Thomas M. Schilling

For whom the bell (curve) tolls: Cortisol rapidly affects memory retrieval by an inverted U-shaped dose–response relationship

Stress and cortisol are generally considered to impair declarative memory retrieval, although opposite results have also been reported. Dose-dependent effects and differences between genomic and non-genomic cortisol effects are possible reasons for these discrepancies. The aim of the current experiment was to assess the non-genomic effects of escalating doses of intravenous cortisol on cued recall of socially relevant information in humans. 40 participants (age range 20-30 years; 20 females) learned associations between male faces with a neutral facial expression and descriptions of either positive or negative social behaviors and were tested one week later in a cued recall paradigm. Escalating doses of cortisol (0, 3, 6, 12, 24 mg) were administered 8 min before testing according to a between-subjects design. An inverted U-shaped dose-response relationship between salivary cortisol levels and recall performance was observed, with moderate elevation of salivary cortisol resulting in the best recall performance. This is the first study in humans demonstrating that cortisol rapidly modulates declarative memory retrieval via a dose-dependent, non-genomic mechanism that follows an inverted U-shaped curve. Our result further emphasizes the importance of fast cortisol effects for human cognition.

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. Hum Brain Mapp 35:1944–1956, 2014.

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.

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

Abstract 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.

Startle effects on saccadic responses to emotional target stimuli

Startle stimuli elicit various physiological and cognitive responses. This study investigated whether acoustic startle stimuli affect saccadic reactions in an emotional pro- or antisaccade task. Startle probes were presented either 500 ms before or simultaneous with an imperative stimulus that indicated whether a saccade towards or away from positive, neutral, or negative peripheral target pictures had to be performed. Valence interacted with saccade direction according to an approach-avoidance pattern of gaze behavior, with delayed prosaccades to negative targets and antisaccades away from positive targets. Acoustic startle stimuli preceding the presentation of peripheral target pictures speeded up the initiation saccades, irrespective of stimulus valence. Results indicate a speeding of cognitive-motor processing by preceding startle stimuli.

Respiratory modulation of startle eye blink: a new approach to assess afferent signals from the respiratory system

Current approaches to assess interoception of respiratory functions cannot differentiate between the physiological basis of interoception, i.e. visceral-afferent signal processing, and the psychological process of attention focusing. Furthermore, they typically involve invasive procedures, e.g. induction of respiratory occlusions or the inhalation of CO2-enriched air. The aim of this study was to test the capacity of startle methodology to reflect respiratory-related afferent signal processing, independent of invasive procedures. Forty-two healthy participants were tested in a spontaneous breathing and in a 0.25 Hz paced breathing condition. Acoustic startle noises of 105 dB(A) intensity (50 ms white noise) were presented with identical trial frequency at peak and on-going inspiration and expiration, based on a new pattern detection method, involving the online processing of the respiratory belt signal. The results show the highest startle magnitudes during on-going expiration compared with any other measurement points during the respiratory cycle, independent of whether breathing was spontaneous or paced. Afferent signals from slow adapting phasic pulmonary stretch receptors may be responsible for this effect. This study is the first to demonstrate startle modulation by respiration. These results offer the potential to apply startle methodology in the non-invasive testing of interoception-related aspects in respiratory psychophysiology. This article is part of the themed issue ‘Interoception beyond homeostasis: affect, cognition and mental health’.

Rapid cortisol enhancement of psychomotor and startle reactions to side-congruent stimuli in a focused cross-modal choice reaction time paradigm

The stress hormone cortisol has been shown to affect hemodynamic activity of human brain structures, presumably via a nongenomic mechanism. However, behavioral implications of this finding remain unknown. In a placebo-controlled, blinded, cross-over design the rapid effects of IV hydrocortisone (5mg) on cross-modal integration of simultaneous, unilateral visual and acoustic signals in a challenging startle and reaction time (RT) paradigm were studied. On two separate days 1 week apart, 24 male volunteers responded by button push to either up- or down pointing triangles presented in random sequence in the periphery of one of the visual hemi-fields. Visual targets were accompanied by unilateral acoustic startle noise bursts, presented at the same or opposite side. Saccadic latency, manual RT, and startle eye blink responses were recorded. Faster manual reactions and increased startle eye blink responses were observed 11-20 min after hydrocortisone administration when visual targets and unilateral acoustic startle noises were presented in the same sensory hemi-field, but not when presented in opposite sensory hemi-fields. Our results suggest that a nongenomic, cortisol-sensitive mechanism enhances psychomotor and startle reactions when stimuli occur in the same sensory hemi-field. Such basic cognitive effects of cortisol may serve rapid adaptation and protection against danger stimuli in stressful contexts.

