2021; Colich et al., 2020), fear learning (Machlin et al.,
As described in the Neurovisceral Integration Model (NVIM; R. Smith 2019), emotion regulation (Lambert et al., 2017; Milojevich et al.,
et al., 2017; Thayer et al., 2009; Thayer and Lane, 2000), the CAN in­ 2019), cognitive ability (Lambert et al., 2017; Machlin et al., 2019;
tegrates autonomic, neuroendocrine, and behavioral responses with Usacheva et al., 2022), as well as physical and mental health (A. B.
emotion, attention, and cognition to support self-regulation and Miller et al., 2017; Usacheva et al., 2022). As confirmed by studies on
goal-directed behavior. The primary output of the CAN is mediated cortisol stress reactivity (Busso et al., 2017; Peckins et al., 2020), it is
through sympathetic and parasympathetic neurons innervating the predicted in the dimensional model of adversity (Sheridan and
heart via the stellate ganglia and the vagus nerve, respectively (Thayer McLaughlin, 2014) that early exposure to threat should result in dis­
and Lane, 2000). The interplay of their inputs to the sinoatrial node rupted physiological reactivity to novel stressors as it influences
(known as the “pacemaker” of the heart) gives rise to heart rate vari­ cortico-limbic circuits involved in fear learning and salience processing.
ability (HRV; Saul, 1990). Therefore, vmHRV is seen as an indicator of In contrast, exposure to deprivation is thought unlikely to result in
central-peripheral neural feedback as well as central and autonomic disrupted physiological reactivity when the co-occurrence of threat
nervous system integration (Thayer and Lane, 2000). exposure is taken into account (Busso et al., 2017).
As childhood adversity has been linked to alterations in structure and
functioning of brain regions involved in vagal regulation (Teicher and 1.3.2. Proximity of adversity
Samson, 2016), it is likely that individuals with a history of adversity The strength of the relation between childhood adversity and vagal
demonstrate alterations in vmHRV as a downstream marker of alter­ regulation may also be influenced by the proximity of adversity. Ad­
ations in central functioning. In line with Polyvagal theory (Porges, versities can exert an effect on an individual either directly (e.g., abuse
2003, 2007) and the NVIM (Thayer and Lane, 2000), atypical vagal or neglect) or indirectly through the living environment (e.g., poverty,
regulation observed in the context of childhood adversity would reflect neighborhood violence, or witnessing inter-parental aggression; Hughes
difficulties in self-regulation during social, emotional and cognitive et al., 2017). In contrast to the effects of direct adversities, the impact of
challenges that impair adaptive functioning. While a number of studies an adverse environment can be buffered by parents, for example through
show that experiences of childhood adversity are associated with sensitive and responsive caregiving (Chen et al., 2011; Depasquale and

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Gunnar, 2020; G. E. Miller et al., 2011). It is therefore possible that function of sex (Nugent et al., 2011), studies have shown that sex dif­
direct adversities exert more pronounced effects on stress physiology as ferences exist in resting vagal activity (Koenig et al., 2017; Koenig and
compared to indirect adversities. Thayer, 2016) and vagal reactivity to challenge (Emery et al., 2018;
Hamidovic et al., 2020; Li et al., 2009; Ordaz and Luna, 2012; T. W.
1.3.3. Severity of adversity Smith et al., 2009). Sex has further been observed to moderate associ­
Another potential moderator is the severity of childhood adversity, ations between specific indexes of resting HRV and correlates of
which is a significant predictor of negative health outcomes (Evans adversity including difficulties in emotion regulation (D. P. Williams,
et al., 2013; Hambrick et al., 2019; Lee et al., 2018; Muzik et al., 2017). Tracy et al., 2019), depressive symptoms (Dietrich et al., 2011) and
Importantly, childhood adversities associated with maladaptive family inflammation (D. P. Williams, Koenig et al., 2019). According to the
functioning including family violence, physical abuse and neglect are Adaptive Calibration Model (Del Giudice et al., 2011), sex could influ­
associated with higher risk and persistence of psychopathology as ence the way physiological systems adapt to conditions of severe envi­
compared to other adversities including parental death and family ronmental stress: While females may more likely develop a vigilant
economic adversity (Kessler et al., 2010; McLaughlin et al., 2010). With pattern of responsivity characterized by low parasympathetic basal ac­
regards to stress reactivity, extreme forms of adversity such as tivity, low to moderate parasympathetic responsivity, and high sympa­
maltreatment have been more strongly associated with alterations in thetic basal activity and responsivity, males may more likely develop an
endocrine stress responses as compared to ‘milder’ forms including unemotional pattern characterized by low sympathetic and para­
parental conflict or witnessing violence (Bunea et al., 2017). It is sympathetic basal activity and responsivity (Del Giudice et al., 2011).
therefore possible that alterations in vagal regulation only emerge when These predictions have so far received partial support in empirical
adversity exceeds a certain threshold of severity. studies (Del Giudice et al., 2012; Ellis et al., 2017).

1.3.4. Timing of exposure to adversity 1.4.2. Psychopathology

Given sensitive periods during which brain regions undergoing Previous research has established that individuals exposed to child­
maturation are particularly vulnerable to stressors (Boyce et al., 2021; hood adversity are at increased risk of developing psychopathology,
Gabard-Durnam and McLaughlin, 2019; Gee, 2020; Lupien et al., 2009), particularly after being exposed to additional adversity in adulthood
the timing of exposure may be important to examine. Potential sensitive (‘stress sensitization’; Bandoli et al., 2017; Hammen et al., 2000; Lin
periods have been identified for brain regions involved in vagal regu­ et al., 2022; Luo et al., 2021). An important difference between studies
lation, including the amygdala and prefrontal cortex (Koenig, 2020; investigating the effects of childhood adversity is whether they involve
Teicher and Samson, 2016). Although there are no consistent cut-offs for participants with or without psychopathology (note that participants in
these sensitive periods across studies, broadly speaking, the amygdala “non-clinical samples” may also experience mental health problems not
appears particularly sensitive to adversity during early childhood, assessed in a study). Reduced levels of resting HRV are considered a core
whereas the prefrontal cortex is likely rather sensitive during adoles­ characteristic of mood and anxiety disorders (Brown et al., 2018;
cence (Andersen and Teicher, 2008; Gard et al., 2020; Humphreys et al., Chalmers et al., 2014; Koch et al., 2019; Koenig, Kemp, Beauchaine
2019; Pechtel et al., 2014). et al., 2016), and have further been observed in individuals diagnosed
The Bucharest Early Intervention Project has provided evidence on a with schizophrenia (Clamor et al., 2016) or borderline personality dis­
potential sensitive period of socio-emotional development during the order (Koenig, Kemp, Feeling et al., 2016). As shown in a recent
first two years of life: Youth from orphanages with very poor quality care meta-analysis on the association between resting vagal activity and
improved more in cognitive and emotion regulatory functions if placed maltreatment (Sigrist et al., 2021), it is possible that alterations in vagal
into foster care before they were two years old, as compared to those regulation are more strongly associated with childhood adversity in
who were placed later (McLaughlin et al., 2015b). Some studies on clinical samples, as individuals who develop psychopathology may be
mental health outcomes also implicate early childhood as a sensitive the ones who experience more difficulties in coping with the stressful
period (Dunn et al., 2020), whereas others point more to middle child­ circumstances.
hood or adolescence (Gerke et al., 2018; Schalinski et al., 2016; Yoon,
2020). Overall, childhood adversity likely impacts multiple develop­
mental periods, rendering it unlikely that there is only one narrow 1.5. Methodological characteristics as potential moderators
window during which adversity affects psychobiological processes
(Nelson and Gabard-Durnam, 2020). 1.5.1. Measurement of childhood adversity
Another line of research highlights the importance of the recency of The measurement of childhood adversity may also yield differences
exposure, indicating that more recent adversity exerts stronger effects in observed effects of childhood adversity on vagal regulation. Child­
on neurodevelopment (Greenough et al., 1987; Shanahan et al., 2011). hood adversity can be quantified by self-, parent-, or teacher-report (e.g.,
Supporting evidence stems from a study of Dunn and colleagues (2018) through questionnaires or interviews), or by extracting information
who demonstrated that child psychopathology symptoms were primar­ from official records (e.g., from Child Protective Services). Importantly,
ily explained by recency effects, whereas evidence for sensitive periods these methods may vary in how accurately they capture an individual’s
was not strong. In contrast, another study of the same group found that experience and appraisal of adversity (Monroe, 2008). To illustrate, in a
the timing of adversity explained more variability in DNA methylation comparison study on adolescents who had been confirmed as victims of
than the recency of exposure, rather supporting the sensitive period maltreatment prior to age 13, Pinto and Maia (2013) found low agree­
model (Dunn et al., 2019). Integrating these findings, it is likely that ment (Kappa <.40) between official records and self-reports for most
both the timing of exposure to adversity and the recency influence as­ subtypes of childhood adversity. Only 17% of self-reports were consis­
sociations between adversity and developmental outcomes. tent with official records. Emotional abuse and emotional neglect had
the highest probabilities of being undocumented in official records,
whereas physical neglect, physical abuse and domestic violence were
1.4. Individual characteristics as potential moderators more likely under-reported in self-reports, possibly because individuals
have had experienced these as discipline or normal (Pinto and Maia,
1.4.1. Sex 2013). It is possible that risk pathways to mental illness differ depending
In line with findings that neural control of the heart may differ as a on the method to assess adversity. For instance, a recent study

