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Original Article |

Somatic Symptoms and Physiologic Responses in Generalized Anxiety Disorderand Panic Disorder:  An Ambulatory Monitor Study FREE

Rudolf Hoehn-Saric, MD; Daniel R. McLeod, PhD; Frank Funderburk, PhD; Pamela Kowalski
[+] Author Affiliations

From the Department of Psychiatry, The Johns Hopkins Medical Institutions,Baltimore, Md.


Arch Gen Psychiatry. 2004;61(9):913-921. doi:10.1001/archpsyc.61.9.913.
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Published online

Background  Physiologic responses of patients with anxiety disorders to everyday events are poorly understood.

Objective  To compare self-reports and physiologic recordings in patients with panic disorder (PD), patients with generalized anxiety disorder (GAD), and nonanxious controls during daily activities.

Design  Participants underwent four 6-hour recording sessions during daily activities while wearing an ambulatory monitor. Physiologic and subjective data were recorded every 30 minutes and during subject-signaled periods of increased anxiety or tension or panic attack.

Setting  Participants' everyday environment.

Participants  Twenty-six patients with PD and 40 with GAD, both without substantial comorbidity, and 24 controls.

Interventions  Recordings obtained during everyday activities.

Main Outcome Measures  Recordings of heart interbeat intervals, skin conductance levels, respirations, motion, and ratings of subjective somatic symptoms and tension or anxiety.

Results  Patients with anxiety disorders rated higher on psychic and somatic anxiety symptoms than did controls. Common to both anxiety disorders was diminished autonomic flexibility that manifested itself throughout the day, accompanied by less precise perception of bodily states. The main differences between patients with PD and GAD were a heightened sensitivity to body sensations and more frequent button presses. There also was a trend toward heightened basal arousal in patients with PD, manifesting itself in a faster heart rate throughout the day.

Conclusions  Patients with PD or GAD are more sensitive to bodily changes than nonanxious individuals, and patients with PD are more sensitive than those with GAD. Patients with PD experience more frequent distress than those with GAD and controls, but their physiologic responses are comparable in intensity. The findings suggest that the perception of panic attacks reflects central rather than peripheral responses. The diminished autonomic flexibility observed in both anxiety conditions may result from dysfunctional information processing during heightened anxiety that fails to discriminate between anxiety-related and neutral inputs.

Figures in this Article

Anxiety is a biological warning system that prepares us for action.Considering subjective and objective body reactions observed in nonanxiousindividuals during acute stress,14 itis reasonable to assume that patients with chronic anxiety disorders exhibitphysiologic hyperarousal at rest or heightened physiologic responses to stressors.This, however, is not uniformly the case. The most consistent finding in patientswith anxiety is increased muscle tension.1 Autonomicchanges are found less consistently. Our group5 foundthat patients with generalized anxiety disorder (GAD) showed normal heartrate, skin conductance, and respiration values while at rest. During laboratorystress, patients with GAD actually had a lower skin conductance response thancontrols.5 In some other studies,68 patientswith GAD exhibited an increased heart rate and decreased cardiac vagal toneduring rest and during mental stress.

Similarly, in some studies, patients with panic disorder (PD) exhibitednormal heart rate, skin conductance, and respiration values while at rest,whereas other studies found increases in those physiologic functions.1,9,10 The most consistentlaboratory finding in patients with chronic anxiety was diminished physiologicflexibility (DPF), namely, a diminished range or variability of physiologicresponses to stressors found in most,1,1013 butnot all,14 studies.

Moreover, most studies of patients with anxiety rely on self-reportsof somatic symptoms, despite the fact that somatic manifestations often correlatepoorly with physiologic states and reactions, and cannot be taken at facevalue.15

Most physiologic studies have been conducted in the laboratory, whichprovides a controlled environment and permits multiple simultaneous recordingsbut rarely reflects stressors experienced in everyday situations. Therefore,physiologic states and responses in laboratory studies may differ from thoseexperienced by patients in real life.

The aim of this study is to measure self-reports and physiologic statesin patients with GAD, patients with PD, and controls in their natural environmentusing an ambulatory monitor. We are interested in how these 3 groups differwhile they are not anxious, in their responses to stress or panic attacks,and in the relationship between experienced states and actual physiologicresponses. We are also interested in determining whether diminished autonomicflexibility occurs in natural settings and represents an altered physiologicresponse pattern in patients with chronic anxiety or whether it representsa laboratory artifact due to diminished attention to tasks that seem irrelevantto the anxious patient.

PARTICIPANTS

A total of 113 individuals, consisting of physically healthy patientswith GAD or PD and volunteers without a psychiatric disorder (controls), wererecruited by advertising and gave informed consent to participate in the study. Structured Clinical Interview for DSM-IV criteria16 were used to confirm the diagnoses, which, in caseof doubt, were reviewed by a second investigator. All other psychiatric disorders,including substance abuse, were excluded, except mild specific phobias thatdid not interfere with the participant's functioning. A physical examination,including a urine toxicology screen, was performed during the initial screening.All participants had to abstain from medications that affect the central andautonomic nervous systems for at least 2 weeks before entering and duringthe study. To be included in the study, patients with GAD and PD were requiredto score 38 or greater on the trait scale of the State-Trait Anxiety Inventory17 and 18 or more on the Hamilton Anxiety Rating Scale(HAM-A).18 Patients with PD had to have atleast 1 panic attack per week during the 4 weeks before testing. On entryinto the study, participants also completed the Beck Depression Inventory,19 the Sheehan Disability Scale,20 theBarsky Amplification Scale,21 and the BodySensations Questionnaire.22 Participants reportedthat they engaged in moderate daily physical activities.

The study sample was predominantly female (76%), with a mean age of36 years (range, 19-55 years). Of the 90 participants who provided usabledata, 24 were controls, 40 were diagnosed as having GAD, and 26 were diagnosedas having PD. More patients with GAD were recruited because we were also interestedin patients with high vs low levels of cardiac symptoms.23 Inthis article we compare the entire GAD group with the other 2 groups. Thecontrol group consisted of 17 whites, 3 African Americans, and 4 Asian Americans.The GAD group consisted of 36 whites, 2 African Americans, 1 Hispanic, and1 Asian American. The PD group consisted of 23 whites and 3 African Americans.As compensation, participants with an anxiety disorder were given free treatmentafter completion of the study, and controls were paid.

DATA COLLECTION PROCEDURES

All participants attended a training session before actual assessment.They wore the ambulatory monitoring device while sitting in a reclining chair.For a half hour, participants were acclimated to the physiologic monitoringequipment and were trained to complete the rating forms. Subsequently, for4 weekdays, they wore the ambulatory monitor and rated themselves on variousscales for at least 6 hours between 9 AM and 5 PM whilepursuing their usual daily activities.

