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Biological Psychology 110 (2015) 167–174

Contents lists available at ScienceDirect

Biological Psychology

jo ur nal home p age: www.elsev ier .com/ locate /b iopsycho

uvenile onset depression alters cardiac autonomic balance inesponse to psychological and physical challenges

auren M. Bylsmaa,∗, Ilya Yaroslavskyb, Jonathan Rottenbergc, J. Richard Jenningsa,harles J. Georgea, Eniko Kissd, Krisztina Kapornaid, Kitti Halasd, Roberta Dochnald,szter Lefkovicsd, István Benákd, Ildikó Bajid, Ágnes Vetród, Maria Kovacsa

University of Pittsburgh, Pittsburgh, PA, United StatesCleveland State University, Cleveland, OH, United StatesUniversity of South Florida, Tampa, FL, United StatesUniversity of Szeged, Szeged, Hungary

r t i c l e i n f o

rticle history:eceived 18 October 2014eceived in revised form 29 April 2015ccepted 7 July 2015vailable online 29 July 2015

eywords:

a b s t r a c t

Cardiac autonomic balance (CAB) indexes the ratio of parasympathetic to sympathetic activation(Berntson, Norman, Hawkley, & Cacioppo, 2008), and is believed to reflect overall autonomic flexibil-ity in the face of environmental challenges. However, CAB has not been examined in depression. Weexamined changes in CAB and other physiological variables in 179 youth with a history of juvenile onsetdepression (JOD) and 161 healthy controls, in response to two psychological (unsolvable puzzle, sadfilm) and two physical (handgrip, and forehead cold pressor) challenges. In repeated measures analyses,controls showed expected reductions in CAB for both the handgrip and unsolvable puzzle, reflecting a

ardiac autonomic balanceardiac autonomic regulationarasympathetic nervous systemympathetic nervous systemuvenile onset depressioneactivity

shift to sympathetic relative to parasympathetic activation. By contrast, JOD youth showed increased CABfrom baseline for both tasks (p’s < .05). No effects were found for the forehead cold pressor or sad filmtasks, suggesting that CAB differences may arise under conditions requiring greater attentional controlor sustained effort.

© 2015 Elsevier B.V. All rights reserved.

elf regulation

Abnormalities in autonomic nervous system functioning haveeen associated with depression. More specifically, there is qual-

fied support for an association between major depression indults and low resting parasympathetic nervous system (PNS)ctivity, as indexed by resting levels of respiratory sinus arrhyth-ia, with mostly positive (RSA; Kemp et al., 2010; Kikuchi et al.,

009; Rottenberg, 2007; Udupa, Sathayaprabha, Thirthalli, Kishore,avekar, et al., 2007; Udupa, Sathayaprabha, Thirthalli, Kishore,aju, et al., 2007) but some negative results (e.g., Lehofer et al.,997; Licht et al., 2008; Yeragani et al., 1991). More consistent find-

ngs have been observed for RSA reactivity in response to laboratoryasks, with depressed adults exhibiting blunted RSA withdrawal to

laboratory speech stressor (Bylsma, Salomon, Taylor-Clift, Morris, Rottenberg, 2014; Rottenberg, Clift, Bolden, & Salomon, 2007), as

ell as a handgrip task (Nugent, Bain, Thayer, Sollers, & Drevets,

011). These patterns are postulated to relate to poorer self regu-ation. Elsewhere, we have found that atypical patterns of resting

∗ Corresponding author at: Department of Psychiatry, University of Pittsburgh,811 O’Hara St., Pittsburgh, PA 15213, United States.

E-mail address: BylsmaL@pitt.edu (L.M. Bylsma).

ttp://dx.doi.org/10.1016/j.biopsycho.2015.07.003301-0511/© 2015 Elsevier B.V. All rights reserved.

RSA and RSA reactivity in youths with a history of juvenile onsetdepressed predicted deficits in mood repair, where mood repairrefers to behaviors that decrease feelings of sadness or dyspho-ria (e.g., Josephson, Singer, & Salovey, 1996), as assessed by bothtrait measures and laboratory probes (Yaroslavsky et al., 2015)).We have also found that atypical patterns of resting RSA and RSAreactivity are more highly concordant in siblings with a history ofdepression, suggesting that aspects of autonomic functioning maybe heritable (Yaroslavsky, Rottenberg, & Kovacs, 2014).

To a lesser extent, abnormalities in sympathetic nervous sys-tem (SNS) activity have also been observed in depressed adults.For example, Saloman, Clift, Karlsdottir, and Rottenberg (2009) andSalomon, Bylsma, White, Panaite, and Rottenberg (2013) foundblunted sympathetic nervous system (SNS) reactivity to a labora-tory stressor task, as indexed by lengthened pre-ejection period(PEP), although others have found shorter PEP in individuals withdepressive symptoms (Light, Kothandapani, & Allen, 1998). Overall,research thus far reveals mixed evidence of PNS and SNS deficits in

depression.

