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52(2014), (2015),••–••. 416–424. Periodicals, Inc. Printed the USA. Psychophysiology, •• WileyWiley Periodicals, Inc. Printed in the in USA. C 2014 Society for Psychophysiological V Psychophysiological Research Research Copyright © 10.1111/psyp.12332 DOI: 10.1111/psyp.12332

Autonomic responses to lateralized cold pressor and facial cooling tasks

JARED J. McGINLEY and BRUCE H. FRIEDMAN Department of Psychology, Virginia Tech, Blacksburg, Virginia, USA

Abstract Asymmetry in central nervous system (CNS) control of autonomic nervous system (ANS) activity, a widely debated topic, was investigated via lateralized presentation of two ANS challenges: cold pressor, which elicits primarily sympathetic activation, and facial cooling, a predominantly vagal task. Seventy-three university students (37 female) engaged in these tasks while cardiovascular and electrodermal measures were acquired. Compared to right-side cold pressor, left cold pressor elicited generally larger cardiac, blood pressure, and skin conductance responses, but did not evoke asymmetric changes in heart rate variability. Facial cooling elicited significant increases in vagally mediated heart rate variability, but they were also not lateralized. These findings are consistent with reports of right hemisphere dominance in sympathetic regulation, but indicate that CNS vagal control is relatively symmetric. These results are framed in terms of polyvagal theory and neurovisceral integration two influential models of CNS-ANS integration in the service of adaptive environmental engagement. Descriptors: Autonomic nervous system laterality, Cold pressor, Facial cooling continues to be relevant in contemporary psychophysiological research (Hagemann, Naumann, Thayer, & Bartussek, 2002; Tullett, Harmon-Jones, & Inzlicht, 2012). As such, clarification of functional asymmetries in autonomic regulation is an important topic to investigate specifically for CNS–ANS models and the psychophysiological literature in general. One possible reason for discrepant findings in the CNS–ANS laterality literature is the diversity of methods that have been used to investigate this topic. The aim of the present study was to use direct presentation of lateralized stimuli to elicit asymmetries in autonomic response. This goal was achieved by taking advantage of the contralateral innervation of afferent pathways stimulated in two tasks: the foot cold pressor, and facial cooling. Lateralized presentation of these tasks was employed to assess possible asymmetric effects on a battery of ANS responses. To frame the rationale for this methodology, we first briefly review the extant findings on asymmetry in ANS responses.

Central nervous system (CNS) pathways play a major role in the regulation of autonomic nervous system (ANS) activity. Various influential models of central control of ANS function have been advanced, such as those of Critchley’s (2005) integration of affect and cognition, Damasio’s (2001) somatic marker hypothesis, neurovisceral integration (Thayer & Lane, 2009), and the central autonomic network (Benarroch, 1993). For a more in-depth view for the particular CNS structures involved in lateralized ANS regulation, see a recent meta-analysis on this topic (Beissner, Meissner, Bar, & Napadow, 2013). Although each representation possesses unique features, these models identify many common neural structures that direct ANS activity in the service of emotion, motivation, and goal-directed behaviors. Human neuroimaging data have further elucidated these pathways (e.g., Critchley, Nagai, Gray, & Mathias, 2011; Gianaros, Van der Veen, & Jennings, 2004; Thayer, Ahs, Fredrikson, Sollers, & Wager, 2012). Relatively little attention, however, has been paid to functional asymmetry in these models. Nevertheless, this topic has been of interest over the years, although no clear consensus has emerged from this literature (Craig, 2005; Galin, 1974; Lane & Jennings, 1995; Wittling, 1997). Moreover, brain asymmetry

Asymmetry in ANS Regulation Functional laterality has long been a major focus of neuroscientific research, and interest in lateralization of ANS function has appeared sporadically over the years. Early speculations on this topic appeared in a review paper by Galin (1974), who mused that ANS laterality is likely to coincide with functional laterality of cognitive and affective processes. Based on the extant literature, he suggested that cardiac ANS control was similarly lateralized for both rate (right side) and contractility (left side) functions in both the sympathetic (SNS) and parasympathetic (PNS; i.e., vagal) branches of the ANS. Galin’s model was framed in psychoanalytic constructs that have diminished in appeal over the intervening years. However, the review is distinguished by its utilization of

The authors would like to thank Derek Spangler, Matt Flamini, Kate Magruder, Anarkali Morrill, and Jessica Worthen for their assistance in the conduction of this study, and Lea Lozier for her methodological trailblazing. Portions of these data were presented at the 51st annual meeting for the Society for Psychophysiological Research in New Orleans, LA, September 2012. Address correspondence to: Bruce H. Friedman, Department of Psychology (0436), Virginia Tech, Blacksburg, VA 24061, USA. E-mail: [email protected]