Self-report Assessment Scales

On study days the participants were required to provide informationon self-report assessment forms at 30-minute intervals throughout the day.The Daily Rating Form allowed participants to rate the severity of symptomscommonly experienced during heightened anxiety on a scale from 0 ("absolutelynone") to 100 ("as bad as it could possibly be"). Symptoms consisted of severityof "rapid heart beat or palpitations," "sweating," "difficulty breathing normally,""feeling tense," and "worrying." A 5-point scale, asking, "How nervous orupset are you now?" with the response choices of "not at all" to "extremely,"allowed participants to rate their level of tension or anxiety while theyrated the symptoms listed on the Daily Rating Form. The Physical ActivityLevel Form allowed participants to rate their level of activity at a particulartime as "low," "mild," "moderate," or "high."

Physiologic Measures

Physiologic measures were monitored continuously throughout the testdays using an ambulatory monitoring device described by Thakor et al.24 The monitor was placed in a carrying case that hadshoulder and waist straps. The key physiologic measures of heart interbeatinterval (IBI), skin conductance level, and respiration rate were obtained,along with the contextual variables of ambient temperature and activity. Ambienttemperature was measured so as not to attribute changes in temperature thataffect physiologic states, including skin conductance, to changes in an emotionalstate. Measures of physical activity levels provide an indicator of when autonomicchanges should be attributed to physical activity. Heart IBI and breathingwere measured using standard electrocardiographic electrodes attached to thesides of the chest. Skin conductance was measured using silver and silverchloride electrodes attached to 2 fingers of the nondominant hand. For skinconductance, a Unibase (Parke-Davis, New York, NY) and isotonic sodium chloridesolution preparation was used as the electrolyte,25 andthe fingers were individually wrapped in self-adhesive gauze. Adhesive diskswere used to allow skin exposure to the electrodes of exactly 1 cm in diameter.Activity level and ambient temperature were measured by sensors located withinthe ambulatory monitoring device. Participants were expected to wear the monitorfor 8 hours each day, but technical problems caused data loss for many participantsin the latter part of the day, so a 6-hour period was established as the standardfor the study. The device automatically stored data in 6-minute epochs every30 minutes. At each recording epoch, the monitor emitted a beep to alert theperson who was wearing it that subjective ratings should be completed. Inaddition to this routine monitoring every 30 minutes, a button was availableon the device to allow participants to signal the occurrence of other importantevents. In this study, patients with GAD and controls were asked to pressthe button to indicate a "stressful occurrence." To avoid possible confusionbetween panic attacks and nonpanic anxiety, patients with PD were asked topress the button only to indicate a panic attack but not a stressful occurrence.Physiologic data for the 3 minutes before and the 3 minutes after the buttonpress were automatically stored. Pressing the button also produced an audiblebeep that served to cue the participants to complete the subjective data forms.

Heart IBI was measured 800 times per second; skin conductance, 4 timesper second; and respiration, 10 times per second. Activity level and ambienttemperature were stored once per second and once per minute, respectively.At the end of the recording time, the data were transferred to a personalcomputer for storage and statistical analysis. Data available for analysisincluded up to 16 epochs per participant session. Twelve 6-minute epochs wereavailable for the routine sampling at 30-minute intervals during the session.Additional 6-minute epochs were allocated for measuring the physiologic statussurrounding each button-press event reported by the participant.

DATA ANALYSIS
Overall Daily Effects

Analyses of overall daily effects focused on data obtained on the firstday of the study. Independent analyses for the physiologic and subjectivevariables were undertaken using the statistical package BMDP-5V (StatisticalSoftware Inc, Los Angeles, Calif), as required for an unbalanced repeated-measuresmodel with structured covariance matrices.2628 Eachanalysis predicted the dependent variable (D) as a function of group membership,measurement occasion (recording epoch), and the interaction between thesefactors. The general form of the model was as follows: D = Status + Time +[Status × Time]. The analysis assumed a first-order autoregressive within-subjectcovariance matrix. A maximum likelihood method was used to estimate parameters.Missing data were computed based on the estimated conditional mean of themissing response, given the values of the responses that were present. "Status"reflected the diagnostic category of the participant, whereas "time" reflectedthe average of the dependent variable during successive measurement occasionsthroughout the day. The first 12 measurement occasions of the daily sessionwere used in these analyses.

Analysis of Response to Stress or Panic

Participants in the 3 diagnostic groups who reported stress (or panicfor the PD group) were examined in more detail to determine whether differencesin response to stress were evident. Any stress period during the experimentalsessions was included in the analysis, so some participants were representedby more than 1 data point. The unbalanced repeated-measures approach usedfor the analysis, implemented through BMDP-5V, took this lack of independenceinto account. Diagnostic group was a between-group factor, whereas the repeated-measurefactor was time in reference to the report of stress (before, during, andafter the button press).

Relation Between Subjective and Physiologic Variables

The relation between objective and subjective responses for the 3 diagnosticgroups was examined for measures of basal level (daily average, not includingbutton-press periods) and change due to stress (as indicated by the buttonpress). A hierarchical set regression approach29 wasused. This approach investigated the relationship between the objective levelof physiologic activity and the subject's report of the subjective state usuallyassociated with that response. In these analyses, the subjective measure wasconsidered the dependent measure, and the physiologic and diagnostic variableswere regarded as predictors. Between-group differences were found in age,and this variable was used as a covariate in all analyses. The statisticalpackage BMDP-2R (Statistical Software Inc) was used to perform the analyses.

Variables were forced into the regression in sets in the following order:age, group membership/physiologic response, linear interactions with group,and quadratic interactions with group. Interaction terms were carried by productvariables as a function of their order of entry into the equation. The primarypurpose of these analyses was to evaluate whether the diagnostic variablemodified the nature of the relationship between physiologic level or physiologicchange (for stress response) and the individual's report of the associatedsubjective variable.

Demographic characteristics of the PD, GAD, and control groups are givenin Table 1. Race and sex distributionsdid not differ as a function of diagnostic category, but control subjectswere younger on average than those diagnosed as having GAD or PD. No interactionsbetween diagnostic groups and sex were found. Both anxiety groups rated higherthan controls on the total HAM-A, the cardiovascular symptoms item of theHAM-A, the state and trait scales of the State-Trait Anxiety Inventory, allitems of the Sheehan Disability Scale, the Barsky Amplification Scale, andthe Body Sensations Questionnaire. The PD group differed from the GAD groupon the total HAM-A, the cardiovascular symptoms item of the HAM-A, and theBody Sensations Questionnaire.

Table Graphic Jump LocationTable 1. Demographic Characteristics of 90 Study Participants*
DAILY CHANGES DURING MONITORING SESSIONS

Table 2 summarizes the significanteffects during the first daily monitoring session. Responses on all of thesubjective measures showed significant differences between groups, as didthe physiologic measures of mean IBI, IBI variance, and skin conductance variance.In general, the analyses distinguished the participants with anxiety disordersfrom the controls. According to Mann-Whitney post hoc comparisons, both anxietygroups rated themselves higher than the controls on rapid heart beat, sweating,difficulty breathing, feeling tense, and worry; however, the anxiety groupsdid not differ from each other.

