Evaluation and update of the expert consensus guidelines for the assessment of the cortisol awakening response (CAR).

The cortisol awakening response (CAR) is frequently assessed in psychobiological (stress) research. Obtaining reliable CAR data, however, requires careful attention to methodological detail. To promote best practice, expert consensus guidelines on the assessment of the CAR were published (Stalder et al., 2016, PNEC). However, it is unclear whether these highly cited guidelines have resulted in actual methodological improvements. To explore this, the PNEC editorial board invited the present authors to conduct a critical evaluation and update of current CAR methodology, which is reported here. (i) A quantitative evaluation of methodological quality of CAR research published in PNEC before and after the guidelines (2013-2015 vs. 2018-2020) was conducted. Disappointingly, results reveal little improvement in the implementation of central recommendations (especially objective time verification) in recent research. (ii) To enable an update of guidelines, evidence on recent developments in CAR assessment is reviewed, which mostly confirms the accuracy of the majority of the original guidelines. Moreover, recent technological advances, particularly regarding methods for the verification of awakening and sampling times, have emerged and may help to reduce costs in future research. (iii) To aid researchers and increase accessibility, an updated and streamlined version of the CAR consensus guidelines is presented. (iv) Finally, the response of the PNEC editorial board to the present results is described: potential authors of future CAR research to be published in PNEC will be required to submit a methodological checklist (based on the current guidelines) alongside their article. This will increase transparency and enable reviewers to readily assess the quality of the respective CAR data. Combined, it is hoped that these steps will assist researchers and reviewers in assuring higher quality CAR assessments in future research, thus yielding more reliable and reproducible results and helping to further advance this field of study.

The effects of suppressing the biological stress systems on social threat-assessment following acute stress.

RATIONALE: Stress is associated with increased sensitivity to threat. Previous investigations examining how stress affects threat processing have largely focused on biomarker responses associated with either the sympathetic-nervous-system (SNS) or the hypothalamus-pituitary-adrenal (HPA) axis. OBJECTIVES: We pharmacologically suppressed activations of SNS, HPA, or both, prior to stress and investigated how each stress system modulates social threat assessment. METHODS: One hundred sixty-one healthy men and women were randomized in a between-subject design, to one of four pharmacological or placebo conditions: dexamethasone-placebo, placebo-propranolol, dexamethasone-propranolol, or placebo-placebo. Participants provided threat assessments for angry and neutral human faces on a baseline day, and immediately after stress induction on a testing day. RESULTS: With both systems responding normally to stress (placebo-placebo), threat assessment was higher for neutral faces compared with angry. Compared with placebo, SNS suppression resulted in increased threat assessment for angry faces. HPA suppression resulted in decreased threat assessment for neutral and angry faces. When both systems were suppressed, there was an increase in threat assessment for angry faces, and no difference from placebo for neutral. CONCLUSION: Our findings demonstrated that when intact, the biological stress systems adaptively support organisms during stress by focusing attention towards specific stimuli that are relevant to the threat. Dysregulations of the stress systems result in important system specific consequences on threat evaluation, such that suppression of either stress system alone resulted in reduced threat assessment for contextually relevant threatening stimuli, whereas when both systems were suppressed, individuals appear indiscriminately attentive to all potential threats in the environment, resulting in increased threat processing of both contextually relevant and irrelevant stimuli. Given that stress-related psychopathologies have been associated with dysregulations of the stress systems and biased responses to social threat, a systematic understanding of the mechanisms that underlie how stress systems modulate social threat assessment is needed, and can provide important insights into the cognitive processes that are involved in the development and maintenance of stress-related psychopathologies.

Physiological adaptations to chronic stress in healthy humans - why might the sexes have evolved different energy utilisation strategies?

KEY POINTS: The human stress response activates the autonomic nervous system and endocrine systems to increase performance during environmental challenges. This response is usually beneficial, improving the chance of overcoming environmental challenges, but costs resources such as energy. Humans and other animals are known to adapt their responses to acute stress when they are stimulated chronically, presumably to optimise resource utilisation. Characterisation of these adaptations has been limited. Using advanced imaging techniques, we show that cardiovascular and endocrine physiology, reflective of energy utilisation during acute stress, and energy storage (fat) differ between the sexes when they are exposed to chronic stress. We examine possible evolutionary explanations for these differences, related to energy use, and point out how these physiological differences could underpin known disparities between the sexes in their risk of important cardiometabolic disorders such as obesity and cardiovascular disease. ABSTRACT: Obesity and associated diseases, such as cardiovascular disease, are the dominant human health problems in the modern era. Humans develop these conditions partly because they consume excess energy and exercise too little. Stress might be one of the factors contributing to these disease-promoting behaviours. We postulate that sex-specific primordial energy optimisation strategies exist, which developed to help cope with chronic stress but have become maladaptive in modern societies, worsening health. To demonstrate the existence of these energy optimisation strategies, we recruited 88 healthy adults with varying adiposity and chronic stress exposure. Cardiovascular physiology at rest and during acute stress (Montreal Imaging Stress Task), and body fat distribution were measured using advanced magnetic resonance imaging methods, together with endocrine function, cardiovascular energy use and cognitive performance. Potential confounders such as lifestyle, social class and employment were accounted for. We found that women exposed to chronic stress had lower adiposity, greater acute stress cardiovascular responses and better cognitive performance. Conversely, chronic stress-exposed men had greater adiposity and lower cardiovascular responses to acute stress. These results provide initial support for our hypothesis that differing sex-specific energy conservation strategies exist. We propose that these strategies have initially evolved to benefit humans but are now maladaptive and increase the risk of disorders such as obesity, especially in men exposed to chronic stress.