416 1

Asymmetry in autonomic regulation 2 multiple converging lines of evidence: clinical case studies, electroencephalogram (EEG) research, the intracarotid amobarbital (Wada) test, spilt-brain research, animal models, and studies of unilateral electroconvulsive therapy (ECT) effects. A variety of techniques have since been employed to assess hemispheric specialization in ANS regulation. Investigations involving patients with lateralized brain damage (e.g., Yokoyama, Jennings, Ackles, Hood, & Boller, 1987; Zoccolotti, Scabini, & Violani, 1982) and observations under the Wada test (e.g., Ahern et al., 2001) have been useful for illuminating the hemispherespecific roles of various structures in ANS regulation. Resting state studies in nonclinical samples using simultaneous recording of EEG and cardiovascular activity have been informative for broader inferences in hemispheric regulation (e.g., Foster, Drago, Ferguson, & Harrison, 2008). The lateralized presentation of stimuli, which has been used to address many brain laterality questions, has also effectively been adopted into paradigms to explore hemisphere-dependent autonomic responses (Davidson, Ekman, Saron, Senulis, & Friesen, 1990; Hugdahl, Franzon, Andersson, & Walldebo, 1983; Wittling, 1990). The aggregate findings from these studies have generally implicated right hemisphere dominance in SNS regulation (Wittling, 1997). Evidence for PNS asymmetry, however, has been divided (e.g., Ahern et al., 2001; cf. Foster et al., 2008). Findings across these studies have vacillated around providing support for right or left hemisphere dominance for PNS lateralization. Two general models have arisen from this body of research: one posits PNS activity as largely dependent on left hemisphere regulation (Craig, 2005), while the other has situated the PNS alongside the SNS in right hemisphere regulation (Thayer & Lane, 2009). Moreover, a recent study using ANS measures derived from the visual system found evidence for right-lateralized sympathetic activity, but failed to detect parasympathetic lateralization (Burtis et al., 2014). Considering how vagal activity has increasingly been demonstrated as an important marker for physical (Gutin, Owens, Slavens, Riggs, & Treiber, 1997), emotional (Stein et al., 2000), cognitive (Brosschot, Gerin, & Thayer, 2006), and cardiovascular health (Thayer, Yamamoto, & Brosschot, 2010), a clearer understanding of PNS regulation is called for. Present Research A notable drawback of the aforementioned research is the absence of designs that have unambiguously lateralized SNS and PNS stimuli within the same study. Additionally, several of the previous studies applied methods for quantifying PNS activity that are now known to be inadequate (e.g., Foster et al., 2008; Yoon, Morillo, Cechetto, & Hachinski, 1997). The present research is an extension of previous paradigms that have used lateralized presentation of stimuli to elicit autonomic responses. Moreover, the previous methods have primarily been directed at eliciting SNS responses, rather than PNS ones. The present research included a modified facial cooling task, which was lateralized to assess asymmetric PNS regulation. The facial cooling task is one of the few noninvasive tasks in psychophysiological research that reliably elicits increased vagal activity (Finley, Bonet, & Waxman, 1979; Friedman & Thayer, 1998; Friedman, Thayer, & Tyrrell, 1996; Khurana, Watabiki, Hebel, Toro, & Nelson, 1980; Wolf, 1978). To our knowledge, this task has never been modified to lateralize the afferents for vagal stimulation. In contrast, current views on vagal lateralization have come from paradigms such as the Wada test, the findings of which are limited by their reliance