Table Graphic Jump LocationTable 2. Summary of Overall Responses Across the First Day for EachSignificant Dependent Variable*

These findings were consistent with orthogonal contrasts, performedas part of the overall analysis comparing the physiologic measures of controlsubjects with those of patients with GAD and PD. The following results wereobtained: mean heart rate was lower (IBI was greater) in controls (z = 1.89; P = .06), but IBI variance (z = 2.74; P = .006) and skin conductancevariance (z = 2.87; P =.004) were greater in controls.

DIFFERENCES BETWEEN GROUPS WHEN STRESS OR PANIC WAS REPORTED

Participants who reported stress or panic during the study did not differin terms of age. However, the PD subgroup reporting panic attacks was predominantlyfemale (88% women), whereas the control subgroup reporting stress was predominantlymale (71% men). The GAD subgroup reporting stress was equally divided (50%women).

Table 3 gives means andstandard deviations for subjective responses that showed a significant differencebetween the last rating before the button press and during the button pressindicating stress or anxiety or, in patients with PD, a panic attack. Patientswith PD showed increased response at the time of button press compared withthe preceding recording for difficulty breathing, rapid heart rate, sweating,feeling tense, and worry. The GAD group showed an increase only for rapidheart rate and feeling tense. The control group showed no significant changes.None of the groups showed differences between ratings obtained before andafter the button press. When the groups were compared for difference in scoresbetween baseline and button press, the PD group differed from the controlgroup in rapid heart beat, sweating, difficulty breathing, and feeling tense,whereas the GAD group differed from the control group only in rapid heartbeat. The PD group differed from the GAD group in sweating, feeling tense,and worry, along with a tendency toward difficulty breathing. There were nostatistically significant differences in measures of skin conductance, heartrate, or respiration. In the control group, 75% of button presses were accompaniedby an increase in heart rate; in the GAD group, 71% of button presses wereaccompanied by an increase in heart rate; and in the PD group, 74% of buttonpresses were accompanied by an increase in heart rate.

Table Graphic Jump LocationTable 3. Subjective Response Ratings of Participants Who Pressed theButton During Stress (Control and GAD Groups) or Panic (Panic Group)a

In addition, an examination of button-press data from all 4 days ofthe experiment revealed between-group differences in the frequency of buttonpressing (Table 4). During theexperiment, 29% of controls (n = 7) indicated at least 1 stressful periodcompared with 42% of patients with GAD (n = 17) and 65% of patients with PD(n = 17) who experienced a full-blown panic attack at least 1 time duringthe study (χ2 = 6.87; P = .03).

Table Graphic Jump LocationTable 4. Frequency of at Least 1 Button Press During the ExperimentalSessions by Diagnostic Group
RELATION BETWEEN SUBJECTIVE AND PHYSIOLOGIC DATA

Relations between subjective and physiologic data were examined usinghierarchical regression analysis and data from the basal period for mean IBIand mean skin conductance level. Figure 1 and Figure 2 illustratehow the relation between basal objective and subjective measures differedas a function of diagnostic category. An overall negative linear relationshipwas identified between mean IBI (inversely related to heart rate) and perceptionof rapid heart rate (F2,78 = 5.62; R2 inc = 0.121; P = .006), but this overalleffect was more pronounced for controls than for individuals with PD or GAD(F1,79 = 10.3; R2 inc = 0.111; P = .001) (Figure 1).Thus, although there was a general trend in all participants to associatelower IBI values with a subjective report of a more rapid heart beat, thetrend was stronger in nonanxious control subjects. This finding suggests that,overall, the participants in the anxiety disorder groups were less "responsive,"as expressed by the slope of subjective vs physiologic relationships, to differencesin the IBI than were nonanxious controls. Again using data from the basalperiod, the relation between skin conductance level and perceived sweatingwas statistically significantly different among the diagnostic groups (Figure 2). The controls associated more accuratelythe 2 conditions (F2,77 = 5.15; R2 inc = 0.112; P = .008). No statisticallysignificant main effects or interactions were found in the analysis of therelationship between basal respiration and reported difficulty of breathing.Patients in each anxiety disorder group differed significantly more amongthemselves in the accuracy of estimation of bodily functions than did controls.

Place holder to copy figure label and caption
Figure 1.

Subjective estimates of rapidheart rate vs recorded mean interbeat interval in nonanxious controls (A),patients with generalized anxiety disorder (B), and patients with panic disorder(C). Data points represent the mean values across a 6-hour period in the absenceof a button press. Estimates of rapid heart rate were rated on a scale from1 to 100.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Subjective estimates of sweatinessvs recorded mean skin conductance level in nonanxious controls (A), patientswith generalized anxiety disorder (B), and patients with panic disorder (C).Data points represent the mean values across a 6-hour period in the absenceof a button press. Estimates of sweatiness were rated on a scale from 1 to100.

Graphic Jump Location

This study described and compared the subjective and physiologic responsesof patients with GAD, patients with PD, and controls who wore a speciallyconstructed ambulatory monitor during daily activities. For calculating subjectiveand physiologic states when not feeling tense or anxious, we used the datafrom the first day's recording because they were most complete. For calculatingchanges when stressed, we included button presses and the recording of thepreceding automatic half-hour recording from all 4 recording days. Becausea button press can occur at any time after the last 6-minute recording period,the time between the 2 recordings, without overlapping, could have been 27minutes or less.

RESPONSES OF PARTICIPANTS WHEN NOT RECORDING ANXIETY OR STRESS

Patients with GAD and PD rated themselves higher on psychic and somaticanxiety, on disability scales, and on sensitivity to body sensations thancontrols. However, patients with PD and GAD differed little from each otheron self-ratings, except on the Body Sensations Questionnaire, where patientswith PD rated higher than patients with GAD, indicating heightened concernwith bodily functions. This finding is consistent with the idea that patientswith PD interpret physical sensations as dangerous and patients with GAD interpretthem as anxiety but is at variance with findings from previous studies3032 indicating that patientswith PD reported significantly more autonomic symptoms than patients withGAD. There are several possible explanations for these differences. Patientswith GAD and PD are not homogenous groups and may vary considerably in typeand severity of physical symptoms. Moreover, preoccupation with somatic symptomsmay not relate to the degree of physiologic change.15 Patientsalso may have different anchoring points of severity for symptoms,33 and self-ratings may depend on the instructions givento the participant.34

Patients with PD, patients with GAD, and controls showed little differencein their physiologic responses when not registering anxiety, except for atrend in patients with PD to have a faster heart rate throughout the day.This finding corresponds with results obtained in some, but not all, laboratorystudies. Differences in the severity of PD may contribute to differences inheart rate. For example, Charney et al35 foundthat physiologic responses to yohimbine challenge in patients with PD correlatedwith the average number of panic attacks. Another possibility is that patientswith PD did less physical exercise than nonanxious subjects. Physical exerciseaffects the physiologic state of an individual.36 However,our patients, by interview and by self-ratings while wearing the monitor,pursued normal daily activities that were comparable to those of the othergroups. If the groups had differed significantly in physical condition, onewould expect differences in their physiologic data, which was not the case.Our data suggest that patients with PD experienced not only heightened sensitivityto bodily sensations but slightly higher autonomic arousal levels than patientswith GAD and controls. Respiration rate did not differentiate the groups,but the monitor recorded only frequency, not volume. Several studies3739 suggest respiratoryirregularity and higher tidal volume in patients with PD that our recordingdevice missed.