To date, depression research has focused almost exclusively onindividual parasympathetic or sympathetic indices. This exclusivefocus is unfortunate in light of recent theory argues arguing for

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68 L.M. Bylsma et al. / Biologica

he critical importance of integrating sympathetic and parasym-athetic control to provide a comprehensive understanding ofehavioral and affective reactivity and regulation (Berntson,acioppo, & Quigley, 1991). In fact, the historical views of recip-ocally determined activity in both branches of the autonomicervous system (e.g., activity increases in one branch would beccompanied by invariable decreases in the other) have beenargely overturned by new theory and data, which indicatehat both autonomic branches can react either independently orogether, resulting in complex physiological patterns, includingo-activation and co-inhibition (Berntson et al., 1991, 2008). Impor-antly, theory and empirical evidence have indicated that reciprocalympathetic activation (increases in sympathetic activity in con-unction with decreases in parasympathetic activity) during stressesponses are ordinarily adaptive, whereas reciprocal parasympa-hetic activation would be most adaptive in calm and relaxed statesBerntson et al., 1994; El-Sheikh et al., 2009). Thus, examination ofhe balance of parasympathetic and sympathetic activity may leado a more complete picture of regulatory functioning and risk forepression.

Berntson et al. (2008) has previously defined two useful indicesor describing complex patterns in autonomic space: cardiac auto-omic balance (CAB) and cardiac autonomic regulation (CAR).hese indices are derived from a parasympathetic index, RSA, and

sympathetic index, PEP. RSA is a parasympathetically mediatedariation in heart rate that is germane to individual differencesn emotional functioning and regulation capacity in adults andouth (e.g., Beauchaine, 2001; Musser et al., 2011; Yaroslavsky,ylsma, Rottenberg, & Kovacs, 2013; Yaroslavsky et al., 2014). PEP

s a sympathetically mediated index that reflects the time betweeneft ventricular depolarization and ejection of blood through theorta, with smaller values indicating greater SNS activity (Berntsont al., 1994). PEP has been viewed as an index of effort mobiliza-ion needed to meet environmental demands (with decreases inEP reflecting increased effort mobilization) required for behav-oral approach (Gendolla, 2012; Kelsey, 2012; Richter & Gendolla,009; Richter, Friedrich, & Gendolla, 2008), and it has been vali-ated as a SNS index in children and adolescents (e.g., Matthews,alomon, Kenyon, & Allen, 2002; McGrath & O’Brien, 2001; Quigley

Stifter, 2006).CAB is computed as the difference between standardized values

f parasympathetic control (RSA) and sympathetic control (PEP)long a bipolar model of autonomic balance. Therefore, higher CABalues reflect greater parasympathetic relative to sympathetic acti-ation. CAR reflects the coactivation or coinhibition of PNS andNS activity and is computed as the normalized sum of RSA andEP. Autonomic dysregulation is often described as overactive SNSnd hypoactive PNS (i.e., lower CAB), which has been associatedith coronary artery disease, increased mortality (for a review, see

hayer, Yamamoto, & Brosschot, 2010), increased risk of metabolicyndrome (Licht, de Gues, & Penninx, 2013), diabetes (Berntson,orman, Hawkley, & Cacioppo, 2008) and chronic stress states

Lampert, Ickovics, Horwitz, & Lee, 2005), and may serve as a linketween negative affect and disease states (Thayer et al., 2010).igh CAR (high PNS and CNS coactivation) has also been associatedith increased risk for metabolic syndrome (Licht et al., 2013) andrior occurrence of myocardial infarction (Berntson et al., 2008).

While CAB and CAR represent potentially useful indices ofutonomic system functioning that reflect autonomic flexibility,hey have not yet been examined in the context of depressionr depression risk. Prior depression-related work with joint auto-omic indices used metrics that have limited interpretability, such

s LF/HF ratio (the ratio of low to high frequency heart rate variabil-ty; Malliani, 2005; Malliani & Montano, 2002). While depressednd depression-vulnerable persons have been found to have aigher LF/HF ratio (Chang et al., 2012; Nugent et al., 2011; Udupa,

hology 110 (2015) 167–174

Sathayaprabha, Thirthalli, Kishore, Lavekar, et al., 2007; Udupa,Sathayaprabha, Thirthalli, Kishore, Raju, et al., 2007), LF is anambiguous sympathetic index because, as it is currently defined,LF is contaminated by parasympathetic activity (Berntson et al.,1997; Eckburg, 1997; Reyes del Paso, Langewitz, Mulder, van Roon,& Duschek, 2013). Further, as Heathers (2014) explains, there is nosound mathematical basis to directly compare LF and HF power,as these measures are only internally consistent (i.e., examin-ing changes over time within an individual), so that comparingtheir relative proportions is questionable. In addition, possible co-activations in the sympathetic and parasympathetic branches arealso not taken into account for the LF/HF ratio (Pagani, Lucini, &Porta, 2012).