417 J.J. McGinley and B.H. Friedman on small samples of brain-damaged subjects (e.g., Ahern et al., 2001). Other models are based on putatively lateralized performance tasks used to indirectly manipulate vagal activity via differential hemispheric activation (e.g., Foster et al., 2008). Our study is the first to employ direct lateralized stimulation of vagal afferents via the trigeminal nerve (Eckberg, Mohanty, & Raczkowska, 1984). Hence, the present study adds unique data to the literature on ANS lateralization. Additionally, a lateralized cold pressor task known for eliciting robust SNS responses was incorporated. Preliminary evidence from this laboratory has demonstrated lateralized cold pressor tasks to evoke larger cardiovascular SNS responses from left side exposure than from right side exposure (Friedman, Lozier, & Vella, 2005; McGinley et al., 2011). Used together, these tasks are useful for assessing functional asymmetry in ANS regulation. The cold pressor task, which lateralizes the majority of its afferent feedback to the contralateral hemisphere, can induce SNS responses that are largely considered to rely on regulation of the recipient hemisphere. The lateralized facial cooling task is also expected to elicit afferent feedback and concomitant lateralized efferent output primarily regulated by the contralateral hemisphere (Jacquin, Chiaia, & Rhoadest, 1990; Marfurt & Rajchert, 1991). A representative montage of indices was used to sample lateralized ANS responses. Blood pressure measures were selected because they are the most salient responses to the cold pressor task (Saab et al., 1993). Electrodermal activity was recorded because it provides a relatively pure index of sympathetic activity (Dawson, Schell, & Filion., 2007), and the HRV measures from the electrocardiography (ECG) were selected to provide evidence for changes in vagal activity (Task Force, 1996). We hypothesized that the left-sided cold pressor task would elicit larger responses than the right-sided cold pressor task in indices associated with SNS activity. In view of the mixed evidence for vagal lateralization, no directional hypotheses were made for the lateralized facial cooling task. However, these results were anticipated to be in line with reports of left-, right-, or nonlateralization of parasympathetic activity, depending on whether a greater right-sided or left-sided increase, or no right-left differences, in HRV measures were observed. Therefore, a greater vagally mediated response from left-side stimulation would indicate greater right hemisphere PNS regulation, a greate r right-side response would suggest greater left hemisphere PNS regulation, and no relative left-right difference point to bilateral vagal representation. Method Subjects Seventy-four subjects were initially recruited through an online system at Virginia Tech designed to provide class extra credit in return for study participation. Data were lost for one subject due to failure to complete tasks. Seventy-three undergraduates (37 female; mean age = 19.77, SD = 1.76) ultimately provided usable data. Requirements for participation were as follows: right-handed, nonsmoking, and no history of neurological and cardiovascular disease. Subjects were asked to list any over-the-counter or prescription medications they were currently taking; none reported using drugs with known analgesic effects. Subjects were also instructed to abstain from alcohol for 24 h, caffeine for 12 h, food for 1 h, and vigorous exercise for 2 h before their laboratory visit.

J.J. McGinley and B.H. Friedman3

418 Asymmetry in autonomic regulation Institutional review board (IRB) approval was attained from Virginia Tech; all subjects gave informed consent for participation. Self-Report Questionnaires The subjects responded to items from several questionnaires during the study. Before the tasks were implemented, questionnaires concerning health history and handedness (Coren, Porac & Duncan, 1979) were completed by the subjects. After each task, subjects answered one item from two different questionnaires: self-report rating for affect (Morris, 1995) and pain experienced during the tasks. The pain scale was designed to use a similar Likert scoring to the affect scale, ranging from 1 (unpleasant or not painful) to 5 (pleasant or extremely painful).

There is no definitive evidence supporting differential skin conductance response between hands (Dawson, Schell, & Filion et al., 2007); therefore, skin conductance was collected from the right hand, and skin conductance level (SCL) was calculated as the mean response during each task. Task Descriptions

Images rated as neutral on valence and low on arousal were selected from the International Affect Picture System (IAPS; Lang, Bradley, & Cuthbert, 2001) for the baseline tasks.

The study consisted of four baselines, four tasks, and four recovery periods. Each of the baseline periods was 3 min in duration and consisted of the participant sitting quietly in a comfortable chair while watching a compilation of neutral IAPS images that were displayed on a computer monitor, in accord with the recommendation for ”vanilla” baselines (Jennings, Kamarck, Stewart, Eddy, & Johnson, 1992). Two of the tasks were modified versions of the common facial cooling procedure. This manipulation involves the use of a cold stimulus on the forehead to induce bradycardia (e.g., Friedman et al., 1996), which primarily operates via afferent projections through the ophthalmic branch of the trigeminal nerve (Eckberg et al., 1984). Our modified version involved bags filled with ice water (∼9°C) that were placed over the maxillary and mandibular divisions of the trigeminal nerve on the lower half of the face. The ophthalmic branch projects bilaterally to nuclei in the brainstem and the somatosensory cortices, while the two lower branches of the trigeminal nerve largely project to the contralateral hemisphere (Jacquin et al., 1990; Marfurt & Rajchert, 1991). Although not the typical application, cold stimulation of the lower branches has previously been shown to elicit a bradycardia response (Khurana et al., 1980). The variation of this task used in the current study allowed for a largely unilateral (and contralateral) afferent stimulation. The facial cooling tasks lasted 2 min each: once on the left side of the face and once on the right side. The second pair of tasks was a modified version of the hand cold pressor. Subjects were instructed to submerge their foot into a bucket of ice water (∼9°C). The foot cold pressor has been demonstrated to have comparable cardiovascular effects to the more common hand cold pressor (Saab et al., 1993). The cold pressor tasks lasted 3 min each: once for the left foot and once for the right foot. For the recovery periods, the subjects were instructed to remain seated and to relax for 3 min.

