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Effects of stressor controllability on psychophysiological, cognitive and behavioural responses in patients with major depression ...

Effects of stressor controllability on psychophysiological, cognitive and behavioural responses... Psychological Medicine (2009), 39, 77–86. f 2008 Cambridge University Press ORIGINAL ARTICLE doi:10.1017/S0033291708003437 Printed in the United Kingdom Effects of stressor controllability on psychophysiological, cognitive and behavioural responses in patients with major depression and dysthymia 1 2 1 1 1 C. Diener *#, C. Kuehner #, W. Brusniak , M. Struve and H. Flor Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany Research Group Longitudinal and Intervention Research, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Germany Background. The experience of uncontrollability and helplessness in the face of stressful life events is regarded as an important determinant in the development and maintenance of depression. The inability to successfully deal with stressors might be linked to dysfunctional prefrontal functioning. We assessed cognitive, behavioural and physiological effects of stressor uncontrollability in depressed and healthy individuals. In addition, relationships between altered cortical processing and cognitive vulnerability traits of depression were analysed. Method. A total of 26 unmedicated depressed patients and 24 matched healthy controls were tested in an expanded forewarned reaction (S1–S2) paradigm. In a factorial design, stressor controllability varied across three consecutive conditions: (a) control, (b) loss of control and (c) restitution of control. Throughout the experiment, error rates, ratings of controllability, arousal, emotional valence and helplessness were assessed together with the post-imperative negative variation (PINV) of the electroencephalogram. Results. Depressed participants showed an enhanced frontal PINV as an electrophysiological index of altered information processing during both loss of control and restitution of control. They also felt more helpless than controls. Furthermore, frontal PINV magnitudes were associated with habitual rumination in the depressed sub- sample. Conclusions. These findings indicate that depressed patients are more susceptible to stressor uncontrollability than healthy subjects. Moreover, the experience of uncontrollability seems to bias subsequent information processing in a situation where control is objectively re-established. Alterations in prefrontal functioning appear to contribute to this vulnerability and are also linked to trait markers of depression. Received 22 June 2007; Revised 20 March 2008; Accepted 27 March 2008; First published online 9 May 2008 Key words: Depression, learned helplessness, post-imperative negative variation, rumination, stress. Introduction structural brain changes (Breier, 1989) that are in line with core features of depression. Despite these Human as well as animal studies emphasize the parallels, studies investigating the psychobiological maladaptive role of stress exposure in the develop- effects of stressor uncontrollability in depressed indi- ment of depression (Czeh et al. 2001; Alfonso et al. viduals are rare. 2005; Henn & Vollmayr, 2005). There is evidence Neuroimaging studies of depression point to that the degree of behavioural control modulates dysfunctions in the limbic–thalamic–cortical network, the impact of environmental stressors (Maier, 1984). indicating hypoactivity in prefrontal brain areas in- Consequences of stressor uncontrollability in humans cluding the cingulate gyrus during resting states range from cognitive, motivational and emotional (Mayberg, 1997; Pizzagalli et al. 2005). In contrast, alterations (Maier & Seligman, 1976) to neuroendo- a majority of studies examining activation during crinological, neurochemical and functional as well as cognitively demanding tasks identified prefrontal hyperactivation in depressed patients at similar per- * Address for correspondence : C. Diener, Ph.D., Department of formance levels as controls (Harvey et al. 2005; Cognitive and Clinical Neuroscience, Central Institute of Mental Wagner et al. 2006; Matsuo et al. 2007), potentially Health, Square J5, 68159 Mannheim, Germany. indicating compensatory activation in order to main- (Email : carsten.diener@zi-mannheim.de) # These authors contributed equally to this work. tain adequate levels of performance. 78 C. Diener et al. Slow cortical potential studies have shown that the dysthymia (n=7) in the age range of 18–60 years were post-imperative negative variation (PINV) is a suitable recruited from the Department of Psychiatry and indicator of information processing during uncon- Psychotherapy, Central Institute of Mental Health, trollability over aversive events. In healthy subjects, Mannheim, Germany (n=10) and by public an- enhanced PINV magnitudes over frontal recording nouncements (n=16). Twenty-four age-, education- sites have been found during an unexpected change and gender-matched healthy controls were recruited from an escape paradigm to uncontrollability by advertisement from the local community. (Rockstroh et al. 1979; Elbert et al. 1982) and during Participants were examined using the structured unpredictable response outcome contingencies in clinical interview for Diagnostic and Statistical general (Kathmann et al. 1990). In addition, it has Manual of Mental Disorders (DSM-IV) (APA, 1994) been shown that anhedonic individuals display Axis I disorders (First et al. 1997). Healthy participants higher PINV magnitudes during uncontrollability were excluded if they met criteria for a current (Lutzenberger et al. 1981). In depressed patients, Bolz & DSM-IV Axis I disorder or lifetime criteria for any Giedke (1981) found higher PINV magnitudes when affective disorder. General exclusion criteria were an aversive stimulus was uncontrollable or when con- current alcohol or drug abuse, current use of psycho- trol was restricted. These data suggest that the PINV tropic medication and current or lifetime psychotic depicts a frontal response evaluation in situations of symptoms and neurological problems. A co-morbid stressor uncontrollability or uncertainty about the anxiety disorder was not an exclusion criterion in the appropriate response. Under such conditions, de- depressed sample. pressed patients seem to be more vulnerable than Participants completed the Beck Depression healthy controls (Bolz & Giedke, 1981; Breier, 1989). Inventory II (BDI-II; Beck et al. 1996) and were eval- In the present study, we expanded a standard fore- uated for depression severity using the Hamilton warned reaction (S1–S2) paradigm (Rockstroh et al. Rating Scale for Depression (HAMD; Hamilton, 1960). 1979) to assess cognitive, behavioural and physiologi- Psychosocial functioning was rated using the social cal effects of stressor uncontrollability in depressed and occupational functioning assessment scale (APA, and healthy individuals. Stressor controllability varied 1994). Habitual rumination was assessed by the across three consecutive conditions: (a) control, (b) German version of the response styles questionnaire loss of control and (c) restitution of control. We hy- (Nolen-Hoeksema & Morrow, 1991; Kuehner et al. pothesized that depressed participants would be more 2007b) with the subscales symptom-focused and self- prone to uncontrollability as indexed by enhanced focused rumination. A ruminative coping style in frontal PINV magnitudes and pronounced feelings response to depressed mood has been found to of helplessness and uncontrollability. Additionally, exaggerate and prolong dysphoric episodes (Nolen- based on learned helplessness theory (Maier & Hoeksema, 2004). The study was in concordance with Seligman, 1976), we expected that loss of control the declaration of Helsinki and was approved by the would bias subsequent information processing Medical Ethics Committee of the Medical Faculty particularly in depressed subjects, as indicated by a Mannheim at the University of Heidelberg, Germany. pattern of elevated frontal PINV magnitude, pro- After complete description of the study to the