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demonstrated that chronic inflammation—a correlate of vmHRV (D. P. activity (Sigrist et al., 2021) or vagal emotion reactivity (Lavi et al.,
Williams, Koenig et al., 2019)—was only predicted by maltreatment if 2019) were included. Accordingly, the objective of the present
assessed via official records but not via self-report (Osborn and Widom, meta-analysis was to quantify overall effect sizes for the association
2020). An explanation could be that the maltreatment experiences that between childhood adversity and vagal regulation by adopting a broad
come to the attention of the authorities may be more severe compared to conceptualization of childhood adversity (see Sheridan and McLaughlin,
those that were retrospectively reported (Groeneveld and Giovannoni, 2014), and by including both baseline vagal activity and task-induced
1977). vagal reactivity to different challenges (such as emotion-eliciting
tasks, cognitive challenges, and stress tests). Given considerable het­
1.5.2. Index of vagally-mediated heart rate variability erogeneity in study designs and outcomes, we further investigated the
Individual differences in vagal regulation are commonly assessed by role of potential moderators in these associations belonging to three
time- or frequency-domain measures of vmHRV (Appelhans and broad categories: 1) childhood adversity characteristics, 2) individual
Luecken, 2006; Shaffer and Ginsberg, 2017). Time-domain indices (also characteristics, and 3) methodological characteristics.
referred to as statistically-derived indices) quantify the amount of The following hypotheses and exploratory research questions were
variability in interbeat intervals (IBIs) and yield numerical estimates of tested: In line with findings showing structural and functional alter­
HRV in temporal units (e.g., milliseconds). The root mean of the square ations of brain regions related to vagal regulation (Teicher and Samson,
successive differences (RMSSD) is considered a primary index of vmHRV 2016), and studies revealing self-regulatory difficulties in individuals
(T. W. Smith et al., 2020; Thayer et al., 2010; Williams, Koenig et al., exposed to adversity (Gruhn and Compas, 2020; Kim et al., 2021), we
2019). Also RSA measured with the peak-valley method (Grossman expected that higher levels of childhood adversity would be associated
et al., 1990) or Porges moving polynomial algorithm (Porges, 1986) are with lower baseline vagal activity and vagal reactivity (i.e., less vagal
indexes of vagal activity (Grossman and Taylor, 2007). Within withdrawal in response to challenge). Based on the Adaptive Calibration
frequency-domain measures, power spectral analysis is employed to Model (Del Giudice et al., 2011), we hypothesized sex differences to
partition the variance of the IBIs into a spectrum of frequencies. The emerge in the association between adversity and vagal reactivity while
amount of variance within a given frequency range represents the no differences were expected for the association with baseline vagal
amount of signal energy or “power” (Appelhans and Luecken, 2006). activity. More specifically, the assumed effect of lower vagal reactivity
The high-frequency component of HRV (HF-HRV), occurring at a res­ in association with childhood adversity was thought to be more pro­
piratory frequency of .15–.40 Hz in adults, reflects vagal activity nounced in males as compared to females. With regards to psychopa­
(Appelhans and Luecken, 2006; Shaffer and Ginsberg, 2017). Estimates thology, we hypothesized that effect sizes would be larger in studies
of vmHRV derived from time-domain and frequency-domain analyses including individuals with psychiatric diagnoses as compared to
are highly correlated with one another (Goedhart et al., 2007; Lewis non-clinical samples (see Sigrist et al., 2021). Following predictions of
et al., 2012) and are similarly associated with top-down self-regulation the dimensional model of adversity (Sheridan and McLaughlin, 2014),
(Holzman and Bridgett, 2017). we expected effect sizes to be larger on associations between vagal
regulation with threat-related adversities as compared to
1.5.3. Type of challenge task deprivation-related adversities. Further, we assumed that direct adver­
Although it has been proposed that vagal withdrawal indicates sities would be more strongly associated with vagal regulation as
regulation across different contextual demands (Thayer and Lane, compared to indirect adversities. Given evidence on larger associations
2000), the association between childhood adversity and vagal reactivity between more severe types of adversity and health outcomes (Hambrick
may depend on the nature of the challenging task. Different tasks have et al., 2019), we expected effect sizes to be larger on associations be­
been used to study vagal reactivity in the context of childhood adversity, tween vagal regulation with maltreatment as compared to other types of
varying in their extent to which they induce emotional arousal. While adversity. As existing studies provide inconsistent results with regards to
some studies have employed cognitive tasks (e.g., Stroop task, mental the influence of sensitive periods and the recency of adversity on psy­
arithmetic task) representing rather affectively neutral (“cool”) con­ chobiological and mental health outcomes (Dunn et al., 2018, 2019), we
texts, other studies have used negative emotion-eliciting tasks (e.g., a tested for these moderators in an exploratory way. Regarding the
film clip showing acts of violence) or stress tests (e.g., public speaking) assessment type of childhood adversity, we expected studies based on
that represent emotionally-loaded (“hot”) contexts (see Zelazo and official records to reveal larger effects as compared to studies based on
Carlson, 2012). As childhood adversity is associated with poor emotion questionnaires (Osborn and Widom, 2020). Further, we expected effect
regulation (Gruhn and Compas, 2020; Raver et al., 2015), it is possible sizes to be larger on associations between vagal reactivity and childhood
that alterations in vagal reactivity are more pronounced during tasks adversity when assessed in stress tests and emotion-eliciting tasks as
that require emotional regulatory processes as compared to relatively compared to cognitive tasks. Last, we tested for a potential moderating
neutral cognitive tasks. Support for this hypothesis stems from a recent role of the index of vmHRV (time- versus frequency-domain), the mea­
study testing 8- to 16-year-olds in which the severity of child abuse was surement of respiration, and the control of artifacts in an exploratory
associated with poor adaptation on an emotional Stroop task indicating way.
difficulties with automatic emotion regulation, but was unrelated to
cognitive control assessed in a similar task without emotional stimuli 2. Methods
(Kim et al., 2021).
2.1. Identification and selection of studies
1.6. Purpose and hypotheses of the present meta-analysis
Articles were identified by searching the electronic databases Psy­
To date, qualitative and quantitative reviews show little agreement cINFO, Web of Science, and Medline on the 15th of September 2020.
on whether alterations in vagal regulation are present in individuals Keywords related to childhood adversity were combined with those
exposed to childhood adversity (Lavi et al., 2019; Propper and Hol­ related to vmHRV. No limits with regards to language, publication year
ochwost, 2013; Sigrist et al., 2021; Young-Southward et al., 2021). or publication type were applied during the search phase. The protocol
Importantly, meta-analytic evidence on the association between child­ for the systematic search can be found in the Supplemental Material
hood adversity and vagal regulation has been limited to maltreatment, provided online. The search results were screened for duplicates with
excluding other adversity types such as poverty or neighborhood Zotero (for tutorial, see Staaks, 2020). We further examined the refer­
violence which have also been linked to ANS alterations (Hill-Soderlund ence lists of reviews and meta-analyses on related topics (e.g., Bunea
et al., 2015; Mellman et al., 2018). Further, only studies on resting vagal et al., 2017; Fogelman and Canli, 2018; Lavi et al., 2019;

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Young-Southward et al., 2020) to identify additional studies for than 30 participants in correlational studies. The latter decision was
inclusion. taken in order to ensure sufficient power of the meta-analysis (for a
Based on a random selection of 10% of the reports identified in the discussion on power for meta-analysis, see Hedges & Pigott, 2001;
systematic search, a master student was trained to screen the articles Valentine et al., 2010). An overview of adversity constructs that were in-
based on title and abstract to determine eligibility for full-text screening and excluded in the present meta-analysis is provided in Table 1. If a
by using the systematic review web application Rayyan (Ouzzani et al., study met the inclusion criteria but did not report the data necessary to
2016). After this reliability training, all remaining reports were assessed compute an effect size, the corresponding author was contacted. If no
by two raters (first author and master student) independently, and in­ data were provided upon request, the study was excluded.
consistencies were discussed by involving a senior author. The agree­
ment between raters was substantial (kappa = 0.74; 93.06% of 2.2. Data extraction and coding
agreement). In a subsequent stage, this procedure was repeated for the
full-text screening. In this screening stage, the agreement between raters A coding system was developed in SPSS by the first author in
was almost perfect (kappa = 0.80; 93.57% of agreement). consultation with the co-authors based on guidelines of Lipsey and
Studies were included if they: (1) investigated childhood adversity Wilson (2001) prior to conducting the systematic search. Coding cate­
(occurring prior to age 18); (2) assessed an index of vmHRV (RSA, gories were adapted in an iterative process during the coding of studies
RMSSD, or HF-HRV) during rest and/or in response to a challenge (i.e., when necessary. The first author extracted the data from each study and
cognitive, social-evaluative performance, or emotion-eliciting tasks, see computed the effect sizes. To assess inter-rater reliability, 20 studies
Hamilton and Alloy, 2016; Kajantie and Phillips, 2006); and (3) were were randomly selected and scored by the second author. Inter-rater
reported in English, German, or Dutch. Both published and unpublished reliability was determined by calculating the percentage of agreement
manuscripts (e.g., dissertations or conference abstracts) were included, for all study characteristics, Cohen’s Kappa for categorical variables and
with no restriction applying to the year of release or the age of partici­ intraclass correlation for continuous variables. The inter-rater agree­
pants. Based on McLaughlin’s conceptualization (2016), negative ex­ ment for categorical variables proved to be moderate to almost perfect,
periences that deviate from the expectable environment, either through with Kappa’s ranging from 0.77 (95% agreement) for artifact control to
presence of unexpected inputs or absence of expected inputs, qualified 1.00 (100% agreement) for type of report (journal article or disserta­
as forms of childhood adversity. Besides chronic adversities (e.g., tion), publication status and country of data collection. The inter-rater
neighborhood violence, prolonged neglect, or witnessing inter-parental reliability for continuous variables was excellent, with intraclass cor­
aggression), also single events were considered if they were expected to relations ranging from 0.94 (95% agreement) for the effect size value to
be severe enough to exert a lasting impact on developmental processes 1.00 (100% agreement) for duration of HRV measurement at baseline.
for most children who experience them (e.g., death of a parent).
Exclusion criteria were related to: (1) the absence of control participants 2.2.1. Study characteristics
without major childhood adversity experiences; (2) a focus on adverse We coded the type of report (journal article or dissertation), publi­
events that represent transient or minor hassles such as moving to a new cation status (published or unpublished), year of publication, country of
school (see McLaughlin, 2016); (3) the exposure to prenatal stress (e.g., data collection (categorized additionally into North-American countries
maternal substance use during pregnancy) only; and (4) the inclusion of vs. other countries), study design (correlational or group comparison
less than 20 participants per group in group comparison studies, or less study), and type of statistic to compute an effect size.