Autonomic Measures

Procedure

Cardiovascular measures in this study were derived from the ECG and BP signals. The interbeat interval (IBI) and metrics of heart rate variability (HRV) were derived from the ECG signal. HRV is often assessed in both temporal and frequency domains, so both were derived from the ECG signal and analyzed in this study. High-frequency (HF; 0.15–0.40 HZ) in the frequency domain spectral power was derived via fast Fourier transform applied to the ECG, and served as an indicator of vagal influence on the heart (Berntson et al., 1997; Task Force, 1996). In the time domain, the root mean square of successive differences in consecutive IBIs (RMSSD) served as an index of cardiac vagal modulation (Penttila et al., 2001). All time-based and spectral-based metrics of HRV were analyzed and extracted from the software program Kubios HRV v2.0 (Biosignal Analysis and Medical Imaging Group, Kuopio, Finland). SBP, DBP, and mean arterial pressure (MAP) were calculated from the blood pressure readings. MAP was calculated from SBP and DBP using a traditional formula: MAP = DBP + (SBP – DBP)/3 (Stern, Ray & Quigley, 2001).

Subjects completed the two facial cooling and two cold pressor tasks in a quasicounterbalanced order. The facial cooling and cold pressor tasks were separated into two phases: phase 1 employed the two facial cooling tasks, and phase 2 employed the two foot cold pressor tasks. The facial cooling tasks were conducted first to minimize task carryover effects, considering the faster withdrawal of parasympathetic cardiovascular effects compared to the slower withdrawal of sympathetic cardiovascular effects. To account for differences that may arise from collecting BP from one arm and not the other, an eight-block, quasirandomized design was implemented: arm with BP cuff, side of the face that was first cooled, and the foot that was first submerged. Each task was preceded by a 3-min baseline and followed by a 3-min recovery period.

Equipment ECG was collected by two thoracic electrodes in a modified lead II configuration, and the ECG signals were amplified through an ECG 100C system (BIOPAC Systems Inc., Goleta, CA). Blood pressure (BP) was recorded using a MedWave Fusion BP monitoring system (MedWave Inc., Danvers, MA). Systolic (SBP) and diastolic (DBP) blood pressure were recorded using semicontinuous BP measurement via a sensor placed over the radial artery; BP estimates are derived from parameters of the pulsatile waveform (Belani, Buckley, & Poliac, 1999). Three different cuffs (child, adult, and extra large) were available for appropriate sizing. Skin conductance was recorded from electrodes placed on the volar surface of the index and middle fingers of the right hand in accordance with the placement recommendations of Fowles et al. (1981). The signals from ECG and BP were interfaced through an MP150 system (BIOPAC Systems Inc, Goleta, CA). All raw signals were digitized at 1000 Hz. Artifact detection was performed by visual inspection and with software assistance using Biopac Acqknowledge 4.1 and Biopac Student Lab Pro 3.7.7. Baseline Stimuli

Design and Statistical Analyses Pairwise t tests were used for pain and affect self-report to assess differences in subjective experience of left-side versus right-side

Asymmetry in autonomic regulation 4

419 J.J. McGinley and B.H. Friedman

Table 1. Lateralized Differences in Physiological Responses during Cold Pressor Tasks (Baseline-to-Task Change) ANS measure

Left (SD)

Right (SD)

Diff. (SE)

F value

df

p value

Effect size (h2)

Cold pressor SBP (mmHg) DBP (mmHg) MAP (mmHg) IBI (ms) SCL (n.u.) HF power RMSSD

2.4 (9.8) 9.35 (9.54) 10.37 (7.95) −84.5 (89.9) 0.09 (0.11) −0.12 (0.46) −9.7 (31.3)

9.98 (11.2) 7.49 (10.27) 8.32 (8.07) −67.6 (77.7) 0.06 (0.11) −0.09 (0.35) −6.5 (23.3)

2.43 (1.04) 1.86 (0.87) 2.05 (0.91) −17.0 (8.5) 0.03 (0.01) −0.30 (0.05) −3.15 (3.04)

5.414 4.561 4.888 3.989 5.273 0.327 1.075

66 67 66 68 62 68 68

.023 .036 .031 .050 .025 .569 .304

0.076 0.064 0.068 0.055 0.078 0.004 0.016

Facial cooling SBP (mmHg) DBP (mmHg) MAP (mmHg) IBI (ms) SCL (n.u.) HF power RMSSD

0.83 (1.30) −0.12 (3.27) 0.21 (3.46) 44.1 (51.6) −.05 (0.11) 0.12 (0.30) 11.4 (21.4)

1.30 (4.74) −0.17 (3.79) 0.32 (3.99) 38.0 (57.2) −0.04 (0.11) 0.07 (0.28) 8.1 (23.8)