CAB has been studied once in a depression-relevant sample:Miller, Wood, Lim, Ballow, and Hsu (2009) found that childrenwith asthma who were high on depression symptoms showedgreater increases in CAB in response to films depicting distressingscenes of loss, death, and dying (greater increases in PNS relativeto SNS activity). In contrast, asthmatic children low on depres-sive symptoms showed the normative pattern of response to stress(greater decreases in CAB—greater increase in sympathetic relativeto parasympathetic activity), which the authors indicated wouldbe most adaptive for airway functioning in these patients. CAR,which reflects the co-activation of sympathetic and parasympa-thetic activity, has yet to be studied in depression.

The present study focused on cardiac autonomic balance (CAB)in youths with histories of early onset depression and healthycontrols with no history of depression. We examined CAB duringbaseline (viewing a neutral film) and across two physical and twopsychological stressor tasks. We expected that the tasks (unsolv-able puzzles, handgrip, sad film, and forehead cold pressor) woulduncover group differences in psychophysiological reactivity. Instudies with healthy individuals, the typical normative responseto most laboratory stressors is a decrease in RSA accompaniedby an increase in sympathetic relative to parasympathetic activ-ity (Key, Campbell, Bacon, & Gerin, 2008; Lackschewitz, Hüther, &Kröner-Herwig, 2008; O’Donnell, Brydon, Wright, & Steptoe, 2008).However, since the forehead cold pressor task elicits a “dive reflex”,which is typically accompanied by activation of the PNS system(Heath & Downey, 1990), we would expect increases in RSA (andlikely increases in CAB) in response to this task. Since previous find-ings have suggested that abnormalities in PNS and SNS activationare associated with depression, we predicted that youth with sucha history will fail to show appropriate changes in CAB in responseto the stressor tasks. In other words, we expected that healthy con-trols would show decreases in CAB for the sad film, puzzle, andhandgrip tasks or increases in CAB for the forehead cold pressor,while youth with a history of depression would fail to show thesechanges. As a point of comparison, we also examined effects forthe LF/HF ratio, which has been considered another index of auto-nomic balance. Finally, we included Cardiac Autonomic Regulation(CAR) as a secondary, exploratory measure, given the lack of priorempirical literature.

1. Methods

1.1. Subjects

This study included 216 probands whose histories of childhood onset majordepressive disorder (MDD) were previously established (e.g., Baji et al., 2009; Kisset al., 2007). The probands are a subset of a larger sample, which were gatheredin Hungary from approximately 1997–2006 for a prior genetic and clinical study(e.g., Baji et al., 2009; Dempster et al., 2009; Tamás et al., 2007). Probands for the

original study were recruited at 23 child mental health and guidance facilities acrossHungary and met several study entry criteria, including having current or recentDSM-IV (American Psychiatric Association, 2000) depressive disorder, being 7–14years old at initial screen, and not mentally retarded. Six probands who came fromfamilies with a history of mania were excluded from analyses. Mean age of the

L.M. Bylsma et al. / Biological Psych

Table 1Characteristics of sample.

% Male Age (SD) BMI (SD)

Probands 64.1 17.0 (1.40) 22.12 (4.77)Controls 64.1 16.1 (2.13) 21.57 (4.29)

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roband sample at the current assessment was 17.0 (SD = 1.40, Range = 11.6–19.1)nd 64.1% were male. Mean age at onset of first MDD episode in the proband youthas 9.07 years (SD = 1.89 years). At the diagnostic assessment for the current study,

8.6% had one MDD episode, 31.9% had 2 episodes, and 9.5% had 3 or more episodes;79 subjects were in full remission from their most recent MDD episode, while1 (14.8%) were currently in a depressive episode. Rates of comorbid psychiatricisorders of probands were as follows: 18.6% dysthymic disorder, 39% any anxietyisorder, 37.6% any behavioral disorder (e.g., ADHD, oppositional defiant disorder).verall, 71% had at least one comorbid psychiatric disorder. Seven probands were

aking psychotropic medications at the time of the psychophysiological assessment.The current study also includes 161 healthy control peers who never had any

ajor psychiatric disorder. Controls were identified in medium size public elemen-ary and secondary schools in the 3 cities in which most of the proband in the currenttudy resided. Controls were recruited to approximate the sex and age distributionf probands. Mean age of the control sample at the current assessment was 16.1SD = 1.40, Range = 11.2–19.0) and 64.1% were male (see Table 1).

.2. Procedure overview

This study was approved by the institutional review boards of the Univer-ity of Pittsburgh and the Hungarian clinical research sites. Parents providedritten informed consent, and youth provided either assent or consent (depend-

ng on their ages) before any data were gathered. Study visits included asychiatric–psychosocial evaluation, the completion of self- and parent-rated ques-ionnaires, and an experimental protocol with psychophysiological recordings.ollowing the questionnaires, the adolescent was familiarized with the experi-ental procedures and equipment. All procedures, schedules, rating scales, and

nstruments used in this study were first developed in English, were translatednto Hungarian, and then back translated by bi-lingual child psychiatrists and clin-cal psychologists. Original and back-translated versions were compared, with anyiscrepancies resolved using an iterative procedure.