2.2.2. Sample characteristics

Table 1
Overview of Childhood Adversity Constructs Included and Excluded in this
For each study, the sample size and the mean sample age, reflecting
Meta-analysis. the age of participants at physiological assessments, were coded. For
studies on school-aged children that only reported children’s grade, we
‘Major’ adversities → included ‘Minor’ adversities → excluded
estimated the sample’s mean age. We also coded the sample’s sex as the
Maltreatment (physical abuse, sexual ‘Normative’ variations in parenting (e. percentage of females, and the sample’s ethnicity as the percentage of
abuse, emotional abuse, physical g., parental sensitivity)
minorities. As the association between childhood adversity and vagal
neglect, emotional neglect)
Adverse parenting (use of corporal regulation may differ between individuals with or without psychopa­
punishment, harsh parenting, hostile- thology, we further coded whether the sample included participants
withdrawn parenting, coercion) with a clinical diagnosis or not. Other sample characteristics coded were
Inter-parental aggression (including Inter-parental conflict (in terms of information on physical health (e.g., cardio-vascular diseases, medica­
verbal or physical aggression) disagreements, without verbal or
physical aggression), marital
tion intake, smoking), education and income of participants or their
dissatisfaction, separation / divorce of families.
parents
Parental psychopathology (e.g., major Parental emotional problem that does 2.2.3. Characteristics of childhood adversity
depression, anxiety disorder, not reach clinical significance, parental
Subtypes of adversity were categorized into direct adversity (e.g.,
schizophrenia) physical disease or illnesses in the
family child abuse), indirect adversity (e.g., poverty), or mixed (i.e., exposure
Death of a parent (bereavement) Changes in family composition to direct and indirect forms of adversity; see Hughes et al., 2017),
Parent incarceration reflecting the proximity of adversity. Based on the dimensional model of
Poverty (i.e., income-to-needs ratio Changes in family finances, socio- adversity of Sheridan and McLaughlin (2014), we further categorized
< 1, family income below federal economic status indicated by parental
poverty line) education or occupation, loss of job by
different forms of adversity into deprivation (e.g., child neglect), threat
parent (e.g., harsh parenting), or mixed (i.e., exposure to both deprivation and
Household chaos / dysfunction Family routines (e.g., having a meal threat). A categorization schema allocating the different adversity types
together every day) to subcategories of proximity and dimension of adversity is integrated in
Relational / peer victimization Quarrels with friends
the script for the statistical analyses available online. Following the
Witnessing a traumatic event according to Changing school
DSM-V definition Moving to a new home approach of Bunea et al. (2017), we coded the severity of adversity as
Breaking up with boy- / girlfriend maltreatment (as a proxy for extreme severity) versus other forms of
Neighborhood / community violence adversity. Further, we coded the recency of exposure to adversity in
Institutionalization years which was calculated by subtracting the age at exposure to
Homelessness (street children)
adversity from the age at vmHRV measurement. Finally, the assessment

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C. Wesarg et al. Neuroscience and Biobehavioral Reviews 143 (2022) 104920

of adversity was categorized into questionnaires (including clinical in­ violated (see Cooper, 2010; Lipsey & Wilson, 2001). In order to deal
terviews), official records (e.g., Child Protective Services’ records or with effect size dependency, a multi-level approach was applied to the
neighborhood violence statistic), and other (e.g., experimenter exami­ current meta-analysis (Assink & Wibbelink, 2016; Cheung, 2015;
nation such as through a checklist on household disorganization, or a Cooper, 2010; Van den Noortgate et al., 2013, 2014). Effect sizes were
naturalistic setting such as homelessness). The assessment of adversity pooled in a three-level random effects model, in which three levels of
was coded as mixed if a composite of these methods of childhood variance were modeled: variation in effect sizes due to random sampling
adversity was used. As only one study employed such a composite, the of effect sizes (Level 1), variation in effect sizes due to differences within
category ‘mixed’ was integrated into the category ‘other’. a single study (Level 2), and variation in effect sizes between different
studies (Level 3; Assink & Wibbelink, 2016). The overall strength of
2.2.4. Measurement of vagal regulation association between childhood adversity and both indicators of vagal
We coded the index of vmHRV (RMSSD, RSA, or HF-HRV), the cor­ regulation was assessed by building separate three-level meta-analytic
responding domain of analysis (time- or frequency-domain analysis), as models without predictors (i.e., intercept-only models). In these models,
well as the duration and condition of baseline measurement. The base­ the estimated intercept values represented the effect of childhood
line condition was further categorized into ‘no task’ (including resting adversity on baseline vagal activity and vagal reactivity.
and relaxing), ‘rather passive task’ (including viewing neutral film clips In order to determine whether heterogeneity in effect sizes was
or pictures, and listening to relaxing sounds or a neutral story), and present within each meta-analysis, the significance of the variance at
‘active task’ (including describing neutral pictures, reading aloud, paced Levels 2 and 3 was assessed through two separate one-tailed log-likeli­
breathing; for categorization schema, see analysis script in the Supple­ hood-ratio tests. In these tests, the deviance of the full model was
mental Material). compared to the deviance of the model excluding one of the variance
It was further assessed whether respiration was measured, and parameters (Assink & Wibbelink, 2016). In case that significant variance
whether artifacts in the electrocardiogram signal were corrected. As was detected at Level 2 and/or 3, moderator analyses were conducted to
only three studies in the meta-analysis on vagal reactivity did not report test whether differences between effect sizes may be explained by
on artifact correction, this variable was not examined in the moderator various study characteristics. Categorical moderator analyses were
analysis. For studies assessing vagal reactivity, we additionally coded restricted to cases where each category included at least five studies.
the nature of the challenging task, categorized into cognitive task Dummy variables were created for each discrete variable, and each
(without social evaluation), stress test, or negative emotion-eliciting continuous variable was centered around its mean. Each potential
task (for categorization schema, see analysis script in the Supple­ moderator was then examined in a separate three-level meta-analytic
mental Material), the duration of this task, and the computation of model in which the moderator was added as a covariate. Given that the
reactivity scores (e.g., residualized change scores, difference scores REstricted Maximum Likelihood (REML) method was used for esti­
subtracting the reactivity from the baseline condition, or task mean mating parameters of the meta-analytic model, omnibus tests were
levels). conducted to determine whether a variable had a significant moderating
effect (Assink & Wibbelink, 2016).
2.3. Effect size computation All analyses were conducted in R (version 3.6.1; R Core Team, 2019)
using the metafor package (Viechtbauer, 2010). The syntax was based on
The Pearson product-moment correlation coefficient r was calculated the tutorial of Assink and Wibbelink (2016) written for three-level
as the common effect size for each reported association on childhood random effects meta-analyses. A significance level of p < 0.05 was
adversity and vagal regulation. Reported associations that were used in all analyses. A summary forest plot was created following the
expressed in other forms than correlations were transformed using the guidelines of Fernández-Castilla et al. (2020) which accounts for the
converter of Wilson (www.campbellcollaboration.org) which is based existence of multiple effect sizes within primary studies. In contrast to
on the formulas of Lipsey and Wilson (2001). For effect sizes on baseline traditional forest plots, each black line no longer portrays an individual
vagal activity, a positive correlation coefficient reflected that higher effect size, but the results of meta-analyses of outcomes within each
levels of childhood adversity were associated with higher levels of study. In addition, caterpillar plots were created based on the syntax
baseline vmHRV. For studies on vagal reactivity, we inverted effect sizes provided by Fernández-Castilla et al. (2020). The complete dataset and
if studies computed a reactivity score by calculating task minus baseline the R syntax employed for the analyses can be found in the Supplemental
or used task mean levels in order to ensure that all reactivity scores were Material available online.
in the same direction. A positive correlation coefficient reflected that
higher levels of childhood adversity were related to higher vagal reac­ 2.5. Risk of bias assessment
tivity, i.e., stronger vagal suppression / withdrawal or larger decreases
in vmHRV from baseline to challenge. In order to assess whether a publication or subjective reporting bias
Pearson correlation coefficients were transformed into Fisher’s Z was present within our set of included studies, various analyses were
scores for the meta-analysis, as the latter are normally distributed performed in R using the metafor package (Viechtbauer, 2010) and code
(Lipsey & Wilson, 2001). To facilitate interpretability, Fisher’s Z scores adapted from Fernández-Castilla et al. (2021). We used a multi-level
were converted back into Pearson correlations after the statistical ana­ extension of Egger’s test (Egger et al., 1997) from Fernández-Castilla
lyses were performed. et al. (2021) in which effect sizes were regressed on the inverse of
standard errors while accounting for effect size dependency. Further, we
2.4. Statistical analysis computed a multi-level extension of the Funnel Plot test (Fernández-­
Castilla et al., 2021) in which sample sizes were used as predictors of the
Two separate meta-analyses were conducted to assess the association effect sizes. In both tests, a significant regression coefficient would
between childhood adversity and baseline vagal activity, and childhood indicate potential bias. In addition, we conducted the Trim and Fill
adversity and vagal reactivity to challenge. Given that several studies method (Duval and Tweedie, 2000a, 2000b; Fernández-Castilla et al.,
reported on multiple forms of childhood adversity or used more than one 2021) in which funnel plot asymmetry stemming from potential bias is
method to assess childhood adversity, it was possible to extract multiple detected and corrected by adding the estimated hypothetical “missing”
effect sizes per study for 54.4% of all baseline studies, and 69.1% of all effect sizes. The presence of bias was evaluated by comparing the value
reactivity studies. As effect sizes from the same study may be more alike of the estimator L+ 0 with cutoffs proposed by Fernández-Castilla et al.
than effect sizes from different studies, the assumption of independent (2021) which depended on the pooled effect size and the number of
effect sizes required by traditional meta-analytic approaches was effect sizes included in each meta-analysis.