−0.48 (0.70) 0.51 (0.64) −0.12 (0.65) 6.03 (6.05) −0.01 (0.02) 0.05 (0.04) 3.23 (2.44)

0.474 0.006 0.712 0.992 0.056 1.921 1.798

69 68 68 68 62 68 68

.494 .937 .863 .323 .813 .170 .184

0.007 0.000 0.000 0.014 0.001 0.027 0.026

Note. SCL and HF HRV values are log transformed. Values listed in bold are significant at p < .05. n.u. = normalized units.

tasks. Next, the hypothesis required a within-subjects comparison for physiological responses to left- versus right-side presentation of the facial cooling and cold pressor tasks. Therefore, the data were analyzed by a 2 × 2 (Task × Side) repeated measures analysis of variance (ANOVA) with the physiological responses (RMSSD, HF power, SCL, IBI, MAP, SBP, and DBP) serving as the dependent variables. Mean scores for each autonomic variable were calculated for each lateralized task and for each baseline period. The mean scores of each physiological variable for the baseline tasks were then subtracted from the lateralized tasks (i.e., task—baseline), thereby creating change scores. These change scores for the right and left tasks were compared using repeated measures ANOVA. Change scores derived in this manner are preferred to residual scores when assessing the generalizability of responses across a variety of tasks, because they present fewer limitations with post hoc contrasts (Llabre, Spitzer, Saab, Ironson, & Schneiderman, 1991). Effect sizes were calculated for each lateralized comparison as eta-squared (η2). All analyses were executed with Statistical Software Package for the Social Sciences (SPSS) v 19.0. Some data points were missing due to equipment malfunction and recording problems (e.g., excessive movement) for eight subjects. As such, the results had slightly uneven N values across the dependent variables. Pairwise deletion was used in cases of missing data. SCL and HF power were log transformed to correct for nonnormality. Differences across tasks in degrees of freedom were examined with a Huynh-Feldt correction for violations in sphericity.

Before making statistical comparisons between the left- and right-side tasks, we checked whether the tasks evoked significant physiological responses. Repeated measures ANOVAs were conducted by comparing the baseline values to the task values for each physiological variable. The cold pressor tasks were expected to elicit large cardiovascular responses as demonstrated by increases in BP metrics and decreases in IBI, while also decreasing vagally mediated measures of HRV. These expected responses for IBI and all BP metrics were significant at the p < .001 level for both tasks (mean changes and standard deviations can be found in Table 1). Although RMSSD was significant for both sides at p < .05, HF power did not reach significance for either side (p > .05). The facial cooling tasks were expected to elicit increases in IBI, RMSSD, and HF power. Although these effects were significant during the first minute of the facial cooling tasks at p < .01, inspection of the data revealed that the effects had dissipated (i.e., did not reach significance) during the second minute of the task at. In all subsequent HRV analyses for the facial cooling tasks, only averages over the first minute of the task were used. Because of this finding, the change scores calculated for the facial cooling tasks were calculated by subtracting the last minute of the preceding baseline tasks. Although longer time periods are traditionally recommended for the spectral and time-series analyses for HRV, the European Task Force for HRV (1996; also see Berntson et al., 1997) states that approximately 1 min is adequate to assess HF ECG spectral power. Potential Moderators

Results Self-Report Ratings Pairwise t tests were conducted to compare lateralized self-report responses on pain and affect. The t tests for lateralized differences on the pain questionnaire (p > .09) and the Self-Assessment Manikin (SAM) (p > .08) were all nonsignificant. Manipulations Checks SCL and HF power were positively skewed, and so a logarithmic transformation was applied to the data.

Bivariate correlations were conducted between physiological and nonphysiological variables to determine if there were systematic relationships between them at baselines and task periods. Body mass index was significantly correlated with several BP metrics for different tasks in the study, but it was not correlated with any of their change scores (all p values > .1) and therefore was not considered in further analyses. Although recent use of caffeine was not significantly correlated with any physiological variables, lifetime caffeine use was negatively correlated with BP at several time periods. However, it also was not significantly correlated with any change scores (all p values > .1) and therefore was not considered in further analyses. BP collection was pseudorandomized between

J.J. McGinley and B.H. Friedman5

420 Asymmetry in autonomic regulation 0.7

Effect Size (h2)

0.6 0.5 0.4

CP Left CP Right

0.3 0.2 0.1 0 SBP

DBP

MAP

IBI

SCL

Figure 1. Significant laterality effects during (baseline-to-task change; all p values > .05).