.3. Diagnostic assessment

As described previously (e.g., Kiss et al., 2007; Tamás et al., 2007), casenessor each proband was established during the original study via a stringent proce-ure that included standardized psychiatric diagnostic evaluations (involving theouth and a parent informant) by trained interviewers (child psychiatrists and psy-hologists), each of whom generated DSM-IV mood-disorder diagnoses, and a finalest-estimate diagnosis (Maziade et al., 1992). DSM-IV diagnoses were based onhe ISCA-D, a semi-structured interview derived from the ISCA (Sherrill & Kovacs,000), which has been described in detail in previous publications (Baji et al., 2009;iss et al., 2007). We have previously reported acceptable inter-rater reliabilityoefficients on the ISCA-D symptom ratings (.63–.92 for current MDD from childnterviews and .65–.87 from parent interviews; Kiss et al., 2007).

.4. Physiological protocol

This study was part of a larger physiological protocol that included a variety oftress reactivity and mood induction tasks. Here we report on a portion of the proto-ol that included a neutral film (baseline comparison for all tasks), two psychologicaltressors (sad film, unsolvable puzzle) and two physical stressors (handgrip, fore-ead cold pressor), described in detail below. In other work with this sample, wexamined RSA patterns of resting RSA and RSA reactivity associated trait mood repairnd mood repair success in the lab following the sad film (Yaroslavsky et al., 2014).he order of the stressors (task order) was randomized into four possible orders withuffer periods in between. Participants were asked to avoid any allergy, cold/flue, orsthma medications the morning of the physiological protocol, and to refrain fromrinking any caffeinated beverages, smoking or engaging in heavy exercise within

h of beginning the physiological protocol.Neutral film. In order to provide an estimate of physiological functioning at rest

Jennings, Kamarck, Stewart, Eddy, & Johnson, 1992), participants viewed a 180 seutral film that depicted fish swimming in an aquarium.

Sad film. We administered a 164 s sad film clip from the movie “The Champ” thatepicts a grief-stricken child observing the death of his boxer champion father after

boxing match (Rottenberg, Gross, & Gotlib, 2005; Rottenberg et al., 2007).Unsolvable puzzle. Subjects completed a task where they tried to re-recreate a

attern on a computer screen. Specifically, subjects had to move pieces (horizontallyr vertically) containing letters of the alphabet to duplicate a displayed pattern.

practice puzzle that was easily solvable was first given to ensure that subjects

ology 110 (2015) 167–174 169

understood the task (15 s). Next, two different unsolvable puzzles were given, whichwere programmed in such a way that the solution was impossible (i.e., mirroringCole et al., 2007; Nolen-Hoeksema, Wolfson, Mumme, & Guskin, 1995). Unsolvablepuzzle tasks have been shown to induce negative affect (sadness, frustration) andparasympathetic withdrawal (e.g., Perry, Calkins, Nelson, Leerkes, & Marcovitch,2012). Subjects were given 360 s to work on the unsolvable puzzles (180 s for eachunsolvable puzzle).

Handgrip. Subjects were asked to squeeze a hand dynamometer at 30%Maximum Voluntary Contraction for 120 s. This task elicits a reduction in parasym-pathetic activity (RSA withdrawal), which may also occur in combination withincreased sympathetic activity (e.g., Freyschuss, 1970; Martin et al., 1974; Nutter,Schlant, & Hurst, 1972; Pollak & Obrist, 1988; Miller, 1994) and has been used suc-cessfully in our age group (e.g., Kelsey, Patterson, Barnard, & Alpert, 2000; Matthews,Woodall, & Stoney, 1990).

Forehead cold pressor. We administered a 60 s forehead cold pressor as follows:While the participant was receiving the instructions for the forehead cold pressor,an ice bag was prepared by filling a plastic bag (25 cm × 18 cm) with 2 dl of roomtemperature tap water and 4 ice cubes (approximately 3.5 cm in diameter each).The room air temperature was held at a consistent temperature across study sites,between 22 and 24 ◦C. The ice bag sat on top of the cooler with the water and icemixture for approximately 5 min before applying it to the participant’s forehead. Thetemperature of the ice bag at the time of application was approximately 8–10 ◦C. Thisversion of the forehead cold pressor been used successfully with children in previ-ous studies (Matthews et al., 2002). This task evokes parasympathetically mediatedheart rate deceleration and is an effective means to stimulate the “dive reflex” (e.g.,Heath & Downey, 1990; Reyners et al., 2000).

1.5. Psychophysiological recording

Physiological data were recorded continuously throughout the protocol. TheECG signal was acquired according to published guidelines (Jennings et al., 1981)using Cleartrace LT disposable Ag/AgCL electrodes (Conmed Andover Medical,Haverhill, MA) placed in a modified Lead II configuration on the chest. We collectedimpedance cardiography using spot electrodes according to the guidelines outlinedby Sherwood (1990). All ECG and dZ/dt signals were sampled online at 1000 Hz usinga Mindware BioNex system with associated BioLab software. The dZ/dt signals wereensemble-averaged over the length of the experimental epochs defined for eachtask. The data were screened for artifact by visual inspection. Psychophysiologicaldata were processed and analyzed as a single epoch for each task.