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For visualization purposes, we created two funnel plots using the 3.3. Moderator analyses
ggplot2 package (Wickham, 2016) in R, following guidelines on funnel
plots for multi-level meta-analyses (Fernández-Castilla et al., 2020): In 3.3.1. Heterogeneity in effect sizes
the first funnel plot, all effect sizes were plotted against their standard We tested whether differences in effect sizes could be attributed to
errors. If no selection bias exists, studies based on large samples should random sampling error (Level 1), within-study variance (Level 2), or
be closer to the pooled effect compared to studies with lower samples between-study variance (Level 3). For the association between child­
which are expected to distribute more widely along both sides of the hood adversity and baseline vagal activity, significant variation was
pooled effect at the base of the graph, yielding a symmetrical inverted present in effect sizes within studies (σ2 =.001, χ2(1) = 8.96, p = .001;
funnel shape. In the second funnel plot, the study effects estimated one-sided) and in effect sizes between studies (σ2 =.003, χ2(1) = 8.05,
through separate random-effects meta-analyses to each study were p = .002; one-sided). With regards to the distribution of variances,
plotted against their meta-analytic standard errors. In this study-funnel 52.44% of the total variance was accounted for by variation in effect
plot, the precision of each study not only depends on the sample size as sizes between studies, 16.18% within studies, and 31.38% by random
in funnel plots of all effects, but further depends on the number of effect sampling variance.
sizes reported and on their variability. Based on visual inspection of the
funnel plots, selection bias could exist if part of the funnel of all effect 3.3.2. Moderator effects
sizes is empty or if the distribution of study-specific effects is As significant heterogeneity within and between studies was present
asymmetrical. in the dataset, we tested whether moderators could potentially explain
part of the variation in effect sizes. An overview of all moderator vari­
3. Results meta-analysis 1: association between childhood ables and results of the moderator analyses are presented in Table 3, in
adversity and baseline vagal activity which the potential moderators are classified into characteristics of the
study, sample, childhood adversity, and vmHRV measurement. In total,
3.1. Study selection and characteristics we identified four moderating variables of which one was part of the
sample characteristics, and three were part of the childhood adversity
A flow diagram for the identification of articles appears in Fig. 1. The characteristics.
search process yielded a total of 3009 potentially relevant records, from First, a significant moderating effect was found for the presence of
which 1852 remained after removing duplications. After the screening psychopathology in the sample. More specifically, childhood adversity
based on title and abstract, 279 reports remained for the screening based was more strongly associated with baseline vagal activity in samples in
on the full-text. which part of the participants had a psychiatric diagnosis (r = − .106,
The meta-analysis on baseline vagal activity included 115 articles p < .001) than in non-clinical samples (r = − .005, p = .586). Second,
reporting on 90 independent studies (k) and comprising 250 effect sizes the severity of adversity was a significant moderator. Stronger relations
(#ES). The publication year of the included studies ranged from 2000 to between childhood adversity and baseline vagal activity were found for
2020 (median = 2015). Studies were predominantly conducted in North studies on maltreatment (r = − .058, p < .001) as compared to studies
America (n = 74), followed by Europe (n = 12), Asia (n = 2), Africa on other forms of adversity (r = .004, p = .736). Third, the dimension of
(n = 1) and Australia (n = 1). The overall sample size was N = 18,716 adversity moderated the association between childhood adversity and
unique participants, with study sample sizes ranging from N = 36 baseline vagal activity. Exposure to deprivation as well as exposure to
(Garland et al., 2019) to N = 3362 participants (Bakema et al., 2020). both deprivation and threat (mixed) showed stronger associations with
The mean age of the participants was 12.85 years (SD = 9.96 years). vmHRV (r = − .044, p = .036; r = − .029, p = .041, respectively) than
Within 11.1% of the studies, a mean of 40.0% (SD = 29.6%) of partic­ exposure to threat with vmHRV (r = − .002, p = .859). Fourth, the
ipants were diagnosed with a psychiatric disorder. The mean number of proximity of adversity was a significant moderator. Stronger associa­
extracted effect sizes per study was 2.58 (SD = 3.0). With regards to the tions between childhood adversity and baseline vagal activity were
childhood adversity type, the majority of effect sizes related to found for exposure to direct adversity (r = − .037, p = .002) as
maltreatment (n = 92), followed by interparental aggression (n = 45), compared to exposure to indirect adversity (r = − .001, p = .950) or
parental psychopathology (n = 28), poverty (n = 20), composites of exposure to both direct and indirect adversity (mixed; r = .039,
different adversity types (n = 19), adverse parenting (n = 17), peer p = .108). All other characteristics (including year of publication,
victimization (n = 14), neighborhood violence (n = 7), and other country of data collection, study design, number of participants, age of
(n = 8). In the Supplemental Material, several characteristics of the participants, percentage females, percentage minorities, assessment of
included studies are summarized in a spreadsheet. adversity, recency of adversity, vmHRV index, duration of vmHRV
baseline measurement, baseline condition, measurement of respiration
and artifact correction) were not significant moderators in the associa­
tion between childhood adversity and baseline vagal activity.
3.2. Overall association

3.3.3. Multiple moderator analysis

No significant association was found between childhood adversity
As moderators may be interrelated, possibly leading to multi­
and baseline vagal activity (r = − .015; 95% CI [− 0.033, 0.003;
collinearity in the analyses, we followed the recommendation by Hox
p = .109; see Table 2).1 Fig. 2 shows the summary forest plot repre­
(2010) and tested the unique effect of the variables that were previously
senting the results of meta-analyses of outcomes within each study. In
identified as significant moderators combined in a single model. To this
Fig. 3A, we have plotted the caterpillar plot with all effect sizes and their
end, we extended the meta-analytic model by adding the variables
confidence intervals, ordered by their magnitude. In Fig. 3B, we have
psychopathology, severity, dimension and proximity of adversity
plotted the study-caterpillar plot, in which effect sizes within studies are
simultaneously. The results of this model are presented in Table 4. The
synthesized (as in the forest plot).
omnibus test showed significant results, F(6243) = 5.52, p < .001,
suggesting that at least one of the regression coefficients of the moder­
1 ators significantly deviated from zero. Results revealed that psychopa­
A sensitivity analysis was performed by excluding studies in which partic­
ipants experienced prenatal adversity or adulthood adversity in addition to thology and the proximity of adversity had a unique moderating effect of
childhood adversity (k = 3, ES = 9). The overall association between childhood the relationship between childhood adversity and baseline vagal activ­
adversity and baseline vagal activity remained non-significant, r = − .014; 95% ity. Consistent with results from the univariate moderator analyses,
CI [− .033, .005], p = .143). childhood adversity was associated with lower baseline vagal activity in

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C. Wesarg et al. Neuroscience and Biobehavioral Reviews 143 (2022) 104920

Fig. 1. PRISMA Flow Diagram.

Table 2
Estimated Pooled Correlations (Fisher’s Z and Pearson’s r) for the Relationships Between Childhood Adversity and Vagally-Mediated Heart Rate Variability.
Association #k #ES N Zr (SE) r (SE) 95% CI (r) t (df) p

Childhood adversity – baseline vagal activity 90 250 18716 -.015 (.009) -.015 (.009) [− .033,.003] -1.61 (249) .109
Childhood adversity – vagal reactivity 55 190 8741 -.017 (.011) -.017 (.011) [− .039,.005] -1.53 (189) .127

Note. #k = number of studies; #ES = number of effect sizes; N = total number of unique participants; Zr = Fisher’s Z correlation; SE = standard error; r = Pearson’s
correlation coefficient r; 95% CI = 95% confidence intervals of Pearson’s r; df = degrees of freedom.

studies in which part of the participants had a psychiatric diagnosis and studies (k), comprising 190 effect sizes (#ES). The publication year of
in those in which direct adversities were investigated. the included studies ranged from 2001 to 2020 (median = 2014).
Studies were predominantly conducted in North America (n = 49), fol­
lowed by Europe (n = 4), Asia (n = 1), and Australia (n = 1). The overall
3.4. Risk of bias assessment sample size was N = 8741 unique participants, with study sample sizes
ranging from N = 36 (Garland et al., 2019) to N = 1047 participants
For the meta-analysis on childhood adversity and baseline vagal (Conradt et al., 2016). The mean age of the participants was 12.80 years
activity, the non-significant regression coefficients from the adapted (SD = 9.24 years). Within 10.9% of the studies, a mean of 27.8% (SD =
Egger’s test (β = − 0.014, SE = 0.026, p = .582) and the adapted Funnel 26.3%) of participants were diagnosed with a psychiatric disorder. The
plot test (β = − 0.013, SE = 0.019, p = .207) yielded no evidence of mean number of extracted effect sizes per study was 3.45 (SD = 3.89).
publication bias. However, the Trim and Fill method indicated potential With regards to the childhood adversity type, the majority of effect sizes
bias. The estimator L+0 was 8.03 and thereby larger than the cutoff of 3 related to maltreatment (n = 56), followed by interparental aggression
which was chosen given that the baseline meta-analysis revealed a non- (n = 25), parental psychopathology (n = 23), (neighborhood) violence
significant pooled effect size of r = − .015 with 250 effect sizes being exposure (n = 19), poverty (n = 12), composites of different adversity
included (see Fernández-Castilla et al., 2021). A visual representation of types (n = 20), adverse parenting (n = 15), peer victimization (n = 10),
the funnel plots can be found in Fig. 4. and other (n = 10). With regards to the challenge task, the majority of
effect sizes pertained to emotion-eliciting tasks (n = 93), followed by
4. Results meta-analysis 2: association between childhood stress tasks (n = 33) and cognitive tasks (n = 33). The mean duration of
adversity and vagal reactivity task recording was 5.34 min (SD = 3.54). In the Supplemental Material,
several characteristics of the included studies are summarized in a
4.1. Study selection and characteristics spreadsheet.

