Cold pressor stress effects on cardiac repolarization.

The cold pressor test (CPT) elicits strong cardiovascular reactions via activation of the sympathetic nervous system (SNS), yielding subsequent increases in heart rate (HR) and blood pressure (BP). However, little is known on how exposure to the CPT affects cardiac ventricular repolarization. Twenty-eight healthy males underwent both a bilateral feet CPT and a warm water (WW) control condition on two separate days, one week apart. During pre-stress baseline and stress induction cardiovascular signals (ECG lead II, Finometer BP) were monitored continuously. Salivary cortisol and subjective stress ratings were assessed intermittently. Corrected QT (QTc) interval length and T-wave amplitude (TWA) were assessed for each heartbeat and subsequently aggregated individually over baseline and stress phases, respectively. CPT increases QTc interval length and elevates the TWA. Stress-induced changes in cardiac repolarization are only in part and weakly correlated with cardiovascular and cortisol stress-reactivity. Besides its already well-established effects on cardiovascular, endocrine, and subjective responses, CPT also impacts on cardiac repolarization by elongation of QTc interval length and elevation of TWA. CPT effects on cardiac repolarization share little variance with the other indices of stress reactivity, suggesting a potentially incremental value of this parameter for understanding psychobiological adaptation to acute CPT stress.

Stress effects on the top-down control of visuospatial attention: Evidence from cue-dependent alpha oscillations.

Stress is assumed to inhibit the top-down control of attention and to facilitate bottom-up processing. Evidence from human experiments, however, remains scarce. Previous studies have addressed how stress affects the interplay of bottom-up and top-down mechanisms of attention. A key open question is in how far such effects can actually be attributed to a stress-induced modulation of top-down attention control. We sought to isolate top-down from bottom-up effects by assessing stress effects on anticipatory changes in alpha oscillations that precede stimulus processing. Participants performed in a cued target detection task in which a cue prompted them to covertly shift their attention to left or right screen positions, 20 min after being exposed to the bilateral feet cold pressor test or a warm water control procedure. The stressor led to a substantial increase in cortisol, peaking 20 min post stressor, along with rises in heart rate, blood pressure, and subjective ratings of stress and arousal. As expected, cued attention deployment led to higher alpha power over posterior electrodes contralateral versus ipsilateral to the attended hemifield during the cue-target interval. Importantly, this purely endogenous effect was potentiated by stress, however, significant differences were restricted to the middle of the cue-target interval and thus temporally separated from the appearance of the target. These results indicate that stress does not impair top-down attentional control per se but may introduce a qualitative change modulating the way attention is deployed to meet action goals.

Glucocorticoid receptor signaling in leukocytes after early life adversity.

Early life adversity (ELA) has been associated with inflammation and immunosenescence, as well as hyporeactivity of the HPA axis. Because the immune system and the HPA axis are tightly intertwined around the glucocorticoid receptor (GR), we examined peripheral GR functionality in the EpiPath cohort among participants who either had been exposed to ELA (separation from parents and/or institutionalization followed by adoption; n = 40) or had been reared by their biological parents (n = 72).Expression of the strict GR target genes FKBP5 and GILZ as well as total and 1F and 1H GR transcripts were similar between groups. Furthermore, there were no differences in GR sensitivity, examined by the effects of dexamethasone on IL6 production in LPS-stimulated whole blood. Although we did not find differences in methylation at the GR 1F exon or promoter region, we identified a region of the GR 1H promoter (CpG 1-9) that showed lower methylation levels in ELA.Our results suggest that peripheral GR signaling was unperturbed in our cohort and the observed immune phenotype does not appear to be secondary to an altered GR response to the perturbed HPA axis and glucocorticoid (GC) profile, although we are limited in our measures of GR activity and time points.

Promoter haplotypes of the corticotropin-releasing hormone encoding gene modulate the physiological stress response in vitro and in vivo.