1.6. Measures

Body mass index (BMI). Since BMI is known to impact SNS reactivity and CAB, wemeasured it to include as a covariate in analyses. Subjects’ height and weight wereobtained at the beginning of the physiological assessment. BMI was calculated asweight in kg/(height in m2). BMI raw scores were Z-transformed for analyses. SeeTable 1 for descriptive information.

Respiratory sinus arrhythmia (RSA) and LF/HF ratio. RSA was calculated usingMindWare HRV 3.0.21 software (MindWare Technologies, Ltd., Gahanna, OH).R-wave markers in the ECG signal were processed with the MAD/MED artifactdetection algorithm (Berntson, Quigley, Jang, & Boysen, 1990) implemented by theMindWare software. The signals were manually inspected and suspected artifactswere corrected. Our approach accords with current guidelines for frequency domainmethods to determine heart rate variability and is well suited for short-term recor-dings (Berntson et al., 2008; Lombardi & Malliani, 1996). To estimate heart rate andRSA during baselines and tasks (using the entire task epoch for each task), a timeseries of interbeat intervals (IBIs: the time in milliseconds between sequential ECGR-spikes) was created from an interpolation algorithm. This IBI time series was (a)linearly detrended, (b) mean-centered, and (c) tapered using a Hanning window.Spectral-power values were determined (in ms2/Hz) with fast Fourier transforma-tions, and the power values in the 0.15–0.50 Hz spectral bandwidth were integrated(ms2). These spectral-power values were natural-log transformed prior to statisticalanalyses because of distributional violations. Our indicator of RSA was defined as theNatural-logged (ln) spectral-power value in the high frequency (HF) 0.15–0.50 Hzbandwidth, and LF was defined by the spectral power in the low frequency .04–.15 Hzbandwidth (see Berntson et al., 1997). For purposes of comparison, LF/HF ratio wascomputed using the ratio of the raw LF and HF values.

Pre-ejection period (PEP). The impedance-derived measure of PEP was derivedusing MindWare IMP 3.0.1 software (MindWare Technologies, Ltd., Gahanna, OH)based on the dZ/dt signal. Specifically, PEP was quantified as the time interval (inmilliseconds) from the onset of the ECG Q wave to the B point (corresponding tothe opening of the aortic value) of the dZ/dt wave (Sherwood, 1990). The max slopemethod was used to place the B point, which was adjusted manually based uponvisual inspection.

Cardiac autonomic balance (CAB) and cardiac autonomic regulation (CAR). CAB and

CAR were computed based on Berntson et al. (2008). Following Berntson’s proce-dure, we first normalized RSA and PEP by transforming these values to z-scores,due to the differences in scaling of these measures. Because greater sympatheticactivity is associated with shortened (lower) PEP values, PEP was multiplied by−1 in order to invert the relationship to a positive association (where greater PEP

170 L.M. Bylsma et al. / Biological Psychology 110 (2015) 167–174

Table 2Characteristics of the unadjusted psychophysiological variables (means; standard deviations) by group and task.

Probands Controls

Baseline Cold Sad Handgrip Unsolvable Baseline Cold Sad Handgrip Unsolvable

HR 72.16 (10.32) 65.52 (9.11) 68.78 (9.52) 77.91 (10.67) 73.96 (9.93) 75.12 (11.49) 67.94 (10.98) 70.88 (11.17) 81.07 (11.69) 77.03 (11.63)RSA 6.58 (1.06) 6.89 (1.17) 6.47 (1.08) 6.31 (1.02) 6.53 (1.00) 6.71 (1.01) 7.03 (1.16) 6.55 (1.07) 6.33 (1.05) 6.48 (0.91)PEP 126.21 (14.01) 124.52 (14.61) 125.58 (13.56) 122.77 (14.60) 122.85 (14.61) 123.53 (14.09) 122.27 (15.03) 123.42 (14.09) 117.12 (14.74) 119.48 (14.90)CAB .13 (1.32) .02 (1.18) .09 (1.30) .18 (1.38) .20 (1.35) −.00 (1.19) .04 (1.79) −.05 (1.32) −.17 (1.33) −.15 (1.33)CAR −.25 (1.42) .03 (1.18) .09 (1.30) .18 (1.38) .20 (1.35) −.01 (1.37) .07 (1.89) −.05 (1.30) .12 (1.32) −.06 (1.30)LF/HF 1.53 (1.71) .85 (1.15) 1.38 (1.50) 1.31 (1.26) 1.67 (1.29) 1.21 (1.27) .71 (1.00) 1.08 (1.09) 1.11 (1.11) 1.42 (.97)

N , CAB = cardiac autonomic balance, CAR = cardiac autonomic regulation, LF/HF = low fre-q

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Fig. 1. RSA changes from baseline across tasks by group. Note: Covariates appearingin the model are evaluated at the following values: body mass Z-score = −.0790, ageyears = 16.6057, RSA baseline = 6.6305.