foot

cold

pressor

arms, so correlations were run between the arm of collection and pressor responses; these responses did not significantly differ by arm. No other self-report data were systematically correlated with physiological responses and thus were ruled out as contributing factors to ANS responses. Laterality Comparisons in Autonomic Data Comparisons of left- versus right-side cold pressor were consistent with predicted greater cardiovascular and electrodermal responses for the latter (see Figure 1). SBP responses for the left-side cold pressor were significantly greater than for the right-side cold pressor, F(1,66) = 5.414, p < .05, η2 = .076. DBP, F(1,67) = 4.561, p < .05, η2 = .064, and MAP, F(1,66) = 4.888, p < .05, η2 = .068, were also significant and in the predicted direction (see Table 1). There was also a significant decrease in IBI in the left-side cold pressor compared to the right-side cold pressor, F(1,68) = 3.989, p = .05, η2 = .055. SCL for the left-side cold pressor was significantly larger than for the right-side cold pressor, F(1,62) = 5.273, p < .05, η2 = .078. The measures of vagal activity did not show lateralized differences between the cold pressor tasks (all p values > .3). Left- vs. right-side IBI response did not reach the significance level for the facial cooling tasks, F(1,68) = .992, p > .1, η2 = .014. Also, left versus right comparisons of the vagal measures of both RMSSD, F(1,68) = 1.798, p > .1, η2 = .026, and HF power, F(1,68) = 1.921, p > .1, η2 = .027, were not significant (see Table 1). Gender effects were explored for each of the autonomic dependent variables, but none reached statistical significance, consistent with pilot data from our lab (Friedman et al., 2005). Discussion The aim of this study was to examine lateralization of ANS responses via manipulations that lateralized afferent autonomic input. This approach represents a novel method of investigation of lateralization of ANS control. Based on consistent evidence for right hemispheric dominance in regulating SNS activity, we predicted that left-side cold pressor would elicit greater SNS reactivity than right-side cold pressor. This prediction was strongly supported: left-side foot immersion elicited larger responses in all ANS measures that possess substantial sympathetic influence (SBP, DBP, MAP, IBI, SCL). Hence, evidence from this study provides continued support for right hemisphere dominance in

regulating SNS activity. Additionally, these results indicate that the cold pressor task is more potent when administered on the left side, assuming that foot and hand immersion evoke similar responses (Saab et al., 1993). Conversely, the results do not indicate significant asymmetry in CNS regulation of PNS activity. Although both tasks elicited significant changes in HRV (RMSSD only for cold pressor; HF and RMSSD for minute 1 of facial cooling), there was no evidence of lateralization of these responses. Thus, in contrast to models that posit left (Craig, 2005; Wittling, 1997) or right (Lane, & Jennings, 1995; Thayer & Lane, 2009) hemisphere dominance in PNS regulation, the present data suggest that cardiac vagal control does not display substantial asymmetry. In addition to the advantages afforded by the lateralization of afferent input, the use of multiple autonomic measures allowed for a broader assessment of SNS activity than was generally observed in previous investigations. Significant increases in all BP metrics and SCL, in conjunction with a decrease in IBI during the cold pressor tasks, provides reliable indicators of greater SNS response for left- than right-side cold pressor. Additionally, most of the effect sizes for variables related to SNS asymmetry were of moderate size. Although these measures are not solely influenced by sympathetic adrenergic receptors, both preliminary findings from this lab (Friedman et al., 2005; McGinley et al., 2011) and the long history of using the cold pressor to elicit SNS responses (Hines & Brown, 1936), collectively provides strong evidence for the dominant role of the right hemisphere in regulating SNS activity. Even though the facial cooling manipulation effectively induced increases in vagal activity, these changes did not indicate asymmetric PNS regulation. As such, PNS regulation might be best represented bilaterally. Indeed, a recent meta-analysis of brain imaging research of vagally mediated HRV did not report consistent laterality differences for either hemisphere (Thayer et al., 2012). Implications of Current Findings The right hemisphere has been implicated in serving a specialized role in various trait- and statelike modes of processing, such as negative affect (Demaree, Everhart, Youngstrom, & Harrison, 2005), hostility (Williamson & Harrison, 2003), depression (Allen, Urry, Hitt, & Coan, 2004), and avoidance mentality (Davidson et al., 1990). Situating the regulation of SNS activity in the same hemisphere makes sense from a functional perspective. Since SNS responses are evoked in situations of fear and threat responding, (Lang, Davis, & Ohman, 2000), right hemisphere dominance in SNS control theoretically complements many of the above asymmetry models. Although the current models for CNS regulation of the ANS have typically posited the PNS as being regulated by either the right (e.g., Lane & Jennings, 1995) or left (e.g., Wittling, 1997) hemisphere, the current findings do not support either theory. In contrast, the present results are consistent with those of Burtis et al. (2014), who did not observe PNS lateralization in the visual system. PNS activity may present a less straightforward picture in terms of CNS lateralization. Cardiac vagal control has been prominent in many contemporary models of environmental engagement and adaptation (e.g., Porges, 2007; Thayer & Lane, 2009). In these models, PNS activity holds a more subtle and complex relationship with behavior than that of SNS activity in a fight-flight scenario. Cardiac vagal control as indexed by HRV is viewed as a peripheral marker for CNS regulation of attention,