DIMINISHED PHYSIOLOGIC FLEXIBILITY

The most prominent physiologic finding of this study was the decreasedvariance in heart IBI and skin conductance throughout the day in both anxietygroups compared with controls. Our group found DPF in the laboratory in patientswith GAD,5 patients with PD,40 andpatients with obsessive-compulsive disorder41;other laboratories confirmed these findings in patients with GAD8 andPD.10,12 Other studies found DPFin patients with phobic anxiety,42 posttraumaticstress disorder,43 depression,44 premenstrualsyndrome,45 and alcoholism46 andin individuals with high neuroticism or social maladjustment.3,47,48 Furthermore,DPF manifests itself in anxious individuals as decreased catecholamine3,47 and cortisol4951 excretionand in electroencephalographic responses to challenges.52,53 Thus,diminished responsiveness to stressors is a nonspecific central and peripheralmanifestation that accompanies prolonged anxiety or stress. There are severalpossible explanations for this phenomenon. First, DPF does not represent a"ceiling effect," as proposed by some investigators,53,54 becausebaseline values of patients with chronic anxiety and their response to stressorsdo not often differ from those of nonanxious subjects. Constitutional factors,as seen in shy children,55 may predispose individualsto DPF and anxiety disorders, but the developmental course and clinical implicationsof such possible effects are not well understood. Diminished physiologic flexibilitymay represent a partial but inadequate attempt by the body to adapt to thephysiologic changes induced by chronic anxiety.56,57 Apsychological explanation is also plausible. Anxiety, particularly worry,preoccupies anxious individuals with internal events and diminishes theirattention to stimuli that are unrelated to their pathologic condition.48,58 Thayer and Lane59 presenteda model in which diminished cardiac vagal tone, manifesting itself in diminishedheart beat variability, represents the peripheral manifestation of inadequatecentral inhibition of the autonomic system in anxious subjects; a high vagaltone is associated with greater behavioral flexibility. According to thismodel, the Central Autonomic Network, a functional unit that appears to supportgoal-directed behavior and adaptability, includes the anterior cingulate,the insular and ventromedial prefrontal cortices, the periaqueductal gray,and nuclei of the hypothalamus, the striatum, and the pontine regions. Itsprimary output system is mediated through the preganglionic sympathetic andparasympathetic neurons. The system interprets visceral, humoral, and environmentalinformation and coordinates autonomic, endocrine, and behavioral responsesto environmental challenges. Anxiety leads to inhibition of the parasympatheticsystem and to dominance of the sympathetic system, which manifests itselfin decreased responsivity of the cardiovascular system to rapid changes inenvironmental demands. Although their model may explain many physiologic responsepatterns, a change in cardiac vagal tone is not invariably associated withDPF. We did not find diminished vagal tone in patients with GAD (D.R.M. andR.H.-S., unpublished data, 2000), and other researchers have not found itin patients with PD60 or in depression despitean increased heart rate.61 Using functionalmagnetic resonance imaging, our group62 foundthat patients with GAD exhibited strong BOLD responses in the prefrontal andlimbic regions to statements that described a personal worry and to neutralstatements. Reduction of anxiety with citalopram therapy led to weaker BOLDresponses to both but particularly to neutral statements. These findings62,63 suggest that during high anxiety,cerebral responses to stimuli become indiscriminate to the nature of the stimulus,leading to dysfunctional central processing of information. The indiscriminantresponses to stimuli may lead to limited modulation of physiologic reactivitywithout necessarily involving the vagal system. Further clarifications ofthe biological function of DPF and its long-term effects on health are needed.59,64

RESPONSES TO A BUTTON PRESS INDICATING PANIC, ANXIETY, OR STRESS

At the time of button press, all 3 groups registered higher reportsof rapid heart beat, sweating, difficulties breathing, feeling of tension,and worry. These increases were strongest in patients with PD and weakestin controls. The greatest increase in self-ratings was in difficulty breathing,which increased 6-fold. In addition, patients with PD pressed the button significantlymore frequently (indicating a panic attack) than did patients with GAD andcontrols, although the latter groups were instructed to press the button wheneverthey felt tense or anxious. Thus, patients with PD experienced not only moresevere but also more frequent anxiety.

Reports of physiologic changes during panic attacks indicate that marked,mild, or no physiologic changes may accompany attacks. Heart rate changes,recorded spontaneously in the laboratory or by ambulatory monitors duringpanic attacks, range from no change to 38 beats per minute.6571 In1 study,69 heart rate did not change disproportionatelyduring 42% of recorded panic attacks. This demonstrates that panic attackscan occur without substantial cardiac changes. Similar to previous ambulatorymonitor studies,68,69,71 74%of our patients with PD had an increase in heart rate during the time of thebutton press. Thus, 26% of the panic attacks occurred without cardiac changes.However, the GAD and control groups had similar heart rate increases, whichranged from no change to 12 beats per minute. Thus, heart rate increase seemsto be associated with increased tension or anxiety irrespective of the presenceof panic attacks or anxiety disorder and despite prominent cardiac symptomsaccompanying panic attacks. However, without obtaining constant analog recordingswe may have missed brief changes in heart rhythm.

RELATION BETWEEN SUBJECTIVE AND PHYSIOLOGIC DATA

As reported by other researchers,22,72 patientswith PD were more sensitive to body sensations on self-ratings. Despite greatersensitivity, patients with PD and GAD were less accurate than controls intheir perception of bodily states and showed substantially more variability.As demonstrated elsewhere,15,73 patientsare accurate in the estimation of the direction of bodily changes but notin their estimation of the degree of change and differ in levels of attentionand expectations, which modify their perceptions. The discrepancy betweenself-reports of physical changes during panic attacks and the lack of suchchanges may be explained by a sensitization of the patients to body changesduring early panic attacks. Recurrent somatic experiences may than create"engrams" in the brain that can induce bodily sensations with minimally alteringperipheral physiologic function. Such centrally induced panic attacks havebeen demonstrated by Lenz et al74 who found,during surgery for intractable pain in a patient with panic attacks, thatthe stimulation of an area in the thalamus evoked panic attacks without causingthe physical changes that the patient described.

LIMITATIONS OF THE AMBULATORY MONITOR STUDY

Ambulatory monitors measure responses in real-life situations, and theirdata have greater external validity than those obtained in the laboratory.However, the number of parameters that can be recorded and the length of therecordings are limited by memory, battery power, and the potential for technicalfailures. Moreover, the type and severity of stressors is unpredictable. Verificationof panic attacks is easier in the laboratory than during ambulatory recording.Despite these shortcomings, we obtained adequate information on physiologicstates throughout a day and responses before and after indication of stress,anxiety, or panic. Further studies are needed to clarify the relationshipbetween reported somatic manifestations and physiologic responses in patientswho differ in diagnosis, severity of illness, and family history and to integratethe data into the framework of imaging studies.