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alues indicate greater sympathetic activity, just as greater RSA values indicatereater parasympathetic activity). Since CAB provides a measure of the balancef parasympathetic to sympathetic activation, CAB was computed using the for-ula: CAB = RSAz − (−PEPz). Consequently, greater CAB values indicate greater

arasympathetic relative to sympathetic activation, and lower CAB values indi-ate greater sympathetic relative to parasympathetic activation. Since CAR reflectshe co-activation of the parasympathetic and sympathetic systems, CAR was com-uted as: CAR = RSAz + (−PEPz). As a result, greater CAR values indicate greatero-activation.

Statistical analyses. First, in preliminary analyses to determine whether thereere any group baseline differences, we used one-way ANCOVAs for each physio-

ogical variable (RSA, PEP, CAB, CAR, and LF/HF) during the neutral film, with groupnd sex as between subjects factors and age and BMI as continuous covariates (seeable 1). The effects of age, sex, and BMI were statistically controlled in all analy-es based on previous literature showing that PNS and SNS activity are significantlynfluenced by these individual characteristics (Berntson et al., 2008). Age and BMI

ere entered as continuous covariates, while sex was added as a between-subjectsategorical factor in all models. Next, we conducted a series of repeated measures

(proband vs. control) × 4 (sad film, forehead cold pressor, handgrip, unsolvableuzzles). ANCOVAS were used for each task for each physiological dependent vari-ble. First we examined RSA, LF/HF Ratio, and PEP as the dependent physiologicalariables. Then we examined CAB and CAR as the dependent variables (as thesere computed using RSA and PEP). In these analyses, we also included means of thehysiological variables during the baseline neutral film to adjust for baseline effects,s well as task order (4 possible task orders) to account for potential confoundingy task order effects. Subjects lacking analyzable data for all tasks included in thenalyses for a particular physiological variable (i.e., due to data acquisition issues oroisy data) were dropped from analyses as follows: RSA = 4 missing, PEP = 8 missing,F/HF = 8 missing). CAB and CAR analyses only included subjects with complete RSAnd PEP data.

. Results

Physiological variable means and standard deviations areeported in Table 2 by group and task. Preliminary analysesevealed no statistically differences between probands and con-rols for any of the physiological variables during the neutral filmaseline: (PEP: F(1,394) = .96, p = .32; RSA: F(1,397) = 1.89, p = .17;F/HF ratio: F(1,397) = 2.67, p = .10; CAB: F(1,394) = .06, p = .81; CAR:(1,394 = 1.29, p = .26), although there was a trend effect for LF/HFatio with probands having slightly higher values relative to con-rols.

Next, we used repeated measures ANCOVA (described in detailbove) to examine whether group status predicted changes in RSAnd PEP. For RSA (Fig. 1), the linear group by time interactionid not reach significance (F(1,385) = 2.24, p = .135), indicating thathe groups did not differ in their change in RSA across the tasks.imilarly, for LF/HF Ratio (Fig. 2), the linear group by time inter-ction did not reach significance (F(1,385) = .029, p = .87). Thereere also no quadratic or cubic effects for RSA or LF/HF. By con-

rast, for PEP (Fig. 3), analyses yield significant group by time linearF(1,373) = 7.51, p = .006) and cubic (F(1,373) = 8.01, p = .005) effects.ollow-up LSD pairwise comparisons revealed that controls exhib-

ted greater decreases in PEP relative to probands to the handgripmean difference = 3.10, 95% CI: 1.30–4.9, p = .001), indicating thatontrols had greater increases in SNS in response to the handgripask.

Fig. 2. LF/HF ratio changes from baseline across tasks by group. Note: Covari-ates appearing in the model are evaluated at the following values: body massZ-score = −.0790, age years = 16.6057, LF/HF ratio baseline = 1.3858.

We then conducted repeated measures ANCOVA to examinewhether group status predicted changes in CAB and CAR. Theanalysis for CAB (Fig. 4), yielded a significant linear group bytime interaction (F(1,373) = 8.71, p = .003). Follow-up LSD pairwisecomparisons revealed significant group differences for both theunsolvable puzzles (mean difference = 0.217, 95% CI: 0.039–0.395,

p = .017) and handgrip tasks (mean difference = 0.428, 95% CI:0.048–0.428, p = .014), such that probands exhibited increased CABrelative to controls. Specifically, for both unsolvable puzzle andhandgrip tasks, controls showed task-appropriate decreases in CAB,

L.M. Bylsma et al. / Biological Psychology 110 (2015) 167–174 171

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Fig. 3. PEP changes from baseline across tasks by group. Note: Covariates appearingin the model are evaluated at the following values: body mass Z-score = −.0781, ageyears = 16.5987, PEP baseline = 124.8564.