The corticotropin-releasing hormone (CRH) is a neuropeptide mediating stress responses. CRH exerts effects via the hypothalamus pituitary adrenal axis as well as immediate effects on the sympathetic-adrenal-medullary system. Genetic variants of the CRH promoter were previously found to be associated with altered CRH promoter activity and physiological reactions. Functional characterization of three CRH promoter haplotypes have been performed in vitro using a reporter gene assay under different stimulation conditions. Furthermore, 232 healthy subjects were genotyped and the influence of CRH haplotypes on basal parameters such as post-awakening cortisol and blood pressure as well as on stress reactivity measured after socially evaluated cold pressor test (SeCPT) was investigated. In vitro, CRH haplotype 2 showed the highest promoter activity under baseline conditions and after forskolin stimulation compared with other haplotypes. Forskolin treatment resulted in a two fold increase of haplotype 2 promoter activity compared with the baseline condition. Cell line-dependent promoter activation was found after hydrocortisone treatment. In vivo, CRH haplotype 2 carriers showed significant higher baseline blood pressure (p = .002) and blood pressure after SeCPT (p < .001), but did not differ in cortisol levels. This study provides converging evidence for the importance of CRH promoter variants on physiological stress response parameters.

Proinflammatory T Cell Status Associated with Early Life Adversity.

Early life adversity (ELA) has been associated with an increased risk for diseases in which the immune system plays a critical role. The ELA immune phenotype is characterized by inflammation, impaired cellular immunity, and immunosenescence. However, data on cell-specific immune effects are largely absent. Additionally, stress systems and health behaviors are altered in ELA, which may contribute to the generation of the ELA immune phenotype. The present investigation tested cell-specific immune differences in relationship to the ELA immune phenotype, altered stress parameters, and health behaviors in individuals with ELA (n = 42) and those without a history of ELA (control, n = 73). Relative number and activation status (CD25, CD69, HLA-DR, CD11a, CD11b) of monocytes, NK cells, B cells, T cells, and their main subsets were assessed by flow cytometry. ELA was associated with significantly reduced numbers of CD69+CD8+ T cells (p = 0.022), increased numbers of HLA-DR+ CD4 and HLA-DR+ CD8 T cells (p < 0.001), as well as increased numbers of CD25+CD8+ T cells (p = 0.036). ELA also showed a trend toward higher numbers of CCR4+CXCR3-CCR6+ CD4 T cells. Taken together, our data suggest an elevated state of immune activation in ELA, in which particularly T cells are affected. Although several aspects of the ELA immune phenotype were related to increased activation markers, neither stress nor health-risk behaviors explained the observed group differences. Thus, the state of immune activation in ELA does not seem to be secondary to alterations in the stress system or health-risk behaviors, but rather a primary effect of early life programming on immune cells.

Effects of basal and acute cortisol on cognitive flexibility in an emotional task switching paradigm in men.

The stress hormone cortisol is assumed to influence cognitive functions. While cortisol-induced alterations of declarative memory in particular are well-investigated, considerably less is known about its influence on executive functions. Moreover, most research has been focused on slow effects, and rapid non-genomic effects have not been studied. The present study sought to investigate the impact of acute cortisol administration as well as basal cortisol levels on cognitive flexibility, a core executive function, within the non-genomic time frame. Thirty-eight healthy male participants were randomly assigned to intravenously receive either cortisol or a placebo before performing a task switching paradigm with happy and angry faces as stimuli. Cortisol levels were measured at six points during the experiment. Additionally, before the experiment, basal cortisol measures for the cortisol awakening response were collected on three consecutive weekdays immediately following awakening and 30, 45, and 60min after. First and foremost, results showed a pronounced impact of acute and basal cortisol on reaction time switch costs, particularly for angry faces. In the placebo group, low basal cortisol was associated with minimal switch costs, whereas high basal cortisol was related to maximal switch costs. In contrast, after cortisol injection, basal cortisol levels showed no impact. These results show that cognitive flexibility-enhancing effects of acute cortisol administration are only seen in men with high basal cortisol levels. This result supports the context dependency of cortisol administration and shows the relevance of taking basal cortisol levels into account.

Stress and selective attention: Immediate and delayed stress effects on inhibition of return.

The relationship between attention and stress is far from understood. In fact, some studies reported better attentional selection during and after stress, some studies reported worse attentional selection, and some studies reported no effects of stress on attentional selection at all. We argue that given the complexity of both concepts more data are needed as to ultimately understand this relationship. Here we use an established attentional task that yields the inhibition of return (IOR) effect which is assumed to tap attentional control of oculomotor behavior. Participants were stressed with a Cold Pressor Test (CPT) and immediate and delayed effects of stress on hypothalamus-pituitary-adrenal (HPA) axis activation and IOR were analyzed. IOR was neither by immediate nor by delayed after-effects of the CPT stress procedure modulated, instead, we observed reliable and significant IOR in all experimental conditions. Attentional control of oculomotor behavior is therefore not altered after CPT stress, nor related to the post-stress activity of the HPA axis.