The screening based on title and abstract was the same as in the
meta-analysis on baseline vagal activity (see Fig. 1). The meta-analysis
on vagal reactivity included 75 articles reporting on 55 independent

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C. Wesarg et al. Neuroscience and Biobehavioral Reviews 143 (2022) 104920

Fig. 2. Summary forest plot showing the results

of the meta-analysis on childhood adversity and
baseline vagal activity. The thickness of the
grey confidence intervals is proportional to the
number of effect sizes reported within studies.
Effect sizes of studies marked with an asterisk
(*) were further reported in other publications
based on the same data set. Effect sizes related
to Buisman et al. (2018) also apply to Buisman
et al. (2019); Cipriano (2010): Cipriano et al.
(2011), Creaven et al. (2014); Connell et al.
(2011): Connell et al. (2015); Conradt et al.
(2014a): Conradt et al. (2014b); (2014c)
(2016); Duprey et al. (2020): Oshri et al.
(2020); El-Sheikh et al. (2001): El-Sheikh
(2001, 2005); El-Sheikh et al. (2009) – study 2:
El-Sheikh et al., (2011, 2013), Hinnant et al.
(2015), Philbrook et al. (2018), Wetter and
El-Sheikh (2012); Fletcher et al. (2017): Beni­
to-Gomez et al. (2019a); b); Keller et al. (2014):
El-Sheikh et al. (2015); McLaughlin et al.
(2014): Busso et al. (2017), McLaughlin et al.
(2015a); Obradović et al. (2010): Obradović
et al. (2011); Oshri et al. (2018): Liu et al.
(2020); Shenk et al. (2010): Shenk et al., (2012,
2014); Skowron et al. (2014): Giuliano et al.,
(2015, 2018b).

A B

1.25

0.75

0.75
Metaanalytic study means
Study means

0.25

0.00

0.25

1.25
0.75

1.25

Fig. 3. Caterpillar plots of the meta-analysis on childhood adversity and baseline vagal activity. (A) Caterpillar plot with all effect sizes and their 95% confidence
intervals and (B) study-caterpillar plot.

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C. Wesarg et al. Neuroscience and Biobehavioral Reviews 143 (2022) 104920

Table 3
Childhood Adversity and Baseline Vagal Activity: Estimated Results (Fisher’s Z, Regression Coefficients, Omnibus-Test) for Continuous and Categorical Moderator
Variables.
Moderator #ka #ES Zr (SE) β1 (SE) F (df1, df2)b p

Study characteristics
Year of publicationcb 90 250 -.015 (.009) -.002 (.002) F(1, 248) = 0.61 .437
Country of data collection F(1, 248) = 0.00 .978
U.S. or Canada (North-America; RC) 74 196 -.015 (.010)
Other countries outside North-America 16 54 -.014 (.022) .001 (.024)
Study design F(1, 248) = 1.98 .161
Correlational (RC) 72 208 -.009 (.010)
Group comparison 22 42 -.037 (.018)* -.028 (.020)
Sample Characteristics
Number of participantsc 90 250 -.015 (.010) -.000 (.000) F(1, 248) = 0.05 .815
Age (in years)c 90 250 -.016 (.009) -.001 (.001) F(1, 248) = 0.74 .390
Sex (% females)c 87 243 -.011 (.009) -.001 (.000) F(1, 241) = 1.71 .192
Ethnicity (% Minorities)c 79 208 -.013 (.010) .000 (.000) F(1, 208) = 0.08 .779
Psychopathology F(1, 248) = 12.40 < .001***
Clinical diagnoses reported (RC) 10 27 -.106 (.027)***
No clinical diagnoses reported 81 223 -.005 (.010) .101 (.029)***
Childhood adversity characteristics
Severity of adversity F(1, 248) = 12.37 < .001***
Maltreatment (RC) 27 92 -.058 (.015)***
Other forms of adversity 70 158 .004 (.011) .062 (.018)***
Dimension of adversity F(2247) = 3.11 .046
Deprivation (RC) 12 26 -.044 (.021)*
Threat 55 144 -.002 (.011) .042 (.020)*
Mixed (deprivation & threat) 45 80 -.029 (.014)* .015 (.024)
Proximity of adversity F(2247) = 5.66 .004**
Direct adversity (RC) 48 129 -.037 (.012)**
Indirect adversity 44 103 -.001 (.013) .037 (.016)*
Mixed (direct & indirect adversity) 12 18 .039 (.023) .077 (.025)**
Assessment of adversity: Informant F(1248) = 3.77 .053+
Self-report (RC) 40 115 -.034 (.013)*
Other 58 135 -.002 (.012) .032 (.016)+
Assessment of adversity: Type F(2247) = 1.49 .227
Questionnaires (RC) 79 224 -.010 (.010)
Official records 7 17 -.029 (.030) -.019 (.032)
Other 8 9 -.075 (.038)+ -.065 (.039)+
Recency of exposure to adversity (in years)c 90 249 -.016 (.009) -.002 (.001) F(1, 247) = 2.52 .114
vmHRV characteristics
vmHRV Index F(1246) = 0.49 .483
Time-Domain (RC) 46 123 -.005 (.012)
Frequency-Domain 46 117 -.016 (.012) -.011 (.016)
Duration of vmHRV baseline measurementc 84 234 -.013 (.009) -.000 (.000) F(1, 232) = 2.58 .110
Baseline condition F(2203) = 1.82 .165
No task (RC) 32 111 -.009 (.017)
Rather passive task 34 67 -.005 (.017) .004 (.023)
Active task 13 28 -.055 (.024)* -.046 (.030)
Measurement of respiration F(1, 247) = 0.15 .696
Respiration measured (RC) 34 94 -.011 (.015)
No respiration measurement reported 58 155 -.018 (.012) -.007 (.018)
Artifact correction F(1248) = 0.39 .534
Artifacts corrected (RC) 85 235 -.014 (.010)
No artifact correction reported 5 15 -.038 (.038) -.024 (.039)

Note. #k = number of studies; #ES = number of effect sizes; Zr = Fisher’s Z correlation; SE = standard error; β1 = estimated regression coefficient; df = degrees of
freedom; RC = reference category; vmHRV = vagally-mediated HRV
a
For categorical moderators, a study can be represented in more than one moderator category if the effect sizes reported relate to different moderator categories. Thus,
the sum of the number of studies (k) included in distinct categories belonging to the same moderator can exceed 90 (the total number of unique studies) b Omnibus test
of all regression coefficients in the model; c continuous variable
+p <.1; * p <.05; ** p <.01; *** p <.001

4.2. Overall association of meta-analyses of outcomes within each study. In Fig. 6A, we have
plotted the caterpillar plot with all effect sizes and their confidence in­
No significant association was found between childhood adversity tervals, ordered by their magnitude. In Fig. 6B, we have plotted the
and vagal reactivity to challenge (r = − .017; 95% CI [− 0.039, 0.005; study-caterpillar plot, in which effect sizes within studies are synthe­
p = .127).2 Fig. 5 shows the summary forest plot representing the results sized (as in the forest plot).

4.3. Moderator analyses

2
A sensitivity analysis was performed by excluding studies in which partic­
ipants experienced prenatal adversity or adulthood adversity in addition to 4.3.1. Heterogeneity in effect sizes
childhood adversity (k = 2, ES = 9). The overall association between childhood For the association between childhood adversity and vagal reac­
adversity and vagal reactivity remained non-significant, r = − .018; 95% CI tivity, significant variation was present in effect sizes between studies
[− .041, .005], p = .130). (σ2 =.003, χ2(1) = 27.08, p < .001; one-sided) but not in effect sizes

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C. Wesarg et al. Neuroscience and Biobehavioral Reviews 143 (2022) 104920

Table 4
Childhood Adversity and Baseline Vagal Activity: Results for the Multiple Moderator Model.
Moderator β (SE) 95% CI t p