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Fig. 4. CAB changes from baseline across tasks by group. Note: Covariates appearingiy

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and sympathetic activation) to these tasks. Our findings are gener-

n the model are evaluated at the following values: body mass Z-score = −.0781, ageears = 16.5987, CAB baseline = .0619.

hile probands showed unexpected increases (greater PNS relativeo SNS activation. For CAR (Fig. 5), there was a marginally signifi-ant quadratic group by time interaction (F(1,373) = 3.50, p = .062).ollow-up LSD pairwise comparisons revealed a significant groupifference for the handgrip task only (mean difference = −.197, 95%I: −.379 to −.014, p = .034), such that probands exhibited reducedAR to the handgrip relative to controls. More specifically, controlshowed an increase in CAR to the handgrip (reflection greater SNSnd PNS coactivation), while probands showed a reduction in CARreflecting less SNS and PNS coactivation). There were no significantroup differences on CAR for any of the other tasks.

Because some probands were currently in a depressive episode,e conducted follow-up analyses of CAB and CAR to examine the

mpact of current depression by modeling it as a dummy codedariable (0 = no current depression, 1 = current depression). Cur-ent depression status was significantly related to changes in CARF(1,372) = 6.61, p = .011). Although the follow up pairwise com-arisons did not reach significance, the pattern of results suggestshat probands with current depression showed greater differencesn their changes in CAR in comparison to controls relative to

robands without current depression. Further, the quadratic groupy time interaction lost significance with current depression sta-us in the model (F = 2.05, p = .15). In contrast, current depression

Fig. 5. CAR changes from baseline across tasks by group. Note: Covariates appearingin the model are evaluated at the following values: body mass Z-score = −.0781, ageyears = 16.5987, CAR baseline = −.1337.

status was not related to changes in CAB (F(1,372) = .168, p = .682),and the linear group by time interaction remained significant(F(1,372) = 8.65, p = .003), as well as the follow-up pairwise compar-isons for handgrip (p = .024) and unsolvable puzzles (p = .003), withresults showing the same pattern of findings. In additional follow-up ANCOVA comparing currently depressed and remitted probandson changes in CAB and CAR, there was also no significant groupby time interaction for CAB (F(1,202) = .20, p = .66). However, cur-rent and remitted probands did significantly differ on CAR (F = 5.04,p = .026), although follow-up pairwise comparisons did not reachsignificance, which may have been due to lack of power to detecteffects in the smaller sample subset.

3. Discussion

Depression has been related to abnormal autonomic nervoussystem functioning and deficits in self-regulation. An adaptive,flexible autonomic nervous system should allow for rapid modu-lation of physiological and emotional states, including deploymentof attention and effortful processes that are critical for effectiveemotion regulation. It has been proposed that examination of thebalance of PNS and SNS activity may lead to a more complete pic-ture of regulatory functioning (Berntson et al., 1991, 2008). CardiacAutonomic Balance (CAB; Berntson et al., 2008) has been proposedas a useful index to capture the relative balance of PNS to SNS acti-vation that may reflect autonomic control better than individualmeasures of PNS and SNS. In this study, we examined changes inCAB in response to a series of stressful laboratory tasks in youthswith a history of juvenile onset depression and control peers. Inexploratory analyses, we also examined Cardiac Autonomic Regu-lation (CAR; Berntson et al., 2008), another autonomic index thatreflects the mutual co-activation of the PNS and SNS.

Partially consistent with predictions, we found that probandswith a history of juvenile onset depression exhibited abnormal-ities in CAB relative to controls, when facing selected stressors.Specifically, probands exhibited increases in CAB to the handgripand unsolvable puzzle tasks relative to baseline (reflecting rel-ative parasympathetic activation and sympathetic withdrawal).In contrast, controls showed the expected normative pattern ofdecreases in CAB (reflecting relative parasympathetic withdrawal

ally consistent with Miller et al. (2009), who reported a similarlyatypical response pattern to a laboratory stressor among asthmaticyouth with depressive symptoms, while nondepressed asthmatic

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72 L.M. Bylsma et al. / Biologica

outh showed the normative response. However, since Miller et al.2009) observed the effect with emotional films, it is unclear whye did not also observe this effect to our sad film. Notably, Miller

t al. (2009) also focused on children with asthma, a condition thatay lead to vagal overactivity. Importantly, we also found that

ur group differences between probands and controls were notxplained by current depression, suggesting that CAB may reflectn underlying vulnerability rather than a mood state dependenthenomenon.