The acute and temporary modulation of PERIOD genes by hydrocortisone in healthy subjects

ABSTRACT The physiological stress system and the circadian clock system communicate with each other at different signaling levels. The steroid hormone cortisol, the end-effector of the hypothalamus–pituitary–adrenal axis, is released in response to stress and acts as a mediator in circadian rhythms. We determined the effect of escalating cortisol doses on the expression of PERIOD genes (PER1, PER2 and PER3) in healthy subjects and analyzed whether the glucocorticoid receptor (GR) is involved in the cortisol-mediated PERIOD gene expression. Forty participants (50% males and 50% females) were randomly assigned to groups receiving a saline placebo solution or 3 mg, 6 mg, 12 mg and 24 mg of hydrocortisone. Blood was drawn every 15 min to measure quantitative gene expression of PER1, PER2 and PER3. A potential role of the GR was determined by an ex vivo study stimulating whole blood with hydrocortisone and RU486 (a GR antagonist). As a result, moderate doses of hydrocortisone produced an acute and temporary induction of PER1 and PER3 mRNA levels, whereas PER2 was not responsive to the hormone administration. The cortisol-dependent induction of PER1 was blocked by the GR antagonist in whole blood after treatment with hydrocortisone and RU486 ex vivo. In conclusion, acute pharmacological stress modulated the expression of PER1 and PER3 in whole blood temporarily in our short-term sampling design, suggesting that these circadian genes mediate stable molecular mechanisms in the periphery.

Emotional stress regulation: The role of relative frontal alpha asymmetry in shaping the stress response

Frontal EEG asymmetry has been proposed as an index of emotional regulation, reflecting both state and trait components, and there is evidence that these factors influence the cortisol response to stress. Here, we asked whether cold pressor stress modulates frontal asymmetry and whether this is predictive of the neuroendocrine stress response. Twenty-four male participants underwent an automatized bilateral feet cold pressor test (bfCPT) and a warm water control procedure in counterbalanced order on two separate days, one week apart. EEG, heart rate and blood pressure were assessed at baseline as well as during and after the bfCPT. Salivary cortisol and subjective ratings of stress and arousal were assessed before and after the bfCPT. The bfCPT led to a significant increase in cortisol, cardiovascular parameters and in subjective ratings of stress and arousal that was absent in the control condition. Furthermore, analysis of relative frontal alpha-band asymmetry revealed a stronger relative right frontal activation during the bfCPT compared to the control condition at electrode pairs F7/8 but not F3/4. However, frontal asymmetry scores during the bfCPT were not predictive for neither physiological responses nor subjective ratings. Moreover, an association between physiological responses and frontal asymmetry assessed during rest at baseline could be observed at electrode pairs F3/F4, with stronger responses being associated with stronger relative right frontal activation. Our results show that cold pressor stress leads to an alteration of emotional processes as reflected in frontal EEG asymmetry at F7/F8. Moreover, physiological responses to the CPT seem to be differentially moderated by trait and state components present in frontal asymmetry.

Supplementary material from "Respiratory modulation of startle eye blink: a new approach to assess afferent signals from the respiratory system"

Current approaches to assess interoception of respiratory functions cannot differentiate between the physiological basis of interoception, i.e. visceral-afferent signal processing and the psychological process of attention focusing. Furthermore, they typically involve invasive procedures, e.g. induction of respiratory occlusions or the inhalation of CO 2 -enriched air. The aim of this study was to test the capacity of startle methodology to reflect respiratory-related afferent signal processing, independent of invasive procedures. Forty-two healthy participants were tested in a spontaneous breathing and in a 0.25 Hz paced breathing condition. Acoustic startle noises of 105 dB(A) intensity (50 ms white noise) were presented with identical trial frequency at peak and on-going inspiration and expiration, based on a new pattern detection method, involving the online processing of the respiratory belt signal. The results show the highest startle magnitudes during on-going expiration compared with any other measurement points during the respiratory cycle, independent of whether breathing was spontaneous or paced. Afferent signals from slow adapting phasic pulmonary stretch receptors may be responsible for this effect. This study is the first to demonstrate startle modulation by respiration. These results offer the potential to apply startle methodology in the non-invasive testing of interoception-related aspects in respiratory psychophysiology.This article is part of the themed issue ‘Interoception beyond homeostasis: affect, cognition and mental health’.