subjects, longed feelings of helplessness and uncontrollability, written informed consent was obtained. and increased error rates during restitution of control. Basic demographic and clinical sample character- In contrast, we did not expect group differences in istics are provided in Table 1. A large percentage of parietal PINV magnitudes during loss of control and depressed patients (73.9%) had suffered from pre- restitution of control. Finally, we hypothesized that vious episodes of depression. a larger frontal PINV – particularly under restitution of control – would be associated with higher levels Experimental design of depression and with habitual rumination, the latter describing a cognitive vulnerability trait to depression The experiment consisted of a modified forewarned characterized by perpetual negative self-focusing (S1–S2) reaction paradigm. S1 was a 600 Hz/60 dB (Kuehner et al. 2007a). tone of 4 s duration immediately followed by S2, which was a 1000 Hz/60 dB tone of 1 s duration. In case of aversive stimulation, an electrical stimu- Method lus of 1 ms duration was applied to the index finger of the non-dominant hand following S2 termination. Participants The intertrial interval varied randomly between Twenty-six medication-free depressed patients with 5 s and 9 s (mean=7 s). Subjects were instructed to a diagnosis of major depressive disorder (n=19) or respond to S2 onset by pressing the correct (left v. Stressor controllability in depression 79 Table 1. Sample characteristics Depressed Healthy subjects subjects F(1, 48) Variable (n=26) (n=24) or x (1) p Age (years) 47.19 (8.94) 44.75 (9.02) 0.92 N.S. Gender (% female) 54.16 64.71 0.46 N.S. Length of education (years) 11.00 (1.57) 11.13 (1.48) 0.08 N.S. DSM-IV diagnosis (SCID) Major depression (%) 73.08 – Pure dysthymia (%) 26.92 – Co-morbid anxiety diagnosis (n)2 – Age at onset (years) 30.42 (22.03) – No. of episodes 3.32 (3.17) – HAMD depression score 18.69 (6.66) 0.25 (0.44) 182.89 <0.001 BDI-II depression score 25.24 (10.62) 0.78 (1.86) 123.48 <0.001 Psychosocial functioning (SOFAS) 61.35 (10.48) 99.58 (2.04) 308.21 <0.001 Electrical stimulus amperage (mA) 3.34 (2.39) 4.13 (3.79) 0.88 N.S. Values are given as mean (standard deviation), % or n. N.S., Non-significant; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition (APA, 1994); SCID, Structured Clinical Interview for DSM-IV Axis I disorders (First et al. 1997); HAMD, Hamilton Rating Scale for Depression (Hamilton, 1960); BDI-II, Beck Depression Inventory, 2nd revision (Beck et al. 1996); SOFAS, Social and Occupational Functioning Scale (APA, 1994). right) button in order to avoid aversive electrical participants had to focus a fixation-cross in the centre stimulation. of the monitor to avoid eye-movement artefacts. The Controllability of the aversive stimulus varied entire protocol lasted about 1 h. The diagnostic inter- across three successive conditions of 40 trials each. view was carried out in a separate session lasting up In the first condition of controllability, the aversive to 2.5 h. stimulus could be avoided by pressing either the right or the left button (counterbalanced across subjects). Apparatus and recording technique Without prior warning, subjects randomly received the electrical stimulus in half of the trials during Participants’ scalp electroencephalography (EEG) was the following condition of uncontrollability so that no recorded from 30 sites based on the extended 10–20 response outcome contingency could be established. system (Nuwer et al. 1998) referenced to linked In the third condition, control was re-established, mastoids and digitally sampled at 500 Hz using a again without prior warning. The left v. right button Neuroscan Synamps DC amplifier (NeuroScan Inc., press as effective response was switched between the Herndon, VA, USA). An Easy Cap (FMS GmbH, conditions of controllability and restitution of control. Munich, Germany) with AgAgCl-electrodes of 10 mm Prior to the experimental manipulation (baseline) diameter was used. The electrodes were prepared and every 15th and 35th trial in each condition, parti- with abrasive paste (Abralyt 2000; FMS GmbH) and cipants rated their current arousal and emotional filled with electrode jelly (Electro-Cap International, valence via a self-assessment manikin (Lang, 1980). Inc., Eaton, OH, USA). Impedances were kept below Controllability and helplessness were rated on visual 5kV. The electro-oculogram (EOG) was recorded analogue scales. The ratings were presented on a from tin electrodes of 9 mm diameter which were monitor y1.2 m in front of the subjects. affixed 1 cm above and below the left eye (vertical During the experiment, the participants sat in a EOG), and at the outer canthi (horizontal EOG) of reclining chair in an electrically shielded room. S1 and both eyes (Picton et al. 1995). S2 tones were presented by means of foam ear inserts For electrical stimulation, a constant current stimu- (MedCaT, Erica, The Netherlands). The intensity of the lator (model DS7A; Digitimer Ltd, Welwyn Garden pain stimulus was individually calibrated as aversive City, Herts, UK) was used with custom-designed foil but tolerable (see Table 1). During the experiment electrodes, which were attached to the distal and 80 C. Diener et al. middle phalanges of the index finger of the non- gender role (Kuehner, 2003), we controlled for poten- dominant hand. tial gender differences in all analyses. Within the patient and healthy control samples, male and female subjects did not differ with regard to any of the as- Data reduction and analysis sessed variables presented in Table 1. Furthermore, Subjects’ button presses were continuously recorded the inclusion of gender in the analyses described be- and classified as erroneous if the response was low did not result in any significant main or interac- followed by electrical stimulation in the control and tion effect of this variable and did not affect the restitution of control conditions. Controllability and significance levels of the other variables in the re- helplessness ratings were scored from 0 to 100, those spective models. Therefore, we only present results for arousal and valence from 1 to 9 (Lang, 1980). The with data collapsed across gender. mean of the two ratings (at trial 15 and 35) per con- Partial correlations with two-tailed significance le- dition was subjected to the statistical analysis. vels are reported for the associations between frontal Brain vision analyzer (version 1.05; Brain Products PINV magnitudes and measures of depression, help- GmbH, Gilching, Germany) was employed for the lessness and habitual rumination for the depressed analyses of EEG data. Based on other studies examin- and the healthy subsample. In these analyses, we ing the PINV (Rockstroh et al. 1979; Elbert et al. 1982) controlled for PINV magnitudes during the initial and our study hypotheses, midline frontal (Fz) and condition of control in analyses involving the PINV parietal (Pz) recording sites, the latter serving as a under loss of control and restitution of control. In control site, were included in the analyses. Data were analyses involving the rumination subscales, we segmented into epochs of 9 s corresponding to S1 further adjusted for current Hamilton depression and S2 presentation (5 s) and a 4 s post-imperative scores to assess net associations between PINV scores interval. Each segment was corrected for eye move- and cognitive vulnerability not attributable to inter- ments (Gratton et al. 1983) and semi-automatically individual differences in depression levels. rejected when corrupted by artifacts (i.e. voltage step/sampling point o50 mV, minimal amplitude <x100 mV, maximal amplitude >100 mV). The re- Results maining trials (minimum 34; i.e. 85%) were then Rating data averaged. There were no group [F(1, 48)=0.15, N.S.], condition [F(2, 47)=0.4, N.S.] or grouprcondition Controllability [F(2, 47)=0.6, N.S.] effects with regard to trials in- For the controllability ratings a main effect of con- cluded. PINV magnitudes were defined as mean ac- dition [Pillai’s trace F(2, 47)=16.86, p<0.001] was tivity (mV) during the segment between 800 ms found that mirrored exactly the experimental design and 3500 ms following S2 termination relative to a (Fig. 1a). Depressed and healthy subjects showed a 1000 ms pre-trial baseline (see Rockstroh et al. 1979; decrease from control (mean=63.40, S.D.