Assessment of the cortisol awakening response: Expert consensus guidelines.

The cortisol awakening response (CAR), the marked increase in cortisol secretion over the first 30-45 min after morning awakening, has been related to a wide range of psychosocial, physical and mental health parameters, making it a key variable for psychoneuroendocrinological research. The CAR is typically assessed from self-collection of saliva samples within the domestic setting. While this confers ecological validity, it lacks direct researcher oversight which can be problematic as the validity of CAR measurement critically relies on participants closely following a timed sampling schedule, beginning with the moment of awakening. Researchers assessing the CAR thus need to take important steps to maximize and monitor saliva sampling accuracy as well as consider a range of other relevant methodological factors. To promote best practice of future research in this field, the International Society of Psychoneuroendocrinology initiated an expert panel charged with (i) summarizing relevant evidence and collective experience on methodological factors affecting CAR assessment and (ii) formulating clear consensus guidelines for future research. The present report summarizes the results of this undertaking. Consensus guidelines are presented on central aspects of CAR assessment, including objective control of sampling accuracy/adherence, participant instructions, covariate accounting, sampling protocols, quantification strategies as well as reporting and interpreting of CAR data. Meeting these methodological standards in future research will create more powerful research designs, thus yielding more reliable and reproducible results and helping to further advance understanding in this evolving field of research.

Multi-atlas segmentation of the whole hippocampus and subfields using multiple automatically generated templates.

INTRODUCTION: Advances in image segmentation of magnetic resonance images (MRI) have demonstrated that multi-atlas approaches improve segmentation over regular atlas-based approaches. These approaches often rely on a large number of manually segmented atlases (e.g. 30-80) that take significant time and expertise to produce. We present an algorithm, MAGeT-Brain (Multiple Automatically Generated Templates), for the automatic segmentation of the hippocampus that minimises the number of atlases needed whilst still achieving similar agreement to multi-atlas approaches. Thus, our method acts as a reliable multi-atlas approach when using special or hard-to-define atlases that are laborious to construct. METHOD: MAGeT-Brain works by propagating atlas segmentations to a template library, formed from a subset of target images, via transformations estimated by nonlinear image registration. The resulting segmentations are then propagated to each target image and fused using a label fusion method. We conduct two separate Monte Carlo cross-validation experiments comparing MAGeT-Brain and basic multi-atlas whole hippocampal segmentation using differing atlas and template library sizes, and registration and label fusion methods. The first experiment is a 10-fold validation (per parameter setting) over 60 subjects taken from the Alzheimer's Disease Neuroimaging Database (ADNI), and the second is a five-fold validation over 81 subjects having had a first episode of psychosis. In both cases, automated segmentations are compared with manual segmentations following the Pruessner-protocol. Using the best settings found from these experiments, we segment 246 images of the ADNI1:Complete 1Yr 1.5 T dataset and compare these with segmentations from existing automated and semi-automated methods: FSL FIRST, FreeSurfer, MAPER, and SNT. Finally, we conduct a leave-one-out cross-validation of hippocampal subfield segmentation in standard 3T T1-weighted images, using five high-resolution manually segmented atlases (Winterburn et al., 2013). RESULTS: In the ADNI cross-validation, using 9 atlases MAGeT-Brain achieves a mean Dice's Similarity Coefficient (DSC) score of 0.869 with respect to manual whole hippocampus segmentations, and also exhibits significantly lower variability in DSC scores than multi-atlas segmentation. In the younger, psychosis dataset, MAGeT-Brain achieves a mean DSC score of 0.892 and produces volumes which agree with manual segmentation volumes better than those produced by the FreeSurfer and FSL FIRST methods (mean difference in volume: 80 mm(3), 1600 mm(3), and 800 mm(3), respectively). Similarly, in the ADNI1:Complete 1Yr 1.5 T dataset, MAGeT-Brain produces hippocampal segmentations well correlated (r>0.85) with SNT semi-automated reference volumes within disease categories, and shows a conservative bias and a mean difference in volume of 250 mm(3) across the entire dataset, compared with FreeSurfer and FSL FIRST which both overestimate volume differences by 2600 mm(3) and 2800 mm(3) on average, respectively. Finally, MAGeT-Brain segments the CA1, CA4/DG and subiculum subfields on standard 3T T1-weighted resolution images with DSC overlap scores of 0.56, 0.65, and 0.58, respectively, relative to manual segmentations. CONCLUSION: We demonstrate that MAGeT-Brain produces consistent whole hippocampal segmentations using only 9 atlases, or fewer, with various hippocampal definitions, disease populations, and image acquisition types. Additionally, we show that MAGeT-Brain identifies hippocampal subfields in standard 3T T1-weighted images with overlap scores comparable to competing methods.