Asymmetry in autonomic regulation 6 emotion, and social interactions. This multifaceted role can lead to directional differences in HRV responses to contextual nuances. For example, vagal withdrawal, as revealed in phasic HRV decreases, is often interpreted as an ANS response to threat or stress (e.g., Beauchaine, Gatzke-Kopp, & Mead, 2007). In contrast, vagal activation has been understood as reflective of greater effort toward emotion regulation challenges (e.g., Segerstrom & Nes, (2007). Ostensibly contradictory findings regarding cardiac vagal withdrawal and activation highlight the importance of considering the intricacies of context when interpreting phasic HRV effects (Hastings et al., 2008). Moreover, this complex pattern of findings is unlikely to be supported by strong lateralization of PNS function. In conjunction with the inconclusive results for directional asymmetry in PNS regulation, it may be that PNS function is best represented bilaterally. An inherent limitation of theories purporting the lateralization of PNS activity is the assumption of inhibition for the opposing hemisphere during activation. Theories that support functional lateralization are often built upon foundational ideas of minimizing metabolic costs by causing compensatory attenuation of activity in the other hemisphere (e.g., Kinsbourne, 1975). However, PNS activity usually serves as the vehicle for restorative and energyconserving processes in the body, and therefore may not necessitate compensatory deactivation of the opposite hemisphere. Also, from a functional perspective, it would be logical for both hemispheres to have adequate access to the modulation of efficient resourcesaving behaviors. Since PNS activity engages fast-acting responses on metabolically costly processes such as cardiac output, then quick access to vagally mediated modulation would be beneficial for either hemisphere to access, regardless of the type of behavioral or cognitive process enacted. Put into simple terms: two hemispheres plus two branches of the ANS does not necessarily require a 1-to-1 differentiation for structural housing. Theories steeped in the need for lateralization of apparent oppositional processes might be limited by tendencies to functionally (and consequently, anatomically) separate what are perceived as oppositional processes. However, there are many nonoppositional situations which PNS and SNS activity can assume (Berntson, Cacioppo, & Quigley, 1991, 1993). Although conceptually useful for understanding a broad range of functions served by each system, it is more accurate to understand them as complementary systems that often work in tandem through a variety of conditions, such as coactivation or cowithdrawal. The multiple modes of activation have been accounted for by the model of autonomic space (Berntson, Cacioppo, & Quigley, 1991, 1993), and suggest a more dynamic model of autonomic functioning than simplified lateralization of its two constituent branches. Additional questions about the hemispheric specialization of PNS regulation can be generated by viewing nervous system development across species. Although controversial in its claims, the polyvagal theory draws from a body of evidence that supports the temporal differentiation of phylogenetic development in branches of the ANS across different species (Porges, 1998, 2007). Specifically, the segment of the vagus nerve that innervates sacral-level organs appears to be present in organisms that have simple nervous systems devoid of SNS functioning. Also, many nonmammalian organisms that possess developed SNSs do not possess myelinated vagal regulation of the heart. Consequently, the theory emerging from these observations has generally supported the view that different processes attributed to PNS activity have evolved both before, and after, basic SNS processes (Porges, 1998, 2007). Therefore, it seems unlikely that the development of different modes of