=35.79) to Bolz & Giedke, 1981; Elbert et al. 1982; Kathmann et al. loss of control (mean=34.10, S.D.=30.00) [t(49)= 1990). x5.90, p<0.001], followed by a subsequent increase during restitution of control (mean=52.00, S.D.=31.82) Statistical analyses [t(49)=4.31, p<0.001]. There were no significant Univariate group comparisons for sociodemographic group [F(1, 48)=0.204, N.S.] or interaction effects and clinical data were performed using analyses of [F(2, 47)=0.019, N.S.], indicating that the two groups variance (ANOVAs) for continuous and x tests for did not differ in the overall amount of perceived con- dichotomous variables. The dependent variables were trol or across conditions (see Fig. 1a). subjected to repeated-measures ANOVAs with group (depressed v. healthy subjects) as between- and con- Helplessness dition (control, loss of control, and restitution of con- trol) as within-subject factors. To test for significance, For the helplessness ratings a main effect of group we used Pillai’s trace statistic, which is most robust [F(1, 48)=7.38, p=0.009] reflected elevated levels of against violations of assumptions. In case of significant perceived helplessness in the depressed participants main or interaction effects, post-hoc paired compari- (mean=33.71, S.D.=25.80) compared with healthy sons were performed by means of paired-samples controls (mean=13.89, S.D.=25.82) throughout the t tests with two-tailed levels of significance. experiment. There was no significant main effect for Since female gender is regarded as an important condition [F(2, 47)=1.95, N.S.] but a marginally sig- risk factor for depression, and learned helplessness nificant conditionrgroup interaction [F(2, 47)=3.01, is thought to be particularly connected to the female p=0.059]. Depressed patients [t(25)=0.65, N.S.] and Stressor controllability in depression 81 condition effect [F(2, 48)=x4.94, p=0.011] indicated a (a) 80 decline in arousal from controllability (mean=3.48, S.D.=3.62) to restitution of control (mean=3.23, S.D.=1.91) [t(49)=x2.18, p=0.034]. A non-significant interaction term [F(2, 47)=1.19, N.S.] indicated similar decreases in both groups. 30 Emotional valence In general, depressed participants (mean=4.87, S.D.= Loss Restitution Control of of 1.63) rated the situation as significantly more un- control control pleasant than healthy controls (mean=3.39, S.D.=1.67) [group: F(1, 48)=10.20, p=0.002]. There was neither (b) 40 a significant main effect for condition [F(2, 47)=2.33, N.S.] nor a significant conditionrgroup interaction [F(2, 47)=0.41, N.S.]. Behavioural data Errors and reaction times The ANOVAs for erroneous responses (ER) and Loss Restitution for reaction times (RT) resulted in no significant Control of of effects [condition: ER F(1, 48)=2.73, N.S.; RT F(2, 47)= control control 0.278; group: ER F(1, 48)=1.35, N.S.; RT F(1, 48)=0.01, (c) –3.0 N.S.; interaction: ER F(1, 48)=0.26, N.S.; RT F(1, 48)= 0.26, N.S.]. –2.5 –2.0 PINV –1.5 Due to insufficient statistical power, the omnibus ANOVA resulted in no significant interaction of –1.0 group, condition and electrode site [F(2, 45)=1.56, p=0.221]. Therefore and according to our hypotheses, –0.5 Loss Restitution we separately report the results for the frontal and Control of of parietal recording sites. control control Fig. 1. Ratings of perceived (a) controllability, (b) helplessness Frontal recording site and (c) magnitudes (mV) of the post-imperative negative variation (PINV) at the midline frontal recording site (Fz) For Fz a main effect for group [F(1, 48)=5.88, p=0.019] during the experimental protocol for depressed ($, n=26) was found. Overall, depressed participants showed and healthy (2, n=24) subjects. higher PINVs (mean=x1.98, S.D.=1.49) than healthy controls (mean=x0.97, S.D.=1.49). Furthermore, controls [t(23)=1.74, N.S.] showed similar non- we identified a marginally significant main effect significant increases from control to loss of control for condition [F(2, 47)=2.98, p=0.060] and a highly [t(49)=1.67, N.S.]. However, in depressed participants significant conditionrgroup interaction [F(2, 47)= the feelings of helplessness further increased during 8.54, p<0.001]. Within-group analyses revealed that restitution of control (mean=36.54, S.D.=30.26) as in contrast to healthy controls [t(23)=x1.07, N.S.] compared with initial control (mean=31.54, S.D.= depressed participants responded with an enhanced 29.69) [t(25)=2.17, p=0.040], a pattern not seen in PINV [t(25)=x3.35, p=0.003] during loss of control healthy participants [t(23)=0.55, N.S., see Fig. 1b]. (mean=x2.71, S.D.=2.48) compared with initial control (mean=x0.87, S.D.=1.43). Additionally, de- Arousal pressed participants showed a higher PINV during restitution of control (mean=x2.38, S.D.=1.58) com- The arousal ratings of the depressed participants pared with initial control [t(25)=x4.30, p<0.001], a were significantly higher throughout the exper- pattern not seen in healthy controls [t(23)=x0.55, N.S., iment (mean =0.17, S.D.=1.68 v. mean=2.66, S.D.= see Fig. 1c]. 1.72) [group: F(1, 48)=9.78, p=0.003]. A significant PINV at Fz (µV) Helplessness (%) Controllability (%) 82 C. Diener et al. (a) Depressed subjects Healthy subjects (n=26) (n=24) –5 µ V Control Fz Loss of control Restit. of control 0 µ V S1 S2 S1 S2 PINV PINV 0 1 2 345678 012345678 Time (s) Time (s) (b) Depressed subjects Fz Pz 5800–8500 ms Healthy subjects –7.0 µ V –0.0 µ V Control Loss of control Restitution of control Fig. 2. (a) Averaged event-related potentials (ERPs, negativity up, filtered with a 6 Hz, 12 dB high cut-off) for the midline frontal recording site (Fz) during S1 (warning stimulus) and S2 (imperative stimulus) presentation, and the post-S2 interval. The post-imperative negative variation [PINV (mV)] was parameterized 800–3500 ms following S2 termination. The lines indicate the ERPs during initial condition of control, subsequent loss of control and restitution of control for depressed (n=26) and healthy (n=24) subjects. (b) Topographic two-dimensional maps of the post-S2 interval (800–3500 ms) for depressed and healthy subjects during initial condition of control, subsequent loss of control and restitution of control [topographic x5 interpolation by spherical splines (order=4, maximum degree of Legendre polynomials=10, l=1re ), see Perrin et al. 1989]. Pz, parietal recording site. To control for a possible influence of perceived Parietal recording site helplessness on the identified main and interaction The ANOVA for Pz as a control site resulted in effects at Fz, we reanalysed the data with baseline no significant effects [group: F(1, 48)=1.28, N.S.; helplessness as a covariate. The reported group and condition: F(2, 47)=2.53, N.S.; conditionrgroup: interaction effects remained statistically significant F(2, 47)=0.424, N.S.]