Intercept -.137 (.032) [− .200; − .075] -4.331 < .001******

Psychopathology: no clinical diagnoses reported (vs. clinical diagnoses reported) .083 (.029) [.025;.140] 2.817 .005******
Severity: other forms of adversity (vs. maltreatment) .025 (.023) [− .021;.071] 1.067 .287
Dimension: threat (vs. deprivation) .029 (.017) [− .005;.063] 1.706 .089+
Dimension: mixed (vs. deprivation) -.011 (.023) [− .057;.034] -0.488 .626
Proximity: indirect adversity (vs. direct adversity) .027 (.021) [− .014;.068] 1.303 .194
Proximity: mixed (vs. direct adversity) .065 (.029) [.008;.122] 1.234 .026*
+
p <.1; * p <.05; *** p <.001

within studies (σ2 =.001, χ2(1) = 1.98, p = .080; one-sided). With 4.3.3. Multiple moderator analysis
regards to the distribution of variances, 62.21% of the total variance was In order to test the unique effect of the variables that were previously
accounted for by variation in effect sizes between studies, 7.96% within identified as significant moderators combined in a single model, we
studies, and 29.83% by random sampling variance. extended the meta-analytic model by adding the variables participant
age, recency of adversity and reactivity computation method simulta­
4.3.2. Moderator effects neously. Results revealed that the recency of adversity and the reactivity
As significant heterogeneity between studies was present in the computation method were unique moderators of the relationship be­
dataset, we tested whether moderators could potentially explain part of tween childhood adversity and vagal reactivity, F(4184) = 7.98,
the variation in effect sizes. An overview of all moderator variables and p < .001, see Table 6. To specify, childhood adversity was associated
results of the moderator analyses are presented in Table 5, in which the with lower vagal reactivity for studies in which individuals had expe­
potential moderators are classified into characteristics of the study, rienced adversity less recently, and for studies in which reactivity was
sample, childhood adversity, and vmHRV measurement. In total, we operationalized through task mean levels of vmHRV.
identified three moderating variables: age of participants, recency of
exposure to adversity, and vagal reactivity computation method.
First, as the sample’s mean age increased, the overall strength of 4.4. Risk of bias assessment
association between childhood adversity and vagal reactivity signifi­
cantly increased. Thus, childhood adversity was associated with less For the meta-analysis on childhood adversity and vagal reactivity, no
vagal withdrawal in older-aged samples. Second, as childhood adversity indication of bias was detected through Egger’s test (β = 0.037, SE =
occurred less recently, the overall strength of association increased. In 0.035, p = .290) or the Funnel Plot test (β = − 0.024, SE = 0.015,
other words, childhood adversity was associated with less vagal with­ p = .105). Also the Trim and Fill method yielded no indication of bias, as
drawal in individuals who had experienced adversity longer ago. Third, L+
0 = 0 < 3 (the cutoff chosen based on recommendations from
while there was a significant negative association between childhood Fernández-Castilla et al. (2021); given a pooled effect size of r = − .017
adversity and vagal reactivity for studies in which reactivity was oper­ and 190 included effect sizes). A visual representation of the funnel plots
ationalized through task mean levels of vmHRV (r = − .079, p < .001), can be found in Fig. 7.
there was no significant association for studies in which reactivity was
computed as a difference score (r = .007, p = .608) or residualized 5. Discussion
change score (r = .013, p = .488). All other characteristics (year of
publication, country of data collection, study design, number of partic­ This meta-analysis examined the association between childhood
ipants, percentage females, percentage minorities, psychopathology, adversity and vagal regulation as indexed by baseline vagal activity and
severity, dimension, proximity, assessment, timing and recency of vagal reactivity to various challenges, including cognitive tasks, nega­
adversity, vmHRV index, duration of vagal reactivity measurement, tive emotion-eliciting tasks and stress tests. In contrast to our hypothe­
challenge task, and measurement of respiration) were not significant ses, no significant overall association was present between childhood
moderators in the association between childhood adversity and vagal adversity and both indexes of vagal regulation. However, significant
reactivity. moderators were found in both meta-analyses after controlling for their
potential interrelatedness. Specifically, childhood adversity was asso­
ciated with lower baseline vagal activity in samples in which part of the

Fig. 4. Funnel plots of the meta-analysis on childhood adversity and baseline vagal activity. (A) Funnel plot of all effect sizes and (B) study-funnel plot that includes
the number of outcomes reported in each study. In Fig. 4B, the size of the dots is proportional to the number of effect sizes included in those studies.

11
C. Wesarg et al. Neuroscience and Biobehavioral Reviews 143 (2022) 104920

Fig. 5. Summary forest plot showing results of

the meta-analysis on childhood adversity and
vagal reactivity. The thickness of the grey con­
fidence intervals is proportional to the number
of effect sizes reported within studies. Effect
sizes of studies marked with an asterisk (*) were
further reported in other publications based on
the same data set. Effect sizes related to Beni­
to-Gomez et al. (2019a) also apply to Benito-­
Gomez et al. (2019b); Buisman et al. (2018):
Buisman et al. (2019); Busso et al. (2014):
Busso et al. (2017), McLaughlin et al. (2014);
Cipriano (2010): Cipriano et al. (2011); Conradt
et al. (2014a): Conradt et al. (2014b); c (2016);
Duprey et al. (2020): Oshri et al. (2020);
El-Sheikh et al. (2009) – study 2: El-Sheikh
et al., (2011, 2013), Hinnant et al. (2015),
Philbrook et al. (2018); Keller et al. (2014):
El-Sheikh et al. (2015), Staton et al. (2014);
Lafko et al. (2015): Breslend et al. (2018);
Obradović et al. (2010): Obradović et al.
(2011); Oshri et al. (2018): Liu et al. (2020);
Shenk et al. (2010): Shenk et al., (2012, 2014);
Skowron et al. (2014): Giuliano et al., (2015,
2018b).

participants were diagnosed with a psychiatric disorder, and direct ad­ regulation have been demonstrated in individuals exposed to adversity
versities such as maltreatment were associated with lower baseline vagal (Koenig, 2020; Teicher and Samson, 2016). However, a significant
activity. Further, childhood adversity was associated with lower vagal overall association between childhood adversity and the functioning of
reactivity for studies in which individuals had experienced adversity less stress regulatory systems such as the hypothalamic-pituitary-adrenal
recently, and for studies in which reactivity was operationalized through (HPA) axis was also not found in other meta-analyses (see e.g., Ber­
task mean levels of vmHRV. nard et al., 2017; Fogelman and Canli, 2018). In line with the model of
‘stress sensitization’ (Hammen et al., 2000), it is possible that alterations
in vagal regulation are more likely to develop in individuals with a
5.1. Overall association between childhood adversity and vagal regulation history of childhood adversity when exposed to additional adversity in
adulthood. In accordance with this hypothesis, a recent study showed
The finding of no overall association suggests that childhood that patients with major depressive disorder who experienced both
adversity does not lead to alterations in vagal regulation per se, indi­ childhood and adulthood adversity had higher rates of suicidal ideation,
cating that this physiological system generally maintains its functional whereas neither childhood nor adulthood adversity alone had a pre­
integrity in the context of adversity. This finding was unexpected, as dictive value (Lin et al., 2022). Along the same lines, recent
structural and functional alterations in brain regions implicated in vagal

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C. Wesarg et al. Neuroscience and Biobehavioral Reviews 143 (2022) 104920

A B
1.5

1.0

0.5
Effect sizes

0.5

Metaanalytic study means

0.0

0.5

1.5

1.0

1.5

Fig. 6. Caterpillar plots of the meta-analysis on childhood adversity and vagal reactivity. (A) Caterpillar plot with all effect sizes and their 95% confidence intervals
and (B) study-caterpillar plot.

interpersonal stressful events were found to predict smaller hippocam­ Back et al., 2022; Moscardino et al., 2021; Scrimin et al., 2018; Somers
pal volumes in adults over and above childhood maltreatment (Lawson and Luecken, 2021).
et al., 2017). As only one study in both meta-analyses included in­ Intriguingly, research suggests that vagal functioning at the time of
dividuals with additional adulthood adversity, we were unable to exposure to adversity may represent a marker of an individual’s sus­
further test for this potential sensitization effect. ceptibility to the negative effects of adversity, with general agreement
that low resting vagal activity portrays a marker of increased risk and
5.2. Moderating effects in the association between childhood adversity relatively high resting vagal activity a protective factor (Carnevali et al.,
and baseline vagal activity 2018; Curtis et al., 2017; Duprey et al., 2018; Koenig, 2020; McLaughlin
et al., 2014; Patron et al., 2021). Similarly, vagal reactivity has been
As suggested by our moderator findings, adversity-related alterations identified as a moderator in the association of adversity to pathology,
in vagal regulation may arise under specific circumstances such as when with inconsistent findings on whether heightened or buffered reactivity
studies included participants with a psychiatric diagnosis in their sam­ acts as a protective factor (Daches et al., 2019; Hagan et al., 2017; Liu
ple. In line with our hypotheses, a small significant association between et al., 2020; McLaughlin et al., 2014; Oshri et al., 2018; Vaughn-Coaxum
childhood adversity and lower baseline vagal activity was observed in et al., 2020). Integrating these findings with our meta-analytic results, it
clinical samples. This finding is consistent with evidence from a recent is possible that vagal functioning at the time of exposure to adversity
meta-analysis showing that resting-state HRV was more reduced in in­ reflects an individual’s ability to cope with stress. Individuals with the
dividuals exposed to early-life maltreatment as compared to non- high-risk endophenotype of low resting vagal activity would more likely
exposed controls in clinical samples in contrast to general population develop alterations in vagal functioning over time, which are preceded
samples (Sigrist et al., 2021). One possible interpretation of these find­ or paralleled by alterations in brain structure and function. In turn, al­
ings would be that adversity-related alterations in vagal activity only terations in vagal functioning would confer vulnerability to psychopa­
develop in those who are more strongly affected by the negative effects thology. So far, several studies were unable to provide evidence for a
of adversity and consequently develop psychopathology, but not in mediating role of vagal regulation (Busso et al., 2017; Fagan et al., 2017;
others who maintain normative functioning in the long run. As studies Hagan et al., 2017; Jankovic et al., 2021). However, this may be related
included in the meta-analysis commonly assessed participant charac­ to the fact that assessments of vagal regulation and psychopathology
teristics such as the presence of psychopathology concurrently to the were commonly conducted at the same time or with only a short time
measurement of vagal regulation, no conclusions can be drawn on the interval in between. While it seems plausible that alterations in vagal
temporal order of alterations in vagal activity and the onset of psycho­ functioning and symptoms of psychopathology reinforce each other
pathology. A possibility could be that psychopathology is an indepen­ recursively over time, longitudinal studies spanning different develop­
dent (moderating) factor determining vulnerability to adversity-related mental periods are needed to shed light on the complex developmental
alterations in vagal regulation. However, this option is rather unlikely cascade leading from adversity to negative health outcomes.
given longitudinal studies suggesting that vagal dysregulation often As expected, direct adversities were more strongly associated with
precedes the onset of psychopathology (Carnevali et al., 2018; Huang lower baseline vagal activity than indirect adversities or a combination
et al., 2018; Jandackova et al., 2016; Wekenborg et al., 2019). Consid­ of direct and indirect adversities (as applies to composite scores of
ering that reduced levels of resting HRV are a core characteristic of adversity). There are different reasons that could explain these findings.
various psychiatric disorders (Brown et al., 2018; Chalmers et al., 2014; First, although indirect adversities such as poverty and neighborhood
Clamor et al., 2016; Koch et al., 2019; Koenig, Kemp, Beauchaine et al., violence likely portray a significant challenge for the developing child,
2016; Koenig, Kemp Feeling et al., 2016) and their temporal precedence the detrimental effects of these adversities can be buffered through
over clinical symptoms, another possibility would be that alterations in sensitive and responsive caregiving (Depasquale and Gunnar, 2020;
vagal regulation mediate the association between childhood adversity Tarsha & Narvaez, 2022). To exemplify, adults who grew up in low
and psychopathology. In turn, other factors are likely involved that socio-economic status households whose mothers expressed high
render an individual vulnerable to both alterations in vagal functioning warmth toward them exhibited lower levels of inflammation as
and the development of psychopathology in the face of adversity. compared to those who experienced low maternal warmth (Chen et al.,
Several individual and environmental factors not limited to the ones 2011). Second, direct adversities may be more strongly associated with
addressed in this meta-analysis (e.g., genetic predisposition, attachment vagal activity as they include more severe adversity types such as
security, social support throughout development) and potential in­ maltreatment. Indeed, inherent to the operationalization of direct
teractions between such factors could play an important role along the adversity, 71.3% of direct adversities in our baseline meta-analysis
pathway from adversity to pathology (see e.g., Allegrini et al., 2017; related to maltreatment, whereas the rest comprised other types such