Group differences were task specific, as our proband and con-rol groups responded similarly to the sad film and cold faceasks. One possible explanation of this finding is that the sadlm and cold face were passive tasks, while the handgrip andnsolvable puzzles required sustained effort and focused attention.

ndeed, other researchers have interpreted blunted physiologicaleactivity in depression in term of deficient “effort mobilization”uring performance of cognitive tasks, which may reflect deficits

n the self-regulation of behavior (e.g., Brinkmann & Franzen, 2015;rinkmann & Gendolla, 2008). Friedman and Thayer (1998) haveuggested links between parasympathetic nervous system activitynd enhanced attention and effective emotion regulation. Success-ul attention deployment is an important component of effectivemotion regulation that involves selecting meaningful informationrom the environment and linking it with appropriate emotionalesponses (Appelhans & Luecken, 2006; Gross, 1998). Indeed, bothhe neurovisceral integration model (Thayer & Lane, 2000) andorges’ Polyvagal theory (Porges, 1995, 2007) suggest that strongNS activity at rest provides increased flexibility to rapidly adjustarasympathetic influence on the autonomic nervous system asalled for by task demands (i.e., to effectively deploy attentionalngagement or disengagement). Sustained attention has been asso-iated with PNS withdrawal and SNS activation, as well as taskerformance in tests of attention and working memory (Backs &eljos, 1994; Duschek, Muckenthaler, Werner, & Reyes del Paso,009; Hansen, Johnsen, & Thayer, 2003; Hansen, Johnsen, Sollers,tenvik, & Thayer, 2004; Luft, Takase, & Darby, 2009). Therefore, its possible that tasks involving sustained effort or focused atten-ion elicit larger normative reductions in CAB, and therefore moreeadily distinguish proband and control cases. Future researchhould examine the impact of effort and attention on changes inAB among depressed and nondepressed individuals. However,iven that Miller et al. (2009) reported group differences in CABhanges to emotional films as a function of depression, it also maye that our sad film stimulus was insufficiently potent. Importantly,lthough CAB reflects the balance of parasympathetic (RSA) andympathetic (PEP) indices, there were no group differences in RSAhanges to either task, and PEP abnormalities in probands were onlyxhibited in response to the handgrip task, but not the unsolvableuzzle. Finally, we also did not find any effects for the LF/HF ratio,nother index of the balance of SNS and PNS activity. It should beoted that the LF/HF ratio and may reflect a blend of PNS and SNSctivity, limiting its interpretability (Berntson et al., 1997; Eckburg,997; Goldstein, Bentho, Park, & Sharabi, 2011).

Given that CAB incorporates both parasympathetic and sym-athetic activation, it provides a more comprehensive index ofutonomic functioning that is more sensitive to autonomic changeshat may reflect aspects of self regulation. Indeed, researchersave suggested that composite measures may be more reliablend sensitive metrics of autonomic functioning than individualndices (Kreibig, Gendolla, & Scherer, 2012). For example, Norman,erntson, and Cacioppo (2014) have observed that while averagedardiovascular responses to orthostatic stress and standard psycho-

ogical stressors tend to be very similar when analyzed at the groupevel, examination of SNS and PNS influences separately reveals a

uch more complex picture, particularly for psychological stress-rs.

hology 110 (2015) 167–174

These findings may also have relevance for physical health,as CAB has been associated with a number of poor health out-comes (Berntson et al., 2008; Licht et al., 2013; Thayer et al.,2010). Our findings may be germane to the large literaturedocuments relationships between depression and cardiovasculardisease (Barth, Schumacher, & Herrmann-Lingen, 2004; Nicholson,Kuper, & Hemingway, 2006; Rugulies, 2002). Thus, elucidating therelationship between CAB and self regulation may also lead to abetter understanding of the links between depression and poorhealth.

Given the lack of empirical literature on the relationshipbetween CAR and depression, we did not have specific predictionsabout group performance. Notably, although CAR also incorporatessympathetic and parasympathetic indices, the only group differ-ence we observed for this measure was for the handgrip task, whichseemed to be driven by changes in PEP, rather than coactivationof both PNS and SNS measures. Further, the group difference inCAR for the handgrip task results did not withstand control for cur-rent depression status, suggesting the possibility that this variablemay index mood state rather than trait vulnerability. The strongerresults for CAB suggest that the balance of PNS and SNS activationis more relevant for self regulation and depression vulnerabilitythan their coactivation or coinhibition, which is consistent withprior literature (e.g., Chang et al., 2012; Nugent et al., 2011; Udupa,Sathayaprabha, Thirthalli, Kishore, Lavekar, et al., 2007; Udupa,Sathayaprabha, Thirthalli, Kishore, Raju, et al., 2007).

Strengths of our study include use of multiple psychological andphysical stress tasks, a large well-characterized sample of high riskyouth and healthy control peers, and a comprehensive assessmentof autonomic functioning. At the same time, we were limited in ourability to assess aspects of effort mobilization or attention that maybe relevant to group differences in CAB. In addition, while CAB andCAR may have interpretable advantages over prior indices, suchas the LF/HF ratio, we are nevertheless limited by the assumptionthat CAB and CAR assume integrated control of chronotropic (i.e.,related to heart rate) and inotropic (i.e., related to force of contrac-tion of the heart) function and are assessing joint sympathetic andparasympathetic control (see Thayer & Uijtdehaage, 2001). In sum,the results from this study suggest that CAB may be a useful indexthat reflects the balance and flexibility of the autonomic nervoussystem to respond to aspects of the environment that may be sen-sitive to psychophysiological abnormalities reflecting depressionvulnerability.

Acknowledgements

This research was supported by NIH Grants MH-084938and MH-056193 and Hungarian Scientific Research Fund GrantNN85285.

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