. Fig. 2b shows the topographic [group F(1, 47)=4.37, p=0.042; conditionrgroup distribution of the PINV during the post-imperative F(2, 46)=8.03, p=0.001]. interval. To further control for a differential effect of the electrical stimulation on PINV magnitudes, we in- Exclusion of patients with dysthymia cluded the number of electrical stimuli during control and during restitution of control as covariates in the To test for potential confounds arising from the in- ANOVA. Again, this procedure did not affect the clusion of mildly chronically depressed patients, we significance of our results [group: F(1, 46)=6.39, p= reanalysed the data by excluding individuals with 0.015; condition: F(2, 45)=3.97, p=0.026; conditionr pure dysthymia (n=7). The results regarding group: F(2, 45)=8.83, p=0.001]. Averaged event- subjective ratings, errors and PINV magnitudes related potentials for Fz are illustrated in Fig. 2 a. remained virtually the same [e.g. PINV at Fz, ERP at Fz (µ V) Stressor controllability in depression 83 symptom-focused rumination and frontal PINV magnitudes during restitution of control in depressed patients. Discussion This study investigated cognitive, behavioural and physiological effects of stressor uncontrollability in –2 depressed individuals and healthy controls. While previous studies have successfully manipulated stres- sor controllability by means of change from a con- –4 dition of control to loss of control in forewarned reaction (S1–S2) paradigms (Rockstroh et al. 1979), we 10 15 20 25 30 expanded the standard procedure by a subsequent Symptom-focused rumination condition of restitution of control to also assess the Fig. 3. Scatterplot for frontal post-imperative negative effects of previous stressor uncontrollability in a situ- variation (PINV) magnitudes (mV) at the midline frontal ation where control was objectively re-established. recording site (Fz) during restitution of control and Additionally, we included ratings of arousal, symptom-focused rumination scores measured by the emotional valence, controllability and helplessness German version of the response styles questionnaire throughout the experiment. (Kuehner et al. 2007). While depressed participants rated the situation as more unpleasant in general, ratings of emotional group: F(1, 41)=7.18, p=0.011; condition: F(2, 40)= valence did not vary with the alternating pattern 3.11, p=0.056; conditionrgroup: F(2, 40)=8.55, p< of controllability. Both groups demonstrated only a 0.001]. slight increase of errors after withdrawal of control. This indicates that the challenge of the task was mod- Correlations between frontal PINV and measures erate and comparable for both healthy and depressed of depression and cognitive vulnerability individuals. In the total sample, higher levels of self-(BDI-II) and Both groups rated their perceived controllability interviewer-(HAMD) rated depression were connec- in concordance with the varying degrees of control- ted to larger (more negative) frontal PINV magnitudes lability. However, depressed participants felt more during loss of control (BDI-II: partial r=x0.363, helpless and aroused throughout the experiment. p<0.05; HAMD: partial r=x0.492, p<0.001) and While withdrawal of control caused a non-significant restitution of control (BDI-II: partial r=x0.489, increase of perceived helplessness in both groups, p<0.001; HAMD: partial r=x0.491, p<0.001). only depressed subjects displayed markedly enhanced However, these results merely mirrored respective levels of helplessness in the subsequent restitution of group differences identified in the ANOVAs, since control condition. separate correlation analyses for the depressed and The most apparent differences between depressed healthy subsamples resulted in no significant corre- and healthy subjects were identified with respect to lations within groups (all p>0.10). Perceived help- frontal PINV magnitudes. During loss of control, de- lessness was not significantly correlated with PINV pressed participants showed an enhanced PINV over values in any condition. Particularly in the depressed frontal sites, indicating that they engaged frontal areas subsample, we identified significant negative corre- to resolve task-induced ambiguity (see Klein et al. lations between the two rumination scores and PINV 1996). Furthermore, depressed participants main- magnitude under restitution of control. In this group, tained this activation pattern in the subsequent con- higher levels of symptom-focused and self-focused dition when control was re-established. They also rumination were connected to larger PINV values felt more helpless than healthy controls, particularly under restitution of control, even if baseline de- under restitution of control. Thus, while the enhanced pression levels were partialled out (n=26, PINV at Fz frontal PINV in depressed subjects during loss of during restitution of control with symptom-focused control may be related to heightened contingency re- rumination: partial r=x0.517, p=0.01, with self- appraisal and task-induced ambiguity, the experience focused rumination: partial r=x0.419, p=0.05). In of uncontrollability appeared to have also biased sub- contrast, respective coefficients failed to reach statisti- sequent cortical processing, as expected by learned cal significance in the healthy subsample (all p>0.10). helplessness theory. Since this was only true for the Fig. 3 presents a scatterplot for the association of depressed subsample, we assume that depressed PINV at Fz (µV) during restitution of control 84 C. Diener et al. individuals are more susceptible to conditions of While the PINV has been established as a reliable uncontrollability. indicator of loss of control in previous work The event-related potential data indicate that (Rockstroh et al. 1979; Bolz & Giedke, 1981; Lutzen- depressed individuals responded to changing levels berger et al. 1981; Elbert et al. 1982; Kathmann et al. of stressor controllability with enhanced prefrontal 1990), this is the first study to show that in depressed activation. Increased prefrontal activity during loss subjects the experience of uncontrollability appears to of control and restitution of control may reflect a induce biased subsequent cortical processing. During compensatory mechanism in order to resolve task- restitution of control, depressed participants still induced ambiguity. These considerations are in line demonstrated elevated frontal PINV magnitudes and with recent studies indicating abnormal prefrontal pronounced feelings of helplessness. Our data suggest hyperactivation during working memory load in that the prefrontal hyperactivation may be considered patients with mood disorders (Hugdahl et al. 2004; as a physiological compensation to resolve ambiguity Harvey et al. 2005; Rose et al. 2006; Wagner et al. 2006; induced by previous loss of control. Furthermore, we Chiu & Deldin, 2007). It is thus conceivable that identified substantial associations between enhanced depressed subjects need enhanced activation of pre- frontal PINV magnitudes with habitual rumination frontal brain regions such as the anterior cingulate in depressed patients. cortex, the ventromedial or the dorsolateral prefrontal Future studies should examine state- versus trait- cortex (Luu et al. 2003; Rose et al. 2006; Siegle et al. characteristics of the PINV, its predictive role for 2007), which are involved in cognitive control during the development and clinical course of depression, ambiguity provoked by uncontrollable stress. In this and its sensitivity to therapeutic change. Furthermore, context, future studies using functional magnetic studies including a simultaneous assessment of EEG resonance imaging (fMRI) to identify specific neuro- and fMRI are needed to link exaggerations of the PINV anatomical areas involved in the observed altered in depressed patients to functional neuroanatomical frontal response pattern in depressed patients are models of depression. warranted. Finally, habitual symptom-focused and self- Acknowledgements focused rumination were specifically linked to the frontal PINV under restitution of control, and this This work was supported by the Deutsche Forschungs- was particularly true for the depressed subsample. gemeinschaft (SFB636/D4). We gratefully acknowl- These results are the first to suggest a possible con- edge the valuable assistance of Elena Maininguer nection between psychological traits reflecting per- in data collection. petual preoccupation with negative aspects of the self and altered prefrontal information processing Declaration of Interest during a learned helplessness paradigm in depressed patients. None. This study has several limitations. First, the PINV cannot be regarded as a depression-specific cortical index of altered information processing. An enhanced References PINV has also been observed in schizophrenic patients Alfonso J, Frasch AC, Flugge G (2005). Chronic stress, where it is similarly regarded as a cortical indicator depression and antidepressants: effects on gene of task-related ambiguity (Klein et al. 1996; Verleger transcription in the hippocampus. Annual Review of et al. 1999). 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Effects of stressor controllability on psychophysiological, cognitive and behavioural responses in patients with major depression ...