Correspondence: Rudolf Hoehn-Saric, MD, Department of Psychiatry,The Johns Hopkins Medical Institutions, 600 N Wolfe St, Meyer Bldg, Room 113,Baltimore, MD 21287-7113 (rhoehn@mail.jhmi.edu).

Submitted for publication January 13, 2003; final revision receivedMarch 10, 2004; accepted March 16, 2004.

This study was supported by grant MH42579 from the National Instituteof Mental Health, Bethesda, Md.

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Barsky  AJGoodson  JDLane  RSCleary  PD The amplification of somatic symptoms. Psychosom Med. 1988;50510- 519
PubMed Link to Article
Chambless  DLCaputo  GCBright  PGallagher  R Assessment of fear in agoraphobics: the Body Sensations Questionnaireand the Agoraphobic Cognitions Questionnaire. J Consult Clin Psychol. 1984;521090- 1097
PubMed Link to Article
Hoehn-Saric  RMcLeod  DRZimmerli  WD Symptoms and treatment responses of generalized anxiety disorder patientswith high versus low levels of cardiovascular complaints. Am J Psychiatry. 1989;146854- 859
PubMed
Thakor  NVYang  MAmaresan  MReiter  EHoehn-Saric  RMcLeod  DR Microcomputer-based ambulatory monitor for vital signs in anxiety disorders. J Ambul Monit. 1989;2277- 294
Fowles  DCChristie  MJEdelberg  R Publication recommendations for electrodermal measurements. Psychophysiology. 1981;18232- 239
PubMed Link to Article
Jennrich  RISchluchter  MD Unbalanced repeated-measures models with structured covariance matrices. Biometrics. 1986;42805- 820
PubMed Link to Article
Jones  RHBoadi  B Unequal spaced longitudinal data with AR(1) serial correlation. Biometrics. 1991;47161- 175
PubMed Link to Article
Willet  JBSayer  AG Using covariance structure analysis to detect correlations and predictorsof individual change over time. Psychol Bull. 1994;116363- 381
Link to Article
Cohen  JCohen  P Applied Multiple Regression/Correlation Analysisfor the Behavioral Science.  Hillsdale, NJ Lawrence Erlbaum Associates1975;
Anderson  DJNoyes  RCrowe  RR A comparison of panic disorder and generalized anxiety disorder. Am J Psychiatry. 1984;141572- 575
PubMed
Hoehn-Saric  R Comparison of generalized anxiety disorder with panic disorder patients. Psychopharmacol Bull. 1982;18104- 108
PubMed
Logue  MBThomas  AMBarbee  JGHoehn-Saric  RMaddock  RJSchwab  JSmith  RDSullivan  MBeitman  BD Generalized anxiety disorder patients seek evaluation for cardiologicalsymptoms at the same frequency as patients with panic disorder. J Psychiatr Res. 1993;2755- 59
PubMed Link to Article
McLeod  DRFoster  GVHoehn-Saric  RSvikis  DSHipsley  PA Family history of alcoholism in women with generalized anxiety disorderwho have premenstrual syndrome: patient reports of premenstrual alcohol consumptionand symptoms of anxiety. Alcohol Clin Exp Res. 1994;18664- 670
PubMed Link to Article
McLeod  DRHoehn-Saric  RFoster  GVHipsley  PA The influence of prementrual syndrome on ratings of anxiety in womenwith generalized anxiety disorder. Acta Psychiatr Scand. 1993;88248- 251
PubMed Link to Article
Charney  DSWoods  SWGoodman  WKHeninger  GR Neurobiological mechanisms of panic anxiety: biochemical and behavioralcorrelates of yohimbine-induced panic attacks. Am J Psychiatry. 1987;1441030- 1036
PubMed
Asmundson  GJStein  MB Resting cardiovascular measures in patients with panic disorder andsocial phobia and health control subjects: relationship to habitual exercisefrequency. Anxiety. 1994;126- 30
PubMed Link to Article
Abelson  JLWeg  JGNesse  RMCurtis  GC Persistent respiratory irregularity in patients with panic disorder. Biol Psychiatry. 2001;49588- 595
PubMed Link to Article
Martinez  JMPapp  LACoplan  JDAnderson  DEMueller  CMKlein  DFGorman  JM Ambulatory monitoring of respiration in anxiety. Anxiety. 1996;2296- 302
PubMed
Roth  WTWilhelm  FHTrabert  W Autonomic instability during relaxation in panic disorder. Psychiatry Res. 1998;80155- 164
PubMed Link to Article
Hoehn-Saric  RMcLeod  DRZimmerli  WD Psychophysiological response patterns in panic disorder. Acta Psychiatr Scand. 1991;834- 11
PubMed Link to Article
Hoehn-Saric  RMcLeod  DRHipsley  P Is hyperarousal essential to obsessive-compulsive disorder? diminishedphysiologic flexibility, but not hyperarousal, characterizes patients withobsessive-compulsive disorder. Arch Gen Psychiatry. 1995;52688- 693
PubMed Link to Article
Kawachi  ISparrow  DVokonas  PSWeiss  ST Decreased heart rate variability in men with phobic anxiety (data fromthe Normative Aging Study). Am J Cardiol. 1995;75882- 885
PubMed Link to Article
Cohen  HKotler  MMatar  AKaplan  ZMiodownik  HCassuto  Y Power spectrum analysis of heart rate variability in posttraumaticstress disorder. Biol Psychiatry. 1997;41627- 629
PubMed Link to Article
Thayer  JFSmith  MRossy  LASollers  JJFriedman  BH Heart period variability in depressive symptoms: gender differences. Biol Psychiatry. 1998;44304- 306
PubMed Link to Article
Kirsch  JRGeer  JH Skin conductance and heart rate in women with premenstrual syndrome. Psychosom Med. 1988;50175- 182
PubMed Link to Article
Ingjaldsson  JTLaberg  JCThayer  JF Reduced heart rate variability in chronic alcohol abuse: relationshipwith negative mood, chronic thought suppression, and compulsive drinking. Biol Psychiatry. 2003;541427- l436
PubMed Link to Article
Forsman  L Habitual catecholamine excretion and its relation to habitual distress. Biol Psychol. 1980;1183- 97
PubMed Link to Article
Shapiro  DCrider  A Psychophysiological approaches in social psychology. Lindzey  GAronson  EedsThe Handbook ofSocial Psychology. 2nd Reading, Pa Addison-Wesley Publishing Co1969;1- 49