421 J.J. McGinley and B.H. Friedman PNS activity would evolve to be clearly rendered to the functional regulation of one hemisphere. Observations of nervous system lateralization in organisms with simple nervous systems (Halpern, Gunturkun, Hopkins, & Rogers, 2005) leads to the inference that the same circuitry that supports regulation of unmyelinated vagal functioning would have had to later develop to support the circuitry for regulation of myelinated vagal functioning. When placed into this evolutionary framework of using cross-sectional evidence of nervous system development from existing species, it does not appear likely that lateralization of these two branches would have developed simultaneously. Lastly, a diffuse distribution of PNS regulation is also beneficial for psychological processes such as cognitive and attentional regulation, which are dependent on fast-acting cardiac-vagal control during states of alertness as well as recovery. For such quick and continuous processes such as attentional control, it would be inefficient to have PNS regulation restricted to functioning of a particular hemisphere. The same holds for approach-related behaviors, which, although typically associated with PNS-dominant function (Porges, Doussard-Roosevelt, Portales, & Greenspan, 1996), are also required in complex organisms when required to perform avoidant behaviors during goal pursuit or when engaging in approach-oriented behaviors to rid of a threat (Norris, Gollan, Berntson, & Cacioppo, 2010). These situations of dual engagement may require more complex architecture of autonomic flexibility for appropriate responding. Limitations and Future Directions Although we view our data as supportive of a more bilateral representation of PNS functioning, further research is needed to more firmly establish this claim. A lateralized presentation of predominantly PNS-afferent input with a longer duration than in the current study might still better serve this issue. Additionally, simultaneous measurement of brain imaging and ANS measures would greatly serve in understanding the brain’s role in regulating the branches of the ANS. Extrapolating from somatosensory projections, although not without strong advantages, is inherently limited in revealing mechanisms in the brain. Although the manipulations in this study can be characterized as predominantly sympathetic or vagal, both engage the PNS and SNS to some degree. Pharmacologic blockade may be a possible route to isolate the effects of each branch in future studies (e.g., Berntson et al., 1991). Another factor is that it cannot be precisely determined from the methodology of this study the degree to which lateralized effects, when present, are due to afferent or efferent influences. Indeed, the importance of vagal afferents is emphasized in both polyvagal theory and neurovisceral integration (Porges, 2007; Thayer & Lane, 2009). Although the increase in BP and SCL and decrease in IBI support the right hemisphere’s role in SNS regulation, this association cannot be made unequivocally without purer measures of cardiovascular sympathetic activity (e.g., contractility and peripheral resistance), which this study lacked. Reliable HRV measures are traditionally collected over long periods of time, but this study was limited by the relatively phasic bradycardia response elicited by the “dive reflex.” One might argue that the lack of prolonged effect of facial cooling might underlie the absence of lateralized effects in this task. However, facial cooling is an established vagal activator, as can be observed in bradycardia (e.g., Khurana et al., 1980) and HF HRV (e.g., Friedman et al., 1996); results during the first minute of facial cooling in this study are consistent with these findings. Morever, we know of no other vagal

J.J. McGinley and B.H. Friedman7

422 Asymmetry in autonomic regulation task than can be administered laterally. Hence, in the present study, this task appeared to elicit vagal activation that was not lateralized in its regulation. Although the original transference of afferent sensory information is assumed to be processed by the hemisphere contralateral to the stimulus induction, it is not certain that this hemisphere remains dominant for the duration of a task spanning several minutes. It should also be noted that pain was self-reported on a single dimension, so it was not possible to distinguish the effects of pain intensity from those of degree unpleasantness. However, the 9°C cold pressor temperature used in this study, which is slightly warmer than is typically seen in the literature, was chosen to minimize both discomfort and the potential confounding of pain and thermoregulatory responses (Allen, Shelley, & Boquet, 1992). Moreover, water in the range of 9°C has been shown to elicit significant cardiovascular cold pressor responses (Maekawaa, Kubokia, Clark, Shinodaa, & Yamashita, 1998). Additionally, it is unlikely that the lateralized effects observed in this study would be diminished by a more potent elicitation with colder water. Finally, it could be argued that these lateralized effects were of small effect sizes. Nonetheless, these differences appear to be reliable and consistent with the literature on right lateralized sympathetic responses. Furthermore, the functional lateralization literature is generally characterized by hemispheric differences that tend to be far more relative than absolute (Brown & Kosslyn, 1993). It is not surprising that autonomic regulation follows this pattern in which function is generally represented bilaterally, with certain processes showing slight hemispheric dominance (Pinel, 2014).

The implications from these findings provide a fresh perspective for understanding various psychopathologies and health implications for stroke and traumatic brain injury victims. Future research might look at how victims of these brain traumas are able to regulate PNS activity, and how that regulation is related to their traumas. Although a thorough addressing is outside the scope of the current paper, it should be noted that other psychological and behavioral phenomena that have been associated with asymmetric hemispheric regulation may also be understood better by the implications of lateralized ANS regulation. Research based on asymmetry models such as anxiety (Blackhart, Minnix, & Kline, 2006), depression (Allen et al., 2004), hyperactivity (Oades, 1998), or the oppositional constructs of dominance and submission (Demaree et al., 2005), could be further developed when including the views of asymmetric ANS regulation. Conclusion The present study addressed the issue of lateralized regulation of ANS activity. The findings are consistent with the literature, which has generally supported right hemisphere dominance in SNS regulation. In contrast, PNS activity did not give evidence of functional lateralization. Coupled with inconsistencies in the literature on PNS asymmetry, this finding suggests that PNS activity is more likely represented by a bilateral distribution. We encourage that other models of psychological functioning steeped in hemispheric asymmetries be informed by this conceptualization of ANS regulation.

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(Received December 24, 2013; Accepted August 5, 2014)