Assessment of the caudate nucleus and its relation to route learning in both congenital and late blind individuals.

BACKGROUND: In the absence of visual input, the question arises as to how complex spatial abilities develop and how the brain adapts to the absence of this modality. As such, the aim of the current study was to investigate the relationship between visual status and an important brain structure with a well established role in spatial cognition and navigation, the caudate nucleus. We conducted a volumetric analysis of the caudate nucleus in congenitally and late blind individuals, as well as in matched sighted control subjects. RESULTS: No differences in the volume of the structure were found either between congenitally blind (CB) and matched sighted controls or between late blind (LB) and matched sighted controls. Moreover, contrary to what was expected, no significant correlation was found between caudate volume and performance in a spatial navigation task. Finally, consistent with previously published reports, the volume of the caudate nucleus was found to be negatively correlated with age in the sighted; however such correlations were not significant in the blind groups. CONCLUSION: Although there were no group differences, the absence of an age-volume correlation in the blind suggests that visual deprivation may still have an effect on the developmental changes that occur in the caudate nucleus.

Detailed assessment of the hemodynamic response to psychosocial stress using real-time MRI.

PURPOSE: To demonstrate that combining the Montreal Imaging Stress Task (MIST) with real-time cardiac magnetic resonance imaging (MRI) allows detailed assessment of the cardiovascular mental stress response. MATERIALS AND METHODS: 22 healthy volunteers (1:1 M:F, 26-64 years) underwent MRI during rest and the MIST. Real-time spiral phase contrast MR, accelerated with sensitivity encoding (SENSE) was used to assess stroke volume (SV), and radial k-t SENSE was used to assess ventricular volumes. Simultaneous heart rate (HR) and blood pressure (BP) measures allowed calculation of cardiac output (CO), systemic vascular resistance (SVR), and arterial compliance (TAC). Endocrine responses were assessed using salivary cortisol. RESULTS: In response to stress, BP increased due to increased CO and reduced TAC but not increased SVR, which fell. HR, not SV, determined CO increases. Greater BP responses occurred in men due to greater CO increases and relatively higher SVR. Older participants had greater BP responses due to greater falls in TAC. Greater cortisol response was correlated with greater falls in TAC but resting cortisol and TAC were not related. CONCLUSION: This new approach allows detailed, accurate assessment of stress physiology. Preliminary findings suggest stress exposes relationships, not seen at rest, of cardiovascular function with age, sex, and endocrine function.

Neural markers of remission in first-episode schizophrenia: a volumetric neuroimaging study of the hippocampus and amygdala.

OBJECTIVE: The temporolimbic region has been implicated in the pathophysiology in schizophrenia. More specifically, significantly smaller hippocampal volumes but not amygdala volumes have been identified at onset in first-episode schizophrenia (FES) patients. However, volumetric differences (namely, in the hippocampus) exhibit an ambiguous relationship with long-term outcome. So, we examined the relationship between hippocampus and amygdala volumes and early remission status. METHODS: We compared hippocampus and amygdala volumes between 40 non-remitted and 17 remitted FES patients and 57 healthy controls. Amygdala and hippocampus were manually traced with the hippocampus additionally segmented into three parts: body, head, and tail. Remission was defined as mild or less on both positive and negative symptoms over a period of 6 consecutive months as per the 2005 Remission in Schizophrenia Working Group criteria. RESULTS: A significant [group x structure x side] interaction revealed outcome groups differed in hippocampus tail volumes; significantly on the left (non-remitted=694+/-175 mm(3); remitted=855+/-133 mm(3); p=0.001) with a trend difference on the right (non-remitted=723+/-162 mm(3); remitted=833+/-126 mm(3); p=0.023). Groups did not differ in body, head, or amygdala volumes bi-laterally. CONCLUSIONS: A smaller hippocampal tail volume may represent a neural marker in FES patients who do not achieve early remission after the first 6 months of treatment. The early identification of patients with poor outcome with respect to the hippocampus tail may encourage the search for new, more target-specific, medications in hope of improving outcome and moving us towards a better understanding of the pathophysiology of schizophrenia.