Hubert  WJong-Meyer  R Saliva cortisol responses to unpleasant film stimuli differ betweenhigh and low trait anxious subjects. Neuropsychobiology. 1992;25115- 120
PubMed Link to Article
Yehuda  RSouthwick  SMNussbaum  GWahby  VGiller  ELMason  JW Low urinary cortisol excretion in patients with post-traumatic stressdisorder. J Nerv Ment Dis. 1990;178366- 369
PubMed Link to Article
Yehuda  RKahana  BBinder-Brynes  KSouthwick  SMMason  JWGiller  EL Low urinary cortisol excretion in Holocaust survivors with possttraumaticstress disorder. Am J Psychiatry. 1995;152982- 986
PubMed
Inz  J EEG Activity in Generalized Anxiety Disorder [doctoraldissertation].  University Park, Pa Penn State University1990;
Tecce  JJ Contingent negative variation (CNV) and psychological processes inman. Psychol Bull. 1972;7773- 108
PubMed Link to Article
Kelly  D Anxiety and Emotions.  Springfield, Ill Charles C Thomas Publisher1980;
Kagan  JReznick  JSSnidman  N Biological bases of childhood shyness. Science. 1988;240167- 171
PubMed Link to Article
Burchfield  SR The stress response: a new perspective. Psychosom Med. 1979;41661- 672
PubMed Link to Article
Yehuda  RResnick  HKahana  BGiller  EL Longlasting hormonal alterations to extreme stress in humans: normativeor maladaptive? Psychosom Med. 1993;55287- 297
PubMed Link to Article
Grillon  CBuchsbaum  MS EEG topography of response to visual stimuli in generalized anxietydisorder. Electroencephalogr Clin Neurophysiol. 1987;66337- 348
PubMed Link to Article
Thayer  JFLane  RD A model of neurovisceral integration in emotion regulation and dysregulation. J Affect Disord. 2000;61201- 216
PubMed Link to Article
Asmundson  GJStein  MB Vagal attenuation in panic disorder: an assessment of parasympatheticnervous system function and subjective reactivity to respiratory manipulations. Psychosom Med. 1994;56187- 193
PubMed Link to Article
Moser  MLehofer  MHoehn-Saric  RMcLeod  DRHildebrandt  GSteinbrenner  BVoica  MLiebermann  PZapotoczky  HG Increased heart rate in depressed subjects in spite of unchanged autonomicbalance? J Affect Disord. 1998;48115- l24
PubMed Link to Article
Hoehn-Saric  RSchlund  MWWong  SHY Effect of citalopram on worry and brain activation in patients withgeneralized anxiety disorder. Psychol Res Neuroimag. In press
Bishop  SDuncan  JBrett  MLawrence  DA Prefrontal cortical function and anxiety: controlling attention tothreat-related stimuli. Nat Neurosci. 2004;7184- 188
PubMed Link to Article
Hoehn-Saric  RMcLeod  DR Anxiety and arousal: physiological changes and their perception. J Affect Disord. 2000;61217- 224
PubMed Link to Article
Lader  MHMathews  A Physiological changes during spontaneous panic attacks. J Psychosom Res. 1970;14377- 382
PubMed Link to Article
Balon  ROrtiz  APohl  RYeragani  VK Heart rate and blood pressure during placebo-associated panic attacks. Psychosom Med. 1988;50434- 438
PubMed Link to Article
Goetz  RRKlein  DFGully  RKahn  JLiebowitz  MRFyer  AJGorman  JM Panic attacks during placebo procedures in the laboratory. Arch Gen Psychiatry. 1993;50280- 285
PubMed Link to Article
Freedman  RRIanni  PEttedgui  EPuthezhath  N Ambulatory monitoring of panic disorder. Arch Gen Psychiatry. 1985;42244- 248
PubMed Link to Article
Taylor  CBSheikh  JAgras  SRoth  WTMargraf  JEhlers  AMaddock  RJGossard  D Ambulatory heart rate changes in patients with panic attacks. Am J Psychiatry. 1986;143478- 482
PubMed
Woods  SWCharney  DSMcPherson  CAGradman  AHHeninger  GR Situational panic attacks: behavioral, physiologic, and biochemicalcharacterization. Arch Gen Psychiatry. 1987;44365- 375
PubMed Link to Article
Taylor  CBSheikh  JAgras  SRoth  WTMargraf  JEhlers  AMaddock  RJGossard  D Ambulatory heart rate changes in patients with panic attacks. Am J Psychiatry. 1986;143478- 482
PubMed
Clark  DMSalkovskis  PMOst  LGBreitholtz  EKoehler  KAWestling  BEJeavons  AGelder  M Misinterpretation of body sensations in panic disorder. J Consult Clin Psychol. 1997;65203- 213
PubMed Link to Article
McLeod  DRHoehn-Saric  RStefan  RL Somatic symptoms of anxiety: comparison of self-report and physiologicalmeasures. Biol Psychiatry. 1986;21301- 310
PubMed Link to Article
Lenz  FAGracely  RHRomanoski  AJHope  EJRowland  LHDaugherty  PM Stimulation in the human somatosensory thalamus can reproduceboth the affective and sensory dimensions of previously experienced pain. Nat Med. 1995;1910- 913
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Subjective estimates of rapidheart rate vs recorded mean interbeat interval in nonanxious controls (A),patients with generalized anxiety disorder (B), and patients with panic disorder(C). Data points represent the mean values across a 6-hour period in the absenceof a button press. Estimates of rapid heart rate were rated on a scale from1 to 100.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Subjective estimates of sweatinessvs recorded mean skin conductance level in nonanxious controls (A), patientswith generalized anxiety disorder (B), and patients with panic disorder (C).Data points represent the mean values across a 6-hour period in the absenceof a button press. Estimates of sweatiness were rated on a scale from 1 to100.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic Characteristics of 90 Study Participants*
Table Graphic Jump LocationTable 2. Summary of Overall Responses Across the First Day for EachSignificant Dependent Variable*
Table Graphic Jump LocationTable 3. Subjective Response Ratings of Participants Who Pressed theButton During Stress (Control and GAD Groups) or Panic (Panic Group)a
Table Graphic Jump LocationTable 4. Frequency of at Least 1 Button Press During the ExperimentalSessions by Diagnostic Group