Altered patterns of heartbeat-evoked potentials in depersonalization/derealization disorder: neurophysiological evidence for impaired cortical representation of bodily signals.

OBJECTIVE: Core features of depersonalization/derealization disorder (DPD) are emotional numbing and feelings of disembodiment. Although there are several neurophysiological findings supporting subjective emotional numbing, the psychobiology of disembodiment remains unclear. METHODS: Heartbeat-evoked potentials (HEPs), which are considered psychophysiological indicators for the cortical representation of afferent signals originating from the cardiovascular system, were assessed in 23 patients with DPD and 24 healthy control individuals during rest and while performing a heartbeat perception task. RESULTS: Absolute HEP amplitudes did not differ between groups. Nevertheless, healthy individuals showed higher HEPs during the heartbeat perception task than during rest, whereas no such effect was found in patients with DPD (p = .031). Patients with DPD had higher total levels of salivary α-amylase than did healthy individuals (9626.6 [8200.0] versus 5344.3 [3745.8] kU min/l; p = .029), but there were no group differences in cardiovascular measures (heart rate = 76.2 [10.1] versus 74.3 [7.5] beats/min, p = .60; normalized low-frequency heart rate variability = 0.63 [0.15] versus 0.56 [0.15] normalized units, p = .099; low frequency/high frequency ratio = 249.3 [242.7] versus 164.8 [108.8], p = .10), salivary cortisol (57.5 [46.7] versus 55.1 [43.6] nmol min/l, p = .86), or cortisone levels (593.2 [260.3] versus 543.8 [257.1] nmol min/l, p = .52). CONCLUSIONS: These results suggest altered cortical representation of afferent signals originating from the cardiovascular system in patients with DPD, which may be associated with higher sympathetic tone. These findings may reflect difficulties of patients with DPD to attend to their actual bodily experiences.

Enhanced stress response by a bilateral feet compared to a unilateral hand Cold Pressor Test.

The Cold Pressor Test (CPT) is a frequently employed laboratory stress protocol. However, with many experimental designs the application in its classic form (immersion of the dominant hand into ice-water) is problematic as unilateral stimulation may need to be avoided and/or hands are required for further measurements. Here, we describe a simple modification of the classic CPT in which both feet are immersed into ice-water and compare the evoked neuroendocrine stress response to the classic CPT in a within-subjects design. Twenty-four healthy participants were exposed to each of both CPT versions on two subsequent days in randomized order. Heart rate, blood pressure, salivary alpha-amylase and cortisol were measured at baseline and during or after CPT exposition, respectively, along with subjective ratings of pain and stress. The bilateral feet CPT induced marked increases in all measured stress parameters. Moreover, with the exception of blood pressure, autonomic and endocrine responses were enhanced compared to the classic CPT. The bilateral feet CPT thus is a valid and simple modification and may be useful when the application of the classic CPT is unfeasible or a stronger neuroendocrine stress response is of interest.

Intranasal insulin increases regional cerebral blood flow in the insular cortex in men independently of cortisol manipulation.

Insulin and cortisol play a key role in the regulation of energy homeostasis, appetite, and satiety. Little is known about the action and interaction of both hormones in brain structures controlling food intake and the processing of neurovisceral signals from the gastrointestinal tract. In this study, we assessed the impact of single and combined application of insulin and cortisol on resting regional cerebral blood flow (rCBF) in the insular cortex. After standardized periods of food restriction, 48 male volunteers were randomly assigned to receive either 40 IU intranasal insulin, 30 mg oral cortisol, both, or neither (placebo). Continuous arterial spin labeling (CASL) sequences were acquired before and after pharmacological treatment. We observed a bilateral, locally distinct rCBF increase after insulin administration in the insular cortex and the putamen. Insulin effects on rCBF were present regardless of whether participants had received cortisol or not. Our results indicate that insulin, but not cortisol, affects blood flow in human brain structures involved in the regulation of eating behavior.

Heart rate response to post-learning stress predicts memory consolidation.