Psychological Medicine , Volume 39 (1) – May 9, 2008

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Abstract

Psychological Medicine (2009), 39, 77–86. f 2008 Cambridge University Press ORIGINAL ARTICLE doi:10.1017/S0033291708003437 Printed in the United Kingdom Effects of stressor controllability on psychophysiological, cognitive and behavioural responses in patients with major depression and dysthymia 1 2 1 1 1 C. Diener *#, C. Kuehner #, W. Brusniak , M. Struve and H. Flor Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany Research Group Longitudinal and Intervention Research, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Germany Background. The experience of uncontrollability and helplessness in the face of stressful life events is regarded as an important determinant in the development and maintenance of depression. The inability to successfully deal with stressors might be linked to dysfunctional prefrontal functioning. We assessed cognitive, behavioural and physiological effects of stressor uncontrollability in depressed and healthy individuals. In addition, relationships between altered cortical processing and cognitive vulnerability traits of depression were analysed. Method. A total of 26 unmedicated depressed patients and 24 matched healthy controls were tested in an expanded forewarned reaction (S1–S2) paradigm. In a factorial design, stressor controllability varied across three consecutive conditions: (a) control, (b) loss of control and (c) restitution of control. Throughout the experiment, error rates, ratings of controllability, arousal, emotional valence and helplessness were assessed together with the post-imperative negative variation (PINV) of the electroencephalogram. Results. Depressed participants showed an enhanced frontal PINV as an electrophysiological index of altered information processing during both loss of control and restitution of control. They also felt more helpless than controls. Furthermore, frontal PINV magnitudes were associated with habitual rumination in the depressed sub- sample. Conclusions. These findings indicate that depressed patients are more susceptible to stressor uncontrollability than healthy subjects. Moreover, the experience of uncontrollability seems to bias subsequent information processing in a situation where control is objectively re-established. Alterations in prefrontal functioning appear to contribute to this vulnerability and are also linked to trait markers of depression. Received 22 June 2007; Revised 20 March 2008; Accepted 27 March 2008; First published online 9 May 2008 Key words: Depression, learned helplessness, post-imperative negative variation, rumination, stress. Introduction structural brain changes (Breier, 1989) that are in line with core features of depression. Despite these Human as well as animal studies emphasize the parallels, studies investigating the psychobiological maladaptive role of stress exposure in the develop- effects of stressor uncontrollability in depressed indi- ment of depression (Czeh et al. 2001; Alfonso et al. viduals are rare. 2005; Henn & Vollmayr, 2005). There is evidence Neuroimaging studies of depression point to that the degree of behavioural control modulates dysfunctions in the limbic–thalamic–cortical network, the impact of environmental stressors (Maier, 1984). indicating hypoactivity in prefrontal brain areas in- Consequences of stressor uncontrollability in humans cluding the cingulate gyrus during resting states range from cognitive, motivational and emotional (Mayberg, 1997; Pizzagalli et al. 2005). In contrast, alterations (Maier & Seligman, 1976) to neuroendo- a majority of studies examining activation during crinological, neurochemical and functional as well as cognitively demanding tasks identified prefrontal hyperactivation in depressed patients at similar per- * Address for correspondence : C. Diener, Ph.D., Department of formance levels as controls (Harvey et al. 2005; Cognitive and Clinical Neuroscience, Central Institute of Mental Wagner et al. 2006; Matsuo et al. 2007), potentially Health, Square J5, 68159 Mannheim, Germany. indicating compensatory activation in order to main- (Email : carsten.diener@zi-mannheim.de) # These authors contributed equally to this work. tain adequate levels of performance. 78 C. Diener et al. Slow cortical potential studies have shown that the dysthymia (n=7) in the age range of 18–60 years were post-imperative negative variation (PINV) is a suitable recruited from the Department of Psychiatry and indicator of information processing during uncon- Psychotherapy, Central Institute of Mental Health, trollability over aversive events. In healthy subjects, Mannheim, Germany (n=10) and by public an- enhanced PINV magnitudes over frontal recording nouncements (n=16). Twenty-four age-, education- sites have been found during an unexpected change and gender-matched healthy controls were recruited from an escape paradigm to uncontrollability by advertisement from the local community. (Rockstroh et al. 1979; Elbert et al. 1982) and during Participants were examined using the structured unpredictable response outcome contingencies in clinical interview for Diagnostic and Statistical general (Kathmann et al. 1990). In addition, it has Manual of Mental Disorders (DSM-IV) (APA, 1994) been shown that anhedonic individuals display Axis I disorders (First et al. 1997). Healthy participants higher PINV magnitudes during uncontrollability were excluded if they met criteria for a current (Lutzenberger et al. 1981). In depressed patients, Bolz & DSM-IV Axis I disorder or lifetime criteria for any Giedke (1981) found higher PINV magnitudes when affective disorder. General exclusion criteria were an aversive stimulus was uncontrollable or when con- current alcohol or drug abuse, current use of psycho- trol was restricted. These data suggest that the PINV tropic medication and current or lifetime psychotic depicts a frontal response evaluation in situations of symptoms and neurological problems. A co-morbid stressor uncontrollability or uncertainty about the anxiety disorder was not an exclusion criterion in the appropriate response. Under such conditions, de- depressed sample. pressed patients seem to be more vulnerable than Participants completed the Beck Depression healthy controls (Bolz & Giedke, 1981; Breier, 1989). Inventory II (BDI-II; Beck et al. 1996) and were eval- In the present study, we expanded a standard fore- uated for depression severity using the Hamilton warned reaction (S1–S2) paradigm (Rockstroh et al. Rating Scale for Depression (HAMD; Hamilton, 1960). 1979) to assess cognitive, behavioural and physiologi- Psychosocial functioning was rated using the social cal effects of stressor uncontrollability in depressed and occupational functioning assessment scale (APA, and healthy individuals. Stressor controllability varied 1994). Habitual rumination was assessed by the across three consecutive conditions: (a) control, (b) German version of the response styles questionnaire loss of control and (c) restitution of control. We hy- (Nolen-Hoeksema & Morrow, 1991; Kuehner et al. pothesized that depressed participants would be more 2007b) with the subscales symptom-focused and self- prone to uncontrollability as indexed by enhanced focused rumination. A ruminative coping style in frontal PINV magnitudes and pronounced feelings response to depressed mood has been found to of helplessness and uncontrollability. Additionally, exaggerate and prolong dysphoric episodes (Nolen- based on learned helplessness theory (Maier & Hoeksema, 2004). The study was in concordance with Seligman, 1976), we expected that loss of control the declaration of Helsinki and was approved by the would bias subsequent information processing Medical Ethics Committee of the Medical Faculty particularly in depressed subjects, as indicated by a Mannheim at the University of