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C. Wesarg et al. Neuroscience and Biobehavioral Reviews 143 (2022) 104920

Table 5
Childhood Adversity and Vagal Reactivity: Estimated Results (Fisher’s Z, Regression Coefficients, Omnibus-Test) for Continuous and Categorical Moderator Variables.
Moderator #ka #ES Zr (SE) β1 (SE) F (df1, df2)b p

Study characteristics
Year of publicationc 55 190 -.017 (.011) -.000 (.003) F(1, 188) = 0.02 .891
Country of data collection F(1, 188) = 0.01 .922
U.S. or Canada (North-America; RC) 49 160 -.017 (.012)
Other countries outside North-America 6 30 -.020 (.031) -.003 (.034)
Study design F(1, 188) = 0.29 .590
Correlational (RC) 44 149 -.014 (.012)
Group comparison 14 41 -.029 (.020) -.012 (.022)
Sample Characteristics
Number of participantsc 55 190 -.018 (.011) .000 (.000) F(1, 188) = 0.49 .486
Age (in years)c 55 190 -.016 (.011) .003 (.001) F(1, 188) = 5.34 .022*
Sex (% females)c 53 181 -.016 (.012) .000 (.001) F(1, 179) = 0.01 .907
Ethnicity (% Minorities)c 53 186 -.020 (.012) -.000 (.000) F(1, 184) = 0.53 .468
Psychopathology F(1, 188) = 0.31 .577
Clinical diagnoses reported (RC) 6 10 .004 (.040)
No clinical diagnoses reported 50 180 -.018 (.012) -.023 (.041)
Childhood adversity characteristics
Severity of adversity F(1, 188) = 1.95 .164
Maltreatment (RC) 15 56 .003 (.018)
Other forms of adversity 46 134 -.023 (.012)+ -.026 (.019)
Dimension of adversity F(2187) = 1.58 .209
Deprivation (RC) 5 13 .010 (.032)
Threat 40 110 -.008 (.013) -.018 (.032)
Mixed (deprivation & threat) 23 67 -.037 (.016)+ -.048 (.035)
Proximity of adversity F(2187) = 1.96 .143
Direct adversity (RC) 32 101 -.004 (.014)
Indirect adversity 27 70 -.023 (.015) -.019 (.017)
Mixed (direct & indirect adversity) 9 19 -.052 (.024)* -.049 (.025)+
Assessment of adversity: Informant F(1188) = 0.57 .453
Self-report (RC) 24 71 -.007 (.017)
Other 39 119 -.022 (.013) -.014 (.019)
Assessment of adversity: Type F(2187) = 0.53 .591
Questionnaires (RC) 47 166 -.013 (.012)
Official records 5 13 -.052 (.036) -.039 (.038)
Other 6 11 -.022 (.037) -.009 (.039)
Timing of exposure to adversity 55 189 -.016 (.011) .002 (.002) F(1187) = 0.82 .367
Recency of exposure to adversity (in years)c 55 189 -.018 (.010) .005 (.002) F(1, 187) = 7.28 .008**
vmHRV characteristics
vmHRV Index F(1185) = 1.87 .173
Time-Domain (RC) 27 79 .000 (.015)
Frequency-Domain 28 108 -.028 (.014)+ -.028 (.020)
Task duration included in analysisc 53 170 -.012 (.011) -.001 (.003) F(1168) = 0.20 .652
Challenge task F(2187) = 0.34 .715
Cognitive task (RC) 10 33 -.004 (.023)
Emotion-eliciting task 41 93 -.016 (.014) -.012 (.025)
Stress test 16 64 -.028 (.019) -.024 (.029)
Reactivity computation F(2187) = 10.13 < .001***
Task mean levelsd (RC) 17 73 -.079 (.018)***
Difference score 31 78 .007 (.014) .086 (.024)***
Residualized change score 12 37 .013 (.019) .092 (.021)***
Measurement of respiration F(1, 187) = 1.36 .245
Respiration measured (RC) 28 89 -.004 (.016)
No respiration measurement reported 29 100 -.028 (.014) -.024 (.020)

Note. #k = number of studies; #ES = number of effect sizes; Zr = Fisher’s Z correlation; SE = standard error; β1 = estimated regression coefficient; df = degrees of
freedom; RC = reference category; vmHRV = vagally-mediated HRV
a
For categorical moderators, a study can be represented in more than one moderator category if the effect sizes reported relate to different moderator categories. Thus,
the sum of the number of studies (k) included in distinct categories belonging to the same moderator can exceed 55 (the total number of unique studies); b Omnibus test
of all regression coefficients in the model; c continuous variable; d as effect sizes on task mean levels were inverted to ensure that all reactivity effect sizes were in the
same direction, a negative coefficient Zr implies that higher levels of childhood adversity are related to higher task mean levels of vmHRV.
+ p <.1; * p <.05; ** p <.01; *** p <.001

as adverse parenting and peer victimization. As hypothesized, the functioning.

severity of adversity was identified as a significant moderator, which Although the dimension of adversity was a significant moderator in
contrasts findings of Sigrist et al. (2021) who did not find an overall the univariate model—showing that deprivation was associated with
association between maltreatment and resting vagal activity. These lower vagal activity than threat—it became non-significant after
inconsistent findings may have arisen due to differences in the employed adjusting for the other moderators in multivariate analyses. As empha­
meta-analytical method and sample composition. However, when we sized in previous studies examining the dimensional model of adversity,
included both proximity and severity of adversity in our multiple it is important to control for the exposure to threat in investigating the
moderator model, the severity did not significantly add to an explana­ effects of deprivation (and vice versa), as both dimensions often co-
tion of variance anymore. Integrating these findings, it seems plausible occur (Busso et al., 2017). However, as we included only raw correla­
that besides severe adversity types such as maltreatment, also other less tions in the meta-analysis, and most studies did not adjust for the
severe types that directly affect the child can influence vagal co-occurrence in adversity dimensions, we were unable to investigate

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C. Wesarg et al. Neuroscience and Biobehavioral Reviews 143 (2022) 104920

Table 6
Childhood Adversity and Vagal Reactivity: Results for the Multiple Moderator Model.
Moderator β (SE) 95% CI t p

Intercept -.082 (.017) [− .115; − .049] -4.954 < .001***

Age -.000 (.002) [− .004;.003] -0.096 .923
Recency of adversity .006 (.003) [.000;.011] 2.152 .033*
Reactivity computation: difference score (vs. mean levels) .091 (.020) [.052;.131] 4.549 < .001***
Reactivity computation: residualized change score (vs. mean levels) .088 (.023) [.043;.133] 3.837 < .001***