Stressful experiences are often well remembered, an effect that has been explained by beta-adrenergic influences on memory consolidation. Here, we studied the impact of stress induced heart rate (HR) responses on memory consolidation in a post-learning stress paradigm. 206 male and female participants saw 52 happy and angry faces immediately before being exposed to the Cold Pressor Test or a non-stressful control procedure. Memory for the faces and their respective expression was tested twice, after 30 min and on the next day. High HR responders (in comparison to low HR responders as well as to the non-stressful control group) showed enhanced recognition memory one day after learning. Our results show that beta-adrenergic activation elicited shortly after learning enhances memory consolidation and that the stress induced HR response is a predictor for this effect.

Hydrocortisone reduces altruistic punishment in healthy men.

Psychosocial stress modulates social cognition and behavior in humans. One potentially mediating factor is cortisol as part of the human endocrine stress response. With a double-blind, placebo-controlled between-subject study design, we tested possible dose-dependent effects of hydrocortisone (0 mg, 5 mg and 20 mg) in 85 healthy males. During a socio-economic decision-making task we measured trust, trustworthiness, sharing, punishment, and non-social risk behavior. Social value orientation (SVO) was also assessed. We observed significantly lower levels of punishment after hydrocortisone, especially in the 20 mg group. Drug-induced salivary cortisol correlated negatively with punishment behavior. None of the other facets of social behavior or the SVO were affected by hydrocortisone. Our results suggest that hydrocortisone reduces the propensity to punish unfair behavior. Future studies are needed to further disentangle the role played by various psychobiological mechanisms within the stress response as well as their complex interplay on social behavior and cognition.

Tune it down to live it up? Rapid, nongenomic effects of cortisol on the human brain.

The stress hormone cortisol acts on the brain, supporting adaptation and time-adjusted coping processes. Whereas previous research has focused on slow emerging, genomic effects of cortisol, we addressed the rapid, nongenomic cortisol effects on in vivo neuronal activity in humans. Three independent placebo-controlled studies in healthy men were conducted. We observed changes in CNS activity within 15 min after intravenous administration of a physiological dose of 4 mg of cortisol (hydrocortisone). Two of the studies demonstrated a rapid bilateral thalamic perfusion decrement using continuous arterial spin labeling. The third study revealed rapid, cortisol-induced changes in global signal strength and map dissimilarity of the electroencephalogram. Our data demonstrate that a physiological concentration of cortisol profoundly affects the functioning and perfusion of the human brain in vivo via a rapid, nongenomic mechanism. The changes in neuronal functioning suggest that cortisol acts on the thalamic relay of background as well as on task-specific sensory information, allowing focus and facilitation of adaptation to challenges.

Acute effects of intravenous heroin on the hypothalamic-pituitary-adrenal axis response: a controlled trial.

Heroin dependence is associated with a stressful environment and with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. The present study examined the acute effects of intravenous heroin versus placebo on the HPA axis response in heroin-dependent patients. Twenty-eight heroin-dependent patients in heroin-assisted treatment and 20 age- and sex-matched healthy participants were included in a controlled trial in which patients were twice administered heroin or saline in a crossover design, and healthy controls were only administered saline. The HPA axis response was measured by adrenocorticotropic hormone (ACTH) levels and by cortisol levels in serum and saliva before and 20 and 60 minutes after substance administration. Craving, withdrawal, and anxiety levels were measured before and 60 minutes after substance application. Plasma concentrations of heroin and its main metabolites were assessed using high-performance liquid chromatography. Heroin administration reduces craving, withdrawal, and anxiety levels and leads to significant decreases in ACTH and cortisol concentrations (P < 0.01). After heroin administration, cortisol concentrations did not differ from healthy controls, and ACTH levels were significantly lower (P < 0.01). In contrast, when patients receive saline, all hormone levels were significantly higher in patients than in healthy controls (P < 0.01). Heroin-dependent patients showed a normalized HPA axis response compared to healthy controls when they receive their regular heroin dose. These findings indicate that regular opioid administration protects addicts from stress and underscore the clinical significance of heroin-assisted treatment for heroin-dependent patients.

Increased pupil and heart-rate responses to sexual stimuli in men after physical exertion.