Heidelberg, Germany. pattern of elevated frontal PINV magnitude, pro- After complete description of the study to the subjects, longed feelings of helplessness and uncontrollability, written informed consent was obtained. and increased error rates during restitution of control. Basic demographic and clinical sample character- In contrast, we did not expect group differences in istics are provided in Table 1. A large percentage of parietal PINV magnitudes during loss of control and depressed patients (73.9%) had suffered from pre- restitution of control. Finally, we hypothesized that vious episodes of depression. a larger frontal PINV – particularly under restitution of control – would be associated with higher levels Experimental design of depression and with habitual rumination, the latter describing a cognitive vulnerability trait to depression The experiment consisted of a modified forewarned characterized by perpetual negative self-focusing (S1–S2) reaction paradigm. S1 was a 600 Hz/60 dB (Kuehner et al. 2007a). tone of 4 s duration immediately followed by S2, which was a 1000 Hz/60 dB tone of 1 s duration. In case of aversive stimulation, an electrical stimu- Method lus of 1 ms duration was applied to the index finger of the non-dominant hand following S2 termination. Participants The intertrial interval varied randomly between Twenty-six medication-free depressed patients with 5 s and 9 s (mean=7 s). Subjects were instructed to a diagnosis of major depressive disorder (n=19) or respond to S2 onset by pressing the correct (left v. Stressor controllability in depression 79 Table 1. Sample characteristics Depressed Healthy subjects subjects F(1, 48) Variable (n=26) (n=24) or x (1) p Age (years) 47.19 (8.94) 44.75 (9.02) 0.92 N.S. Gender (% female) 54.16 64.71 0.46 N.S. Length of education (years) 11.00 (1.57) 11.13 (1.48) 0.08 N.S. DSM-IV diagnosis (SCID) Major depression (%) 73.08 – Pure dysthymia (%) 26.92 – Co-morbid anxiety diagnosis (n)2 – Age at onset (years) 30.42 (22.03) – No. of episodes 3.32 (3.17) – HAMD depression score 18.69 (6.66) 0.25 (0.44) 182.89 <0.001 BDI-II depression score 25.24 (10.62) 0.78 (1.86) 123.48 <0.001 Psychosocial functioning (SOFAS) 61.35 (10.48) 99.58 (2.04) 308.21 <0.001 Electrical stimulus amperage (mA) 3.34 (2.39) 4.13 (3.79) 0.88 N.S. Values are given as mean (standard deviation), % or n. N.S., Non-significant; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition (APA, 1994); SCID, Structured Clinical Interview for DSM-IV Axis I disorders (First et al. 1997); HAMD, Hamilton Rating Scale for Depression (Hamilton, 1960); BDI-II, Beck Depression Inventory, 2nd revision (Beck et al. 1996); SOFAS, Social and Occupational Functioning Scale (APA, 1994). right) button in order to avoid aversive electrical participants had to focus a fixation-cross in the centre stimulation. of the monitor to avoid eye-movement artefacts. The Controllability of the aversive stimulus varied entire protocol lasted about 1 h. The diagnostic inter- across three successive conditions of 40 trials each. view was carried out in a separate session lasting up In the first condition of controllability, the aversive to 2.5 h. stimulus could be avoided by pressing either the right or the left button (counterbalanced across subjects). Apparatus and recording technique Without prior warning, subjects randomly received the electrical stimulus in half of the trials during Participants’ scalp electroencephalography (EEG) was the following condition of uncontrollability so that no recorded from 30 sites based on the extended 10–20 response outcome contingency could be established. system (Nuwer et al. 1998) referenced to linked In the third condition, control was re-established, mastoids and digitally sampled at 500 Hz using a again without prior warning. The left v. right button Neuroscan Synamps DC amplifier (NeuroScan Inc., press as effective response was switched between the Herndon, VA, USA). An Easy Cap (FMS GmbH, conditions of controllability and restitution of control. Munich, Germany) with AgAgCl-electrodes of 10 mm Prior to the experimental manipulation (baseline) diameter was used. The electrodes were prepared and every 15th and 35th trial in each condition, parti- with abrasive paste (Abralyt 2000; FMS GmbH) and cipants rated their current arousal and emotional filled with electrode jelly (Electro-Cap International, valence via a self-assessment manikin (Lang, 1980). Inc., Eaton, OH, USA). Impedances were kept below Controllability and helplessness were rated on visual 5kV. The electro-oculogram (EOG) was recorded analogue scales. The ratings were presented on a from tin electrodes of 9 mm diameter which were monitor y1.2 m in front of the subjects. affixed 1 cm above and below the left eye (vertical During the experiment, the participants sat in a EOG), and at the outer canthi (horizontal EOG) of reclining chair in an electrically shielded room. S1 and both eyes (Picton et al. 1995). S2 tones were presented by means of foam ear inserts For electrical stimulation, a constant current stimu- (MedCaT, Erica, The Netherlands). The intensity of the lator (model DS7A; Digitimer Ltd, Welwyn Garden pain stimulus was individually calibrated as aversive City, Herts, UK) was used with custom-designed foil but tolerable (see Table 1). During the experiment electrodes, which were attached to the distal and 80 C. Diener et al. middle phalanges of the index finger of the non- gender role (Kuehner, 2003), we controlled for poten- dominant hand. tial gender differences in all analyses. Within the patient and healthy control samples, male and female subjects did not differ with regard to any of the as- Data reduction and analysis sessed variables presented in Table 1. Furthermore, Subjects’ button presses were continuously recorded the inclusion of gender in the analyses described be- and classified as erroneous if the response was low did not result in any significant main or interac- followed by electrical stimulation in the control and tion effect of this variable and did not affect the restitution of control conditions. Controllability and significance levels of the other variables in the re- helplessness ratings were scored from 0 to 100, those spective models. Therefore, we only present results for arousal and valence from 1 to 9 (Lang, 1980). The with data collapsed across gender. mean of the two ratings (at trial 15 and 35) per con- Partial correlations with two-tailed significance le- dition was subjected to the statistical analysis. vels are reported for the associations between frontal Brain vision analyzer (version 1.05; Brain Products PINV magnitudes and measures of depression, help- GmbH, Gilching, Germany) was employed for the lessness and habitual rumination for the depressed analyses of EEG data. Based on other studies examin- and the healthy subsample. In these analyses, we ing the PINV (Rockstroh et al. 1979; Elbert et al. 1982) controlled for PINV magnitudes during the initial and our study hypotheses, midline frontal (Fz) and condition of control in analyses involving the PINV parietal (Pz) recording sites, the latter serving as a under loss of control and restitution of control. In control site, were included in the analyses. Data were analyses involving the rumination subscales, we segmented into epochs of 9 s corresponding to S1 further adjusted for current Hamilton depression and S2 presentation (5 s) and a 4 s post-imperative scores to assess net associations between PINV scores interval. Each segment was corrected for eye move- and cognitive vulnerability not attributable to inter- ments (Gratton et al. 1983) and semi-automatically individual differences in depression levels. rejected when corrupted by artifacts (i.e. voltage step/sampling point o50 mV, minimal amplitude <x100 mV, maximal amplitude >100 mV). The re- Results maining trials (minimum 34; i.e. 85%) were then Rating data averaged. There were no group [F(1, 48)=0.15, N.S.], condition [F(2, 47)=0.4, N.S.] or grouprcondition Controllability [F(2, 47)=0.6, N.S.] effects with regard to trials in- For the controllability ratings a main effect of con- cluded. PINV magnitudes were defined as mean ac- dition [Pillai’s trace F(2, 47)=16.86, p<0.001] was tivity (mV) during the segment between 800 ms found that mirrored exactly the experimental design and 3500 ms following S2 termination relative to a (Fig. 1a). Depressed and healthy subjects showed a 1000 ms pre-trial baseline (see Rockstroh et al. 1979; decrease from control (mean=63.40, S.D.