References

Hoehn-Saric  RMcLeod  DR Somatic manifestations of normal and pathological anxiety. Hoehn-Saric  RMcLeod  DRedsBiology of AnxietyDisorders. Washington, DC American Psychiatric Press1993;177- 222
Ursin  HMurison  RCC Classification and description of stress. Brown  GMKoslow  SHReichlin  SedsNeuroendocrinologyand Psychiatric Disorder. New York, NY Raven Press1984;123- 131
Frankenhaeuser  M Psychoneuroendocrine approaches to the study of emotion as relatedto stress and coping. Howe  HEJedNebraska Symposium on Motivation. Lincoln University of Nebraska Press1979;123- 161
 Generalized anxiety disorder Noyes  RJHoehn-Saric  RThe Anxiety Disorders New York, NY Cambridge University Press1998;37- 85
Hoehn-Saric  RMcLeod  DRZimmerli  WD Somatic manifestations in women with generalized anxiety disorder. Arch Gen Psychiatry. 1989;461113- 1119
PubMed Link to Article
Kollai  MKollai  B Cardiac vagal tone in generalised anxiety disorder. Br J Psychiatry. 1992;161831- 835
PubMed Link to Article
Lyonfields  JDBorkovec  TDThayer  JF Vagal tone in generalized anxiety disorder and the effects of aversiveimagery and worrisome thinking. Behav Ther. 1995;26457- 466
Link to Article
Thayer  JFFriedman  BHBorkovec  TD Autonomic characteristics of generalized anxiety disorder and worry. Biol Psychiatry. 1996;39255- 266
PubMed Link to Article
Stein  MBAsmundson  GJ Autonomic function in panic disorder: cardiorespiratory and plasmacatecholamine responsivity to multiple challenges of the autonomic nervoussystem. Biol Psychiatry. 1994;36548- 558
PubMed Link to Article
Friedman  BHThayer  JF Autonomic balance revisited: panic anxiety and heart rate variability. J Psychosom Res. 1998;44133151;
PubMed Link to Article
Friedman  BHThayer  JF Anxiety and autonomic flexibility: a cardiovascular approach. Biol Psychol. 1998;49303- 323
PubMed Link to Article
Yeragani  VKBalon  RPohl  RRamesh  CGlitz  DWeinberg  PMerlos  B Decreased R-R variance in panic disorder patients. Acta Psychiatr Scand. 1990;81554- 559
PubMed Link to Article
Klein  ECnaani  EHarel  TBrown  SHaim  SA Ben Altered heart rate variability in panic disorder patients. Biol Psychiatry. 1995;3718- 24
PubMed Link to Article
Wilhelm  FHTrabert  WRoth  WT Physiological instability in panic disorder and generalized anxietydisorder. Biol Psychiatry. 2001;49596- 605
PubMed Link to Article
McLeod  DRHoehn-Saric  R Perception of physiological changes in normal and pathological anxiety. Hoehn-Saric  RMcLeod  DRedsBiology of AnxietyDisorders. Washington, DC American Psychiatric Press1993;223- 243
First  MBSpitzer  RLGibbon  MWilliams  J Structured Clinical Interview for DSM-IV Axis I Disorders,Clinician Version (SCID-CV).  Washington, DC American Psychiatric Press1997;
Spielberger  CDGorsuch  RLLushene  RE Manual for the State-Trait Anxiety Inventory.  Palo Alto, Calif Consulting Psychologists Press1970;
Hamilton  M The assessment of anxiety states by rating. Br J Med Psychol. 1959;3250- 55
PubMed Link to Article
Beck  ATRush  AJShaw  BFEmery  G Cognitive Therapy of Depression.  New York, NY Guilford Press1979;
Sheehan  DV The Anxiety Disease.  New York, NY Scribner1983;
Barsky  AJGoodson  JDLane  RSCleary  PD The amplification of somatic symptoms. Psychosom Med. 1988;50510- 519
PubMed Link to Article
Chambless  DLCaputo  GCBright  PGallagher  R Assessment of fear in agoraphobics: the Body Sensations Questionnaireand the Agoraphobic Cognitions Questionnaire. J Consult Clin Psychol. 1984;521090- 1097
PubMed Link to Article
Hoehn-Saric  RMcLeod  DRZimmerli  WD Symptoms and treatment responses of generalized anxiety disorder patientswith high versus low levels of cardiovascular complaints. Am J Psychiatry. 1989;146854- 859
PubMed
Thakor  NVYang  MAmaresan  MReiter  EHoehn-Saric  RMcLeod  DR Microcomputer-based ambulatory monitor for vital signs in anxiety disorders. J Ambul Monit. 1989;2277- 294
Fowles  DCChristie  MJEdelberg  R Publication recommendations for electrodermal measurements. Psychophysiology. 1981;18232- 239
PubMed Link to Article
Jennrich  RISchluchter  MD Unbalanced repeated-measures models with structured covariance matrices. Biometrics. 1986;42805- 820
PubMed Link to Article
Jones  RHBoadi  B Unequal spaced longitudinal data with AR(1) serial correlation. Biometrics. 1991;47161- 175
PubMed Link to Article
Willet  JBSayer  AG Using covariance structure analysis to detect correlations and predictorsof individual change over time. Psychol Bull. 1994;116363- 381
Link to Article
Cohen  JCohen  P Applied Multiple Regression/Correlation Analysisfor the Behavioral Science.  Hillsdale, NJ Lawrence Erlbaum Associates1975;
Anderson  DJNoyes  RCrowe  RR A comparison of panic disorder and generalized anxiety disorder. Am J Psychiatry. 1984;141572- 575
PubMed
Hoehn-Saric  R Comparison of generalized anxiety disorder with panic disorder patients. Psychopharmacol Bull. 1982;18104- 108
PubMed
Logue  MBThomas  AMBarbee  JGHoehn-Saric  RMaddock  RJSchwab  JSmith  RDSullivan  MBeitman  BD Generalized anxiety disorder patients seek evaluation for cardiologicalsymptoms at the same frequency as patients with panic disorder. J Psychiatr Res. 1993;2755- 59
PubMed Link to Article
McLeod  DRFoster  GVHoehn-Saric  RSvikis  DSHipsley  PA Family history of alcoholism in women with generalized anxiety disorderwho have premenstrual syndrome: patient reports of premenstrual alcohol consumptionand symptoms of anxiety. Alcohol Clin Exp Res. 1994;18664- 670
PubMed Link to Article
McLeod  DRHoehn-Saric  RFoster  GVHipsley  PA The influence of prementrual syndrome on ratings of anxiety in womenwith generalized anxiety disorder. Acta Psychiatr Scand. 1993;88248- 251
PubMed Link to Article
Charney  DSWoods  SWGoodman  WKHeninger  GR Neurobiological mechanisms of panic anxiety: biochemical and behavioralcorrelates of yohimbine-induced panic attacks. Am J Psychiatry. 1987;1441030- 1036
PubMed
Asmundson  GJStein  MB Resting cardiovascular measures in patients with panic disorder andsocial phobia and health control subjects: relationship to habitual exercisefrequency. Anxiety. 1994;126- 30
PubMed Link to Article
Abelson  JLWeg  JGNesse  RMCurtis  GC Persistent respiratory irregularity in patients with panic disorder. Biol Psychiatry. 2001;49588- 595
PubMed Link to Article
Martinez  JMPapp  LACoplan  JDAnderson  DEMueller  CMKlein  DFGorman  JM Ambulatory monitoring of respiration in anxiety. Anxiety. 1996;2296- 302