Physical stress has been found to enhance arousability by visual sexual stimuli on a short-term basis, as reflected in higher phasic pupil dilation responses, probably mediated by sympathetic nervous system (SNS)-related processes. However, previous research has not addressed the specificity of this effect in terms of emotional valence, that is, whether it reflects an instance of general excitation transfer or a more specific mechanism. Thus, to further investigate changes in sexual processing after acute stress exposure, 40 male participants underwent either a predominantly sympathetic stressor (3 min sustained handgrip) or similar control procedure. After stress induction, pictures varying in valence as well as sexual versus non-sexual arousal were presented (for 5000 ms each). Using principal component analysis, pupillary responses during picture viewing were dissociated into fast and slow components (early vs. late response phases). In addition, startle eyeblink responses were elicited by bursts of white noise (50 ms, 105 dB) in half of the trials and recorded at the orbicularis oculi via electromyography. Skin conductance and heart rate were co-registered, as well. While affective startle modulation and skin conductance responses to emotional stimuli were unaffected by previous stress exposure, both evoked heart-rate deceleration (but not acceleration) and pupil responses were specifically enhanced with sexually arousing stimuli in stressed participants, and this effect was mediated by blood pressure reactivity as an index of preceding SNS activation. Taken together, our findings provide strong evidence for enhancement of sexual processing by acute stress exposure in men and suggest differential involvement of parasympathetic versus sympathetic mechanisms.

Close(d) to you? Avoidant attachment is associated with attenuated pupil responsivity to social stimuli.

Insecure attachment is thought to impair romantic relationships, presumably also contributing to mental health problems. Previous research has suggested a link to biased automatic processing of social information, potentially reflected in pupil dilation responses. To address this hypothesis, 37 adults were presented with attachment-related, emotional pictures of erotic couples, everyday couples, or interpersonal violence after assessment with the Experiences in Close Relationships Scale. Considerable variation in self-reported attachment behaviors regarding both attachment anxiety and avoidance was observed in our sample. Overall, pupil dilation was most pronounced during viewing of erotica and violence-related pictures. Relative to nature pictures as control, attachment avoidance was associated with attenuated pupillary responses to social content. However, this was not significant with erotica. For pictures of violence, this avoidant bias was also evident in reduced subjective arousal. In contrast, attachment anxiety was unrelated to differential pupil dilation. Our findings, although preliminary, suggest that previous attachment-related experiences may bias the processing of social stimuli, which in turn may be reflected in altered patterns of pupillary responses.

The relationship between self-reported chronic stress, physiological stress axis dysregulation and medically-unexplained symptoms.

The positive feedback model of medically-unexplained symptoms posits that chronic stress affects the activity of the physiological stress axes, which in turn generates medically-unexplained symptoms. As a first step to empirically test its model assumptions, we investigated potential associations between chronic stress, physiological stress axis activity and medically-unexplained in a cross-sectional study. One hundred-ninety-nine healthy individuals provided self-reports on chronic stress and medically-unexplained symptoms, resting heart rate/variability (HR/HRV; e.g., root mean square of successive differences/RMSSD, low frequency/LF power), cortisol awakening response (CAR) and diurnal cortisol. Significant positive contributors to medically-unexplained symptoms were the chronic stress scales 'lack of social appreciation' and 'chronic worries', as well as CAR and LF HRV; diurnal cortisol was a negative contributor. Mediation analyses showed that the impact of neural indicators associated with physiological stress axis activity (HR/HRV) related to medically-unexplained symptoms, which was mediated by chronic stress, whereas the mediation effect as suggested by the positive feedback model was not significant. These cross-sectional findings do not support the positive feedback model. Longitudinal studies are required to conclude about potential mechanistic and causal relationships in the model. Nevertheless, our mediation analyses give first indication that the constitution of physiological stress axes may play a major role in how stressors are perceived and which kind of health-consequences (e.g., medically-unexplained symptoms) this may have.

Optimal timing of oral metyrapone intake for the suppression of cold-pressor stress-induced cortisol release.