=35.79) to Bolz & Giedke, 1981; Elbert et al. 1982; Kathmann et al. loss of control (mean=34.10, S.D.=30.00) [t(49)= 1990). x5.90, p<0.001], followed by a subsequent increase during restitution of control (mean=52.00, S.D.=31.82) Statistical analyses [t(49)=4.31, p<0.001]. There were no significant Univariate group comparisons for sociodemographic group [F(1, 48)=0.204, N.S.] or interaction effects and clinical data were performed using analyses of [F(2, 47)=0.019, N.S.], indicating that the two groups variance (ANOVAs) for continuous and x tests for did not differ in the overall amount of perceived con- dichotomous variables. The dependent variables were trol or across conditions (see Fig. 1a). subjected to repeated-measures ANOVAs with group (depressed v. healthy subjects) as between- and con- Helplessness dition (control, loss of control, and restitution of con- trol) as within-subject factors. To test for significance, For the helplessness ratings a main effect of group we used Pillai’s trace statistic, which is most robust [F(1, 48)=7.38, p=0.009] reflected elevated levels of against violations of assumptions. In case of significant perceived helplessness in the depressed participants main or interaction effects, post-hoc paired compari- (mean=33.71, S.D.=25.80) compared with healthy sons were performed by means of paired-samples controls (mean=13.89, S.D.=25.82) throughout the t tests with two-tailed levels of significance. experiment. There was no significant main effect for Since female gender is regarded as an important condition [F(2, 47)=1.95, N.S.] but a marginally sig- risk factor for depression, and learned helplessness nificant conditionrgroup interaction [F(2, 47)=3.01, is thought to be particularly connected to the female p=0.059]. Depressed patients [t(25)=0.65, N.S.] and Stressor controllability in depression 81 condition effect [F(2, 48)=x4.94, p=0.011] indicated a (a) 80 decline in arousal from controllability (mean=3.48, S.D.=3.62) to restitution of control (mean=3.23, S.D.=1.91) [t(49)=x2.18, p=0.034]. A non-significant interaction term [F(2, 47)=1.19, N.S.] indicated similar decreases in both groups. 30 Emotional valence In general, depressed participants (mean=4.87, S.D.= Loss Restitution Control of of 1.63) rated the situation as significantly more un- control control pleasant than healthy controls (mean=3.39, S.D.=1.67) [group: F(1, 48)=10.20, p=0.002]. There was neither (b) 40 a significant main effect for condition [F(2, 47)=2.33, N.S.] nor a significant conditionrgroup interaction [F(2, 47)=0.41, N.S.]. Behavioural data Errors and reaction times The ANOVAs for erroneous responses (ER) and Loss Restitution for reaction times (RT) resulted in no significant Control of of effects [condition: ER F(1, 48)=2.73, N.S.; RT F(2, 47)= control control 0.278; group: ER F(1, 48)=1.35, N.S.; RT F(1, 48)=0.01, (c) –3.0 N.S.; interaction: ER F(1, 48)=0.26, N.S.; RT F(1, 48)= 0.26, N.S.]. –2.5 –2.0 PINV –1.5 Due to insufficient statistical power, the omnibus ANOVA resulted in no significant interaction of –1.0 group, condition and electrode site [F(2, 45)=1.56, p=0.221]. Therefore and according to our hypotheses, –0.5 Loss Restitution we separately report the results for the frontal and Control of of parietal recording sites. control control Fig. 1. Ratings of perceived (a) controllability, (b) helplessness Frontal recording site and (c) magnitudes (mV) of the post-imperative negative variation (PINV) at the midline frontal recording site (Fz) For Fz a main effect for group [F(1, 48)=5.88, p=0.019] during the experimental protocol for depressed ($, n=26) was found. Overall, depressed participants showed and healthy (2, n=24) subjects. higher PINVs (mean=x1.98, S.D.=1.49) than healthy controls (mean=x0.97, S.D.=1.49). Furthermore, controls [t(23)=1.74, N.S.] showed similar non- we identified a marginally significant main effect significant increases from control to loss of control for condition [F(2, 47)=2.98, p=0.060] and a highly [t(49)=1.67, N.S.]. However, in depressed participants significant conditionrgroup interaction [F(2, 47)= the feelings of helplessness further increased during 8.54, p<0.001]. Within-group analyses revealed that restitution of control (mean=36.54, S.D.=30.26) as in contrast to healthy controls [t(23)=x1.07, N.S.] compared with initial control (mean=31.54, S.D.= depressed participants responded with an enhanced 29.69) [t(25)=2.17, p=0.040], a pattern not seen in PINV [t(25)=x3.35, p=0.003] during loss of control healthy participants [t(23)=0.55, N.S., see Fig. 1b]. (mean=x2.71, S.D.=2.48) compared with initial control (mean=x0.87, S.D.=1.43). Additionally, de- Arousal pressed participants showed a higher PINV during restitution of control (mean=x2.38, S.D.=1.58) com- The arousal ratings of the depressed participants pared with initial control [t(25)=x4.30, p<0.001], a were significantly higher throughout the exper- pattern not seen in healthy controls [t(23)=x0.55, N.S., iment (mean =0.17, S.D.=1.68 v. mean=2.66, S.D.= see Fig. 1c]. 1.72) [group: F(1, 48)=9.78, p=0.003]. A significant PINV at Fz (µV) Helplessness (%) Controllability (%) 82 C. Diener et al. (a) Depressed subjects Healthy subjects (n=26) (n=24) –5 µ V Control Fz Loss of control Restit. of control 0 µ V S1 S2 S1 S2 PINV PINV 0 1 2 345678 012345678 Time (s) Time (s) (b) Depressed subjects Fz Pz 5800–8500 ms Healthy subjects –7.0 µ V –0.0 µ V Control Loss of control Restitution of control Fig. 2. (a) Averaged event-related potentials (ERPs, negativity up, filtered with a 6 Hz, 12 dB high cut-off) for the midline frontal recording site (Fz) during S1 (warning stimulus) and S2 (imperative stimulus) presentation, and the post-S2 interval. The post-imperative negative variation [PINV (mV)] was parameterized 800–3500 ms following S2 termination. The lines indicate the ERPs during initial condition of control, subsequent loss of control and restitution of control for depressed (n=26) and healthy (n=24) subjects. (b) Topographic two-dimensional maps of the post-S2 interval (800–3500 ms) for depressed and healthy subjects during initial condition of control, subsequent loss of control and restitution of control [topographic x5 interpolation by spherical splines (order=4, maximum degree of Legendre polynomials=10, l=1re ), see Perrin et al. 1989]. Pz, parietal recording site. To control for a possible influence of perceived Parietal recording site helplessness on the identified main and interaction The ANOVA for Pz as a control site resulted in effects at Fz, we reanalysed the data with baseline no significant effects [group: F(1, 48)=1.28, N.S.; helplessness as a covariate. The reported group and condition: F(2, 47)=2.53, N.S.; conditionrgroup: interaction effects remained statistically significant F(2, 47)=0.424, N.S.]