+p <.1; * p <.05; *** p <.001

adjusted associations. With regards to the categorization into di­ childhood adversity and vagal reactivity was only present in studies
mensions of adversity, it further needs to be remarked that deprivation which assessed reactivity through task mean levels as compared to
and threat may not always be clearly distinguishable, as for instance studies which computed difference scores or residualized change scores
being neglected portrays a major threat to an infant’s life. Given that no from baseline to task. Childhood adversity was associated with higher
moderation effect of the dimension of adversity was further found for mean levels of vmHRV during the challenge task, which reflects less
vagal reactivity, we could not confirm that both dimensions of adversity arousal in the face of challenge. Integrating this finding with meta-
differentially relate to vagal functioning. However, this may have been analytic results showing no adversity-related differences in baseline
related to methodological aspects of the present meta-analysis and the vagal activity, it is conceivable that individuals with a history of
studies included, and more research is needed to shed light on whether adversity tend to demonstrate a rather blunted response to challenge,
deprivation and threat affect vagal functioning in distinct ways. indicated by a lack of vagal withdrawal. However, this hypothesis is
difficult to reconcile with the finding that no association between
childhood adversity and vagal reactivity was present when reactivity
5.3. Moderating effects in the association between childhood adversity scores included the baseline, which would rather suggest a similar extent
and vagal reactivity to challenge of vagal withdrawal in adversity-exposed and non-exposed individuals.
To further examine these inconclusive results, we conducted post-hoc
In the meta-analysis on vagal reactivity to challenge, we found that exploratory analyses that revealed a small but significant positive as­
childhood adversity was more strongly associated with vagal reactivity sociation (r = .051, p = .047) between childhood adversity and baseline
in older individuals and if adversity had occurred less recently. These vagal activity in a subsample comprised of those studies in which vagal
findings were in line with evidence from a recent meta-analysis showing reactivity was operationalized through task mean levels of vmHRV. As
that greater reductions in resting-state HRV in association with more this result does not accord with the non-significant overall association
severe exposure to maltreatment appeared in studies including older- obtained based on the entire sample, and given that several studies re­
aged samples as compared to younger samples (Sigrist et al., 2021). ported no changes in vmHRV from baseline to task (e.g., Erath et al.,
As in our meta-analysis, the recency of adversity was operationalized by 2012; Goulter et al., 2019; Lynch et al., 2015), we suspect that evidence
subtracting the age at exposure to adversity from the age at vagal for a significant association between childhood adversity and task mean
reactivity measurement, and 60.6% of studies assessed these measures levels of vmHRV is rather weak and might have arisen as an artifact of
concurrently, both moderator variables were highly interrelated higher baseline levels observed in relation to adversity in these studies.
(r = .91, p < .01). This dependency of moderators may explain why the
variable age did not withstand the multiple moderator model. Inte­
grating these findings, the recency of adversity as compared to the mere 5.4. Strengths and limitations of the meta-analysis
age of participants seems to more strongly influence whether
adversity-related alterations in vagal reactivity arise; however, a larger This study has several strengths. Based on two separate meta-
time in between exposure to adversity and assessments of vagal reac­ analyses, we examined associations between childhood adversity with
tivity naturally implies that individuals are older. Therefore, our find­ both vagal activity under baseline conditions and vagal reactivity in
ings suggest that childhood adversity can set in motion a detrimental response to challenge, providing a quantitative summary of a complex
developmental cascade in which alterations in physiological system literature with heterogeneous findings. In order to include unpublished
functioning become more apparent in the long run. effect sizes that may therefore more likely represent ‘null results’, we
As a methodological moderator, the computation method of reac­ sent data requests to authors of studies in which the relevant measures of
tivity scores determined the strength of association between childhood childhood adversity and vagal regulation were assessed. Indeed, many
adversity and vagal reactivity. A small significant association between of the provided correlations were non-significant and inclusion of these

A 0.00 B 0.00

0.05 0.05
Metaanalytic standard error
Standard Error

0.10 0.10

0.15 0.15

1 0 1 1 0 1
Study mean effect Study mean effect

Fig. 7. Funnel plots of the meta-analysis on childhood adversity and vagal reactivity. (A) Funnel plot of all effect sizes and (B) study-funnel plot that includes the
number of outcomes reported in each study. In Fig. 7B, the size of the dots is proportional to the number of effect sizes included in those studies.

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C. Wesarg et al. Neuroscience and Biobehavioral Reviews 143 (2022) 104920

was likely to contribute to the overall lack of association in both meta- studies included in our meta-analysis did not assess respiration, a gen­
analyses. Given the reliance on a three-level meta-analytic model, we eral recommendation is to monitor respiration to ascertain that partic­
were able to include multiple effect sizes per study, thereby allowing for ipants were breathing at a normal rate corresponding to the HF band
the examination of different adversity types that can vary within studies. (Laborde et al., 2017). Besides the study of physiological reactivity to
Further, researchers interested in conducting more nuanced analyses challenge, future studies on childhood adversity should additionally
such as comparing different abuse subtypes or testing for moderators address individual differences in the recovery period after the challenge
within specific adversity types are referred to the Supplemental Material (see e.g., McLaughlin et al., 2014), as impairments in physiological re­
in which the data set and script for statistical analyses are provided. covery have previously been associated with psychopathology (Burke
Another strength portrays the rigorous testing of the significance of in­ et al., 2005). Further, as adversity does not necessarily end at the
dividual moderators by combining them in a unique moderator model. transition from adolescence to adulthood, longitudinal studies testing
The present work has several limitations as well. First, we focused on stress sensitization effects on vagal (re)activity are recommended.
only one specific aspect of ANS functioning, while other indices Likewise, prenatal and post-natal adversities often co-occur (Lebel et al.,
reflecting the functioning of the parasympathetic and sympathetic 2019), posing the challenge for future investigations to determine how
branch (or a combination of both) may be uniquely influenced by these exposures uniquely, cumulatively and/or interactively contribute
childhood adversity, including the ratio between low- and high- to psychobiological and health outcomes. Another important issue for
frequency power (LF/HF), blood pressure, skin conductance, and heart future research is to identify under which circumstances adversity ulti­
rate (Appleton et al., 2017; Misiak et al., 2015; Tell et al., 2021; Voell­ mately leads to aberrations in vagal functioning, identifying individual
min et al., 2015; Wiltshire et al., 2022). Second, we did not include effect and environmental factors of resilience.
sizes on the association between childhood adversity and vagal recovery
after challenge. While poor cardiovascular recovery following stress 5.6. Conclusions
may be more relevant for the development of pathology than stress
reactivity itself (Panaite et al., 2015), not many studies have specifically In conclusion, although meta-analytic results did not reveal a sig­
investigated recovery (for an exception, see e.g., McLaughlin et al., nificant association between childhood adversity and vagal regulation,
2014). Third, we did not account for factors that can influence vagal such an association may be present under certain circumstances. More
functioning, including smoking, alcohol consumption, meal intake, specifically, lower levels of baseline vagal activity were found in asso­
physical training, and daytime (Laborde et al., 2017). While several ciation with childhood adversity in samples including participants with
studies implemented specific instructions in the study protocol for clinical diagnoses and in association with direct adversity (including
handling these issues, others statistically corrected for potential con­ maltreatment, adverse parenting and peer victimization). Further, the
founds or did not report on it. Given these different approaches, we association between childhood adversity and lower levels of vagal
relied on raw correlations between childhood adversity and vagal reactivity was stronger when adversity had occurred longer ago and
regulation to avoid potential variability in methodology. Last, a major when reactivity scores were operationalized through task mean levels.
drawback that specifically applies to the reactivity meta-analysis was More research is needed to gain an integrated understanding of bio­
that effect sizes based on correlations between adversity and vagal logical mechanisms underlying the association between childhood
reactivity failed to do justice to the fact that adversity-related alterations adversity and (psycho)pathology, factors of vulnerability and resilience
may pertain to both vagal augmentation and vagal withdrawal. Put along this pathway, and the malleability of physiological systems
simply, while some individuals exposed to adversity may react to chal­ following intervention.
lenges with excessive vagal withdrawal, others may demonstrate
excessive vagal augmentation, and approaches such as group compari­ Other information
sons or correlations would conceal these more specific alterations in
vagal reactivity. As an alternative, a pattern-based approach to vagal This meta-analysis was pre-registered on the 15th of September 2020
reactivity may be more suitable to capture heterogeneity in through a web-based protocol on the International Prospective Register
adversity-related alterations in vagal reactivity. Applying such an of Systematic Reviews (PROSPERO; Booth et al., 2012) before study
approach, Cui et al. (2019) found that neighborhood violence was selection (registration number: CRD42020198115). Amendments to
positively associated with aggressive behavior only in those adolescents information provided at registration are reported in the online Supple­
who showed RSA augmentation to a film clip portraying bullying but not mental Material. Further, data sets and scripts for statistical analyses can
in those who showed RSA suppression. be found online (link for peer review:).

5.5. Recommendations for future studies Declaration of Competing Interest

To date, meta-analyses on psychobiological correlates of childhood The authors declare that they have no competing financial interests.
adversity have commonly focused on a single biological system such as
the PNS (Sigrist et al., 2021), the HPA axis (Bernard et al., 2018; Bunea Data Availability
et al., 2017; Fogelman and Canli, 2018), or the immune system (Kuhl­
man et al., 2020). However, it is possible that alterations only become The datasets used in both meta-analyses and corresponding scripts
apparent at the level of interaction between multiple biological systems. for statistical analyses are available online (https://osf.io/cuynb/).
To exemplify, it has been proposed that the degree of covariation be­
tween psychological arousal, the HPA axis, and inflammation may Acknowledgements
predict long-term health outcomes after adversity (Kuhlman et al.,
2017). More studies are needed that incorporate the measurement of This work was supported by the UvA-FMG Research Priority Area
multiple systems in the same sample to advance the understanding of (RPA) Yield. We would like to thank all students for their great help in
how childhood adversity increases risk for later (psycho)pathology (see the study screening and data extraction process: Isabel Boerrigter,
e.g., Goulter et al., 2021; Rudd et al., 2021). Given common reliance on Kimberley Booij, Xin Lin Chia, Anouk de Vries, Coen Koevoet, Michaela
time- and frequency domain (linear) measures of vagal regulation, the Ohme and Femke Schipmölder. Further, we are grateful to all authors
inclusion of nonlinear measures of HRV that would capture potential and their student assistants who responded to our manuscript or data
alterations in the structure or complexity of the IBI time series is an requests: Erinn Bernstein Duprey, Lourdes Dale, Maria Densmore, Mona
important issue for future research (Kleiger et al., 2005). As many of the El-Sheikh, Lynn Fainsilber Katz, Nashla Feres, Tiffany Field, Anne

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C. Wesarg et al. Neuroscience and Biobehavioral Reviews 143 (2022) 104920

Fletcher, Ryan Giuliano, Sarah Gray, Melissa Hagan, Sari Herzog, Jes­ Boyce, W.T., Levitt, P., Martinez, F.D., McEwen, B.S., Shonkoff, J.P., 2021. Genes,
environments, and time: the biology of adversity and resilience. Pediatrics 147 (2).
sica Jenness, Michael Kaess, Julian Koenig, Ruth Lanius, Sihong Liu,
https://doi.org/10.1542/peds.2020-1651.
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