BACKGROUND: Pharmacological manipulation of cortisol levels is instrumental in elucidating mechanisms underlying acute stress effects and for distinguishing the physiological and behavioral effects of cortisol from those of the adrenergic system. Administration (oral or IV) of hydrocortisone is a direct and efficient method to elevate cortisol, and thus, frequently used in psychobiological stress research. However, lowering of cortisol (i.e. blockade of stress cortisol) requires a more sophisticated approach, such as the administration of the corticostatic compound metyrapone (MET). However, there is insufficient knowledge about the temporal dynamics of MET for the blocking of stress-induced cortisol reactivity. Thus, the present study aimed to build up an experimental protocol suitable to suppress acute behavioral stress-induced cortisol secretion by MET. METHODS: 50 healthy young men were randomly assigned to one of five treatment groups. They received 750 mg oral MET either 30 (n = 9), 45 (n = 11), or 60 (n = 10) minutes before exposure to a combined cold pressor and mental arithmetic test (stress induction), or were subjected to two different control treatments (placebo 60 min before stress (n = 10) or MET 30 min before non-stressful warm-water condition (n = 10)). Salivary cortisol concentration, hemodynamics, and subjective ratings were assessed. RESULTS: Suppression of cold stress-induced cortisol release was strongest when MET intake was scheduled 30 min prior to stress onset. Cardiovascular stress-responses and subjective ratings remained unaffected by MET. CONCLUSION: In healthy young males, 750 mg of MET efficiently block cold stress-induced cortisol release when oral administration is scheduled 30 min prior to stress onset. This finding may guide future research in improving timing of suppression of stress-induced cortisol secretion.

Stressed in afterthought: Neuroendocrine effects of social self-threat during physical effort are counteracted by performance feedback after stress exposure.

Social self-threat during physical stress, such as exposure to the cold pressor test and isometric handgrip test, has been shown to induce activation of the HPA axis, in addition to autonomic responses. However, previous research has suggested that dysfunctional post-event processing may play a major role in neuroendocrine reactivity at initial as well as subsequent social stress exposure. In the present study, we investigated how the interplay of context (i.e. performance feedback) with state (i.e., self-esteem) as well as trait-like factors (i.e., ruminative tendencies) affects stress responses to repeated, short bouts of physical activity. On two sessions, 1 week apart, 53 participants (27 women) performed an isometric handgrip task for 3 min, during which they were exposed to social-evaluative threat. In addition, participants received fake feedback on their performance immediately after the task, labeling it as either 'above' (positive) or 'below average' (negative). In addition to neuroendocrine (cortisol), cardiovascular (heart rate, blood pressure) and subjective stress reactivity, performance-related and social dimensions of state self-esteem were assessed before and after stress induction. Substantial increases in cardiovascular parameters were found on both days, regardless of feedback condition. However, positive feedback led to significantly diminished neuroendocrine responses on day 1, whereas baseline cortisol on session 2 was significantly higher in the negative feedback group. Conversely, social self-esteem decreased after stress induction on both days only for participants who had received negative feedback. Changes in self-esteem reported on day 1 were associated with increased baseline cortisol at the second session, while interindividual differences in self-reported (trait) rumination were associated with cortisol reactivity at session 1. Taken together, the results suggest that effects of social evaluation during short periods of physical stress rely on post-event processing and might be counteracted by positive appraisal directly after stress exposure. Post-hoc framing (in terms of success vs. failure) may predict subsequent stress-related hormonal effects better than task demands per se, which should be considered as a potential moderator in future acute stress research, but might also be relevant to many practical applications in fields ranging from sports/performance to health psychology.

Affective reactivity in heroin-dependent patients with antisocial personality disorder.

The Antisocial personality disorder (ASPD), one of the most common co-morbid psychiatric disorders in heroin-dependent patients, is associated with a lack of affective modulation. The present study aimed to compare the affect-modulated startle responses of opioid-maintained heroin-dependent patients with and without ASPD relative to those of healthy controls. Sixty participants (20 heroin-dependent patients with ASPD, 20 heroin-dependent patients without ASPD, 20 healthy controls) were investigated in an affect-modulated startle experiment. Participants viewed neutral, pleasant, unpleasant, and drug-related stimuli while eye-blink responses to randomly delivered startling noises were recorded continuously. Both groups of heroin-dependent patients exhibited significantly smaller startle responses (raw values) than healthy controls. However, they showed a normal affective modulation: higher startle responses to unpleasant, lower startle responses to pleasant stimuli and no difference to drug-related stimuli compared to neutral stimuli. These findings indicate a normally modulated affective reactivity in heroin-dependent patients with ASPD.