. Fig. 2b shows the topographic [group F(1, 47)=4.37, p=0.042; conditionrgroup distribution of the PINV during the post-imperative F(2, 46)=8.03, p=0.001]. interval. To further control for a differential effect of the electrical stimulation on PINV magnitudes, we in- Exclusion of patients with dysthymia cluded the number of electrical stimuli during control and during restitution of control as covariates in the To test for potential confounds arising from the in- ANOVA. Again, this procedure did not affect the clusion of mildly chronically depressed patients, we significance of our results [group: F(1, 46)=6.39, p= reanalysed the data by excluding individuals with 0.015; condition: F(2, 45)=3.97, p=0.026; conditionr pure dysthymia (n=7). The results regarding group: F(2, 45)=8.83, p=0.001]. Averaged event- subjective ratings, errors and PINV magnitudes related potentials for Fz are illustrated in Fig. 2 a. remained virtually the same [e.g. PINV at Fz, ERP at Fz (µ V) Stressor controllability in depression 83 symptom-focused rumination and frontal PINV magnitudes during restitution of control in depressed patients. Discussion This study investigated cognitive, behavioural and physiological effects of stressor uncontrollability in –2 depressed individuals and healthy controls. While previous studies have successfully manipulated stres- sor controllability by means of change from a con- –4 dition of control to loss of control in forewarned reaction (S1–S2) paradigms (Rockstroh et al. 1979), we 10 15 20 25 30 expanded the standard procedure by a subsequent Symptom-focused rumination condition of restitution of control to also assess the Fig. 3. Scatterplot for frontal post-imperative negative effects of previous stressor uncontrollability in a situ- variation (PINV) magnitudes (mV) at the midline frontal ation where control was objectively re-established. recording site (Fz) during restitution of control and Additionally, we included ratings of arousal, symptom-focused rumination scores measured by the emotional valence, controllability and helplessness German version of the response styles questionnaire throughout the experiment. (Kuehner et al. 2007). While depressed participants rated the situation as more unpleasant in general, ratings of emotional group: F(1, 41)=7.18, p=0.011; condition: F(2, 40)= valence did not vary with the alternating pattern 3.11, p=0.056; conditionrgroup: F(2, 40)=8.55, p< of controllability. Both groups demonstrated only a 0.001]. slight increase of errors after withdrawal of control. This indicates that the challenge of the task was mod- Correlations between frontal PINV and measures erate and comparable for both healthy and depressed of depression and cognitive vulnerability individuals. In the total sample, higher levels of self-(BDI-II) and Both groups rated their perceived controllability interviewer-(HAMD) rated depression were connec- in concordance with the varying degrees of control- ted to larger (more negative) frontal PINV magnitudes lability. However, depressed participants felt more during loss of control (BDI-II: partial r=x0.363, helpless and aroused throughout the experiment. p<0.05; HAMD: partial r=x0.492, p<0.001) and While withdrawal of control caused a non-significant restitution of control (BDI-II: partial r=x0.489, increase of perceived helplessness in both groups, p<0.001; HAMD: partial r=x0.491, p<0.001). only depressed subjects displayed markedly enhanced However, these results merely mirrored respective levels of helplessness in the subsequent restitution of group differences identified in the ANOVAs, since control condition. separate correlation analyses for the depressed and The most apparent differences between depressed healthy subsamples resulted in no significant corre- and healthy subjects were identified with respect to lations within groups (all p>0.10). Perceived help- frontal PINV magnitudes. During loss of control, de- lessness was not significantly correlated with PINV pressed participants showed an enhanced PINV over values in any condition. Particularly in the depressed frontal sites, indicating that they engaged frontal areas subsample, we identified significant negative corre- to resolve task-induced ambiguity (see Klein et al. lations between the two rumination scores and PINV 1996). Furthermore, depressed participants main- magnitude under restitution of control. In this group, tained this activation pattern in the subsequent con- higher levels of symptom-focused and self-focused dition when control was re-established. They also rumination were connected to larger PINV values felt more helpless than healthy controls, particularly under restitution of control, even if baseline de- under restitution of control. Thus, while the enhanced pression levels were partialled out (n=26, PINV at Fz frontal PINV in depressed subjects during loss of during restitution of control with symptom-focused control may be related to heightened contingency re- rumination: partial r=x0.517, p=0.01, with self- appraisal and task-induced ambiguity, the experience focused rumination: partial r=x0.419, p=0.05). In of uncontrollability appeared to have also biased sub- contrast, respective coefficients failed to reach statisti- sequent cortical processing, as expected by learned cal significance in the healthy subsample (all p>0.10). helplessness theory. Since this was only true for the Fig. 3 presents a scatterplot for the association of depressed subsample, we assume that depressed PINV at Fz (µV) during restitution of control 84 C. Diener et al. individuals are more susceptible to conditions of While the PINV has been established as a reliable uncontrollability. indicator of loss of control in previous work The event-related potential data indicate that (Rockstroh et al. 1979; Bolz & Giedke, 1981; Lutzen- depressed individuals responded to changing levels berger et al. 1981; Elbert et al. 1982; Kathmann et al. of stressor controllability with enhanced prefrontal 1990), this is the first study to show that in depressed activation. Increased prefrontal activity during loss subjects the experience of uncontrollability appears to of control and restitution of control may reflect a induce biased subsequent cortical processing. During compensatory mechanism in order to resolve task- restitution of control, depressed participants still induced ambiguity. These considerations are in line demonstrated elevated frontal PINV magnitudes and with recent studies indicating abnormal prefrontal pronounced feelings of helplessness. Our data suggest hyperactivation during working memory load in that the prefrontal hyperactivation may be considered patients with mood disorders (Hugdahl et al. 2004; as a physiological compensation to resolve ambiguity Harvey et al. 2005; Rose et al. 2006; Wagner et al. 2006; induced by previous loss of control. Furthermore, we Chiu & Deldin, 2007). It is thus conceivable that identified substantial associations between enhanced depressed subjects need enhanced activation of pre- frontal PINV magnitudes with habitual rumination frontal brain regions such as the anterior cingulate in depressed patients. cortex, the ventromedial or the dorsolateral prefrontal Future studies should examine state- versus trait- cortex (Luu et al. 2003; Rose et al. 2006; Siegle et al. characteristics of the PINV, its predictive role for 2007), which are involved in cognitive control during the development and clinical course of depression, ambiguity provoked by uncontrollable stress. In this and its sensitivity to therapeutic change. Furthermore, context, future studies using functional magnetic studies including a simultaneous assessment of EEG resonance imaging (fMRI) to identify specific neuro- and fMRI are needed to link exaggerations of the PINV anatomical areas involved in the observed altered in depressed patients to functional neuroanatomical frontal response pattern in depressed patients are models of depression. warranted. Finally, habitual symptom-focused and self- Acknowledgements focused rumination were specifically linked to the frontal PINV under restitution of control, and this This work was supported by the Deutsche Forschungs- was particularly true for the depressed subsample. gemeinschaft (SFB636/D4). 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Journal

Psychological MedicinePubmed Central

Published: May 9, 2008

References