PubMed
Roth  WTWilhelm  FHTrabert  W Autonomic instability during relaxation in panic disorder. Psychiatry Res. 1998;80155- 164
PubMed Link to Article
Hoehn-Saric  RMcLeod  DRZimmerli  WD Psychophysiological response patterns in panic disorder. Acta Psychiatr Scand. 1991;834- 11
PubMed Link to Article
Hoehn-Saric  RMcLeod  DRHipsley  P Is hyperarousal essential to obsessive-compulsive disorder? diminishedphysiologic flexibility, but not hyperarousal, characterizes patients withobsessive-compulsive disorder. Arch Gen Psychiatry. 1995;52688- 693
PubMed Link to Article
Kawachi  ISparrow  DVokonas  PSWeiss  ST Decreased heart rate variability in men with phobic anxiety (data fromthe Normative Aging Study). Am J Cardiol. 1995;75882- 885
PubMed Link to Article
Cohen  HKotler  MMatar  AKaplan  ZMiodownik  HCassuto  Y Power spectrum analysis of heart rate variability in posttraumaticstress disorder. Biol Psychiatry. 1997;41627- 629
PubMed Link to Article
Thayer  JFSmith  MRossy  LASollers  JJFriedman  BH Heart period variability in depressive symptoms: gender differences. Biol Psychiatry. 1998;44304- 306
PubMed Link to Article
Kirsch  JRGeer  JH Skin conductance and heart rate in women with premenstrual syndrome. Psychosom Med. 1988;50175- 182
PubMed Link to Article
Ingjaldsson  JTLaberg  JCThayer  JF Reduced heart rate variability in chronic alcohol abuse: relationshipwith negative mood, chronic thought suppression, and compulsive drinking. Biol Psychiatry. 2003;541427- l436
PubMed Link to Article
Forsman  L Habitual catecholamine excretion and its relation to habitual distress. Biol Psychol. 1980;1183- 97
PubMed Link to Article
Shapiro  DCrider  A Psychophysiological approaches in social psychology. Lindzey  GAronson  EedsThe Handbook ofSocial Psychology. 2nd Reading, Pa Addison-Wesley Publishing Co1969;1- 49
Hubert  WJong-Meyer  R Saliva cortisol responses to unpleasant film stimuli differ betweenhigh and low trait anxious subjects. Neuropsychobiology. 1992;25115- 120
PubMed Link to Article
Yehuda  RSouthwick  SMNussbaum  GWahby  VGiller  ELMason  JW Low urinary cortisol excretion in patients with post-traumatic stressdisorder. J Nerv Ment Dis. 1990;178366- 369
PubMed Link to Article
Yehuda  RKahana  BBinder-Brynes  KSouthwick  SMMason  JWGiller  EL Low urinary cortisol excretion in Holocaust survivors with possttraumaticstress disorder. Am J Psychiatry. 1995;152982- 986
PubMed
Inz  J EEG Activity in Generalized Anxiety Disorder [doctoraldissertation].  University Park, Pa Penn State University1990;
Tecce  JJ Contingent negative variation (CNV) and psychological processes inman. Psychol Bull. 1972;7773- 108
PubMed Link to Article
Kelly  D Anxiety and Emotions.  Springfield, Ill Charles C Thomas Publisher1980;
Kagan  JReznick  JSSnidman  N Biological bases of childhood shyness. Science. 1988;240167- 171
PubMed Link to Article
Burchfield  SR The stress response: a new perspective. Psychosom Med. 1979;41661- 672
PubMed Link to Article
Yehuda  RResnick  HKahana  BGiller  EL Longlasting hormonal alterations to extreme stress in humans: normativeor maladaptive? Psychosom Med. 1993;55287- 297
PubMed Link to Article
Grillon  CBuchsbaum  MS EEG topography of response to visual stimuli in generalized anxietydisorder. Electroencephalogr Clin Neurophysiol. 1987;66337- 348
PubMed Link to Article
Thayer  JFLane  RD A model of neurovisceral integration in emotion regulation and dysregulation. J Affect Disord. 2000;61201- 216
PubMed Link to Article
Asmundson  GJStein  MB Vagal attenuation in panic disorder: an assessment of parasympatheticnervous system function and subjective reactivity to respiratory manipulations. Psychosom Med. 1994;56187- 193
PubMed Link to Article
Moser  MLehofer  MHoehn-Saric  RMcLeod  DRHildebrandt  GSteinbrenner  BVoica  MLiebermann  PZapotoczky  HG Increased heart rate in depressed subjects in spite of unchanged autonomicbalance? J Affect Disord. 1998;48115- l24
PubMed Link to Article
Hoehn-Saric  RSchlund  MWWong  SHY Effect of citalopram on worry and brain activation in patients withgeneralized anxiety disorder. Psychol Res Neuroimag. In press
Bishop  SDuncan  JBrett  MLawrence  DA Prefrontal cortical function and anxiety: controlling attention tothreat-related stimuli. Nat Neurosci. 2004;7184- 188
PubMed Link to Article
Hoehn-Saric  RMcLeod  DR Anxiety and arousal: physiological changes and their perception. J Affect Disord. 2000;61217- 224
PubMed Link to Article
Lader  MHMathews  A Physiological changes during spontaneous panic attacks. J Psychosom Res. 1970;14377- 382
PubMed Link to Article
Balon  ROrtiz  APohl  RYeragani  VK Heart rate and blood pressure during placebo-associated panic attacks. Psychosom Med. 1988;50434- 438
PubMed Link to Article
Goetz  RRKlein  DFGully  RKahn  JLiebowitz  MRFyer  AJGorman  JM Panic attacks during placebo procedures in the laboratory. Arch Gen Psychiatry. 1993;50280- 285
PubMed Link to Article
Freedman  RRIanni  PEttedgui  EPuthezhath  N Ambulatory monitoring of panic disorder. Arch Gen Psychiatry. 1985;42244- 248
PubMed Link to Article
Taylor  CBSheikh  JAgras  SRoth  WTMargraf  JEhlers  AMaddock  RJGossard  D Ambulatory heart rate changes in patients with panic attacks. Am J Psychiatry. 1986;143478- 482
PubMed
Woods  SWCharney  DSMcPherson  CAGradman  AHHeninger  GR Situational panic attacks: behavioral, physiologic, and biochemicalcharacterization. Arch Gen Psychiatry. 1987;44365- 375
PubMed Link to Article
Taylor  CBSheikh  JAgras  SRoth  WTMargraf  JEhlers  AMaddock  RJGossard  D Ambulatory heart rate changes in patients with panic attacks. Am J Psychiatry. 1986;143478- 482
PubMed
Clark  DMSalkovskis  PMOst  LGBreitholtz  EKoehler  KAWestling  BEJeavons  AGelder  M Misinterpretation of body sensations in panic disorder. J Consult Clin Psychol. 1997;65203- 213
PubMed Link to Article
McLeod  DRHoehn-Saric  RStefan  RL Somatic symptoms of anxiety: comparison of self-report and physiologicalmeasures. Biol Psychiatry. 1986;21301- 310
PubMed Link to Article
Lenz  FAGracely  RHRomanoski  AJHope  EJRowland  LHDaugherty  PM Stimulation in the human somatosensory thalamus can reproduceboth the affective and sensory dimensions of previously experienced pain. Nat Med. 1995;1910- 913
PubMed Link to Article

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