Marie-France Marin

Chronic stress, cognitive functioning and mental health.

This review aims to discuss the evidence supporting the link between chronic stress, cognitive function and mental health. Over the years, the associations between these concepts have been investigated in different populations. This review summarizes the findings that have emerged from older populations as well as from populations suffering from pathological aging, namely Mild Cognitive Impairment and Alzheimers Disease. Although older adults are an interesting population to study in terms of chronic stress, other stress-related diseases can occur throughout the lifespan. The second section covers some of these stress-related diseases that have recently received a great deal of attention, namely burnout, depression, and post-traumatic stress disorder. Given that chronic stress contributes to the development of certain pathologies by accelerating and/or exacerbating pre-existing vulnerabilities that vary from one individual to the other, the final section summarizes data obtained on potential variables contributing to the association between chronic stress and cognition.

A transdisciplinary perspective of chronic stress in relation to psychopathology throughout life span development.

The allostatic load (AL) model represents an interdisciplinary approach to comprehensively conceptualize and quantify chronic stress in relation to pathologies throughout the life cycle. This article first reviews the AL model, followed by interactions among early adversity, genetics, environmental toxins, as well as distinctions among sex, gender, and sex hormones as integral antecedents of AL. We next explore perspectives on severe mental illness, dementia, and caregiving as unique human models of AL that merit future investigations in the field of developmental psychopathology. A complimenting transdisciplinary perspective is applied throughout, whereby we argue that the AL model goes beyond traditional stress-disease theories toward the advancement of person-centered research and practice that promote not only physical health but also mental health.

The Stress Model of Chronic Pain: Evidence from Basal Cortisol and Hippocampal Structure and Function in Humans.

Recent theories have suggested that chronic pain could be partly maintained by maladaptive physiological responses of the organism facing a recurrent stressor. The present study examined the associations between basal levels of cortisol collected over seven consecutive days, the hippocampal volumes and brain activation to thermal stimulations administered in 16 patients with chronic back pain and 18 healthy control subjects. Results showed that patients with chronic back pain have higher levels of cortisol than control subjects. In these patients, higher cortisol was associated with smaller hippocampal volume and stronger pain-evoked activity in the anterior parahippocampal gyrus, a region involved in anticipatory anxiety and associative learning. Importantly, path modelling-a statistical approach used to examine the empirical validity of propositions grounded on previous literature-revealed that the cortisol levels and phasic pain responses in the parahippocampal gyrus mediated a negative association between the hippocampal volume and the chronic pain intensity. These findings support a stress model of chronic pain suggesting that the sustained endocrine stress response observed in individuals with a smaller hippocampii induces changes in the function of the hippocampal complex that may contribute to the persistent pain states.

A clinical allostatic load index is associated with burnout symptoms and hypocortisolemic profiles in healthy workers

Chronic stress causes stress hormones to strain many biological systems in a process referred to as allostatic load (AL) that is measurable using an index of biomarkers. While the AL framework has been successfully applied in studies of workplace stress, few studies have investigated burnout, a debilitating condition sometimes characterized by blunted stress hormone levels. Using an AL index based on clinical norms, we hypothesized that higher AL indices would be associated with increased chronic stress, burnout symptoms, as well as hypoactive diurnal and reactive stress hormone levels. Fifteen neuroendocrine, immune, metabolic, and cardiovascular biomarkers were collected for 30 healthy participants from various professions and values were transformed into an AL index using clinical norms. Stress reactivity was assessed for salivary cortisol and α-amylase levels in response to the Trier Social Stress Test. Diurnal cortisol was measured at five time points (awakening, 30 min after awakening, 14:00 h, 16:00 h, and before bedtime) over two working days. We also administered questionnaires of chronic stress, burnout, and depression. Our results demonstrate that increased AL is associated with increased chronic stress, burnout symptoms, but not depressive symptoms. The High AL group demonstrated lower morning and stress reactive cortisol levels in comparison to the Low AL group, but no significant effects were detected for salivary α-amylase. These findings provide preliminary support for the utility of a new clinical AL index that is sensitive to physiological recalibrations intermittently observed in burnout research.

Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: three negative psychophysiological studies.

Posttraumatic stress disorder (PTSD) may involve over-consolidated emotional memories of the traumatic event. Reactivation (RP) can return a memory to an unstable state, from which it must be restabilized (reconsolidated) if it is to persist. Pharmacological agents administered while the memory is unstable have been shown to impair reconsolidation. The N-methyl-d-aspartate (NMDA) partial agonist d-cycloserine (DCS) may promote memory destabilization. In the three studies reported here, we investigated whether the β-adrenergic blocker propranolol or the glucocorticoid (GR) antagonist mifepristone, given at the time of traumatic memory reactivation, could reduce PTSD symptoms and physiological responding during subsequent traumatic imagery. Individuals with PTSD were randomized as follows: Study One: propranolol with memory reactivation (n=10) or without reactivation (n=8); Study Two: reactivation mifepristone (n=13), non-reactivation (NRP) mifepristone (n=15), or double placebo (PL) (n=15); Study Three: reactivation mifepristone plus d-cycloserine (n=16), or two placebos (n=15). Subjects underwent memory retrieval by describing their traumatic event. A week later they engaged in script-driven traumatic mental imagery, while heart rate (HR), skin conductance (SC), and facial electromyogram (EMG) responses were measured. There were no significant group differences in physiological responsivity or change in PTSD symptoms in any of the studies. These results do not support successful blockade of reconsolidation of traumatic memories in PTSD.

DEVICE‐BASED BRAIN STIMULATION TO AUGMENT FEAR EXTINCTION: IMPLICATIONS FOR PTSD TREATMENT AND BEYOND

Conditioned fear acquisition and extinction paradigms have been widely used both in animals and humans to examine the neurobiology of emotional memory. Studies have also shown that patients suffering from posttraumatic stress disorder (PTSD) exhibit deficient extinction recall along with dysfunctional activation of the fear extinction network, including the ventromedial prefrontal cortex, amygdala, and hippocampus. A great deal of overlap exists between this fear extinction network and brain regions associated with symptom severity in PTSD. This suggests that the neural nodes of fear extinction could be targeted to reduce behavioral deficits that may subsequently translate into symptom improvement. In this article, we discuss potential applications of brain stimulation and neuromodulation methods, which, combined with a mechanistic understanding of the neurobiology of fear extinction, could be used to further our understanding of the pathophysiology of anxiety disorders and develop novel therapeutic tools. To this end, we discuss the following stimulation approaches: deep‐brain stimulation, vagus nerve stimulation, transcranial direct current stimulation, and transcranial magnetic stimulation. We propose new translational research avenues that, from a systems neuroscience perspective, aim to expand our understanding of circuit dynamics and fear processing toward the practical development of clinical tools, to be used alone or in combination with behavioral therapies.

Timing is everything: anticipatory stress dynamics among cortisol and blood pressure reactivity and recovery in healthy adults.

Psychological states of anticipation modulate biological stress responsivity. While researchers generally investigate how subjective distress corresponds to the magnitude of stress reactivity, physiological recovery after acute stressors must also be considered when investigating disease vulnerabilities. This study assessed whether anticipatory stress would correspond to stress reactivity and recovery of salivary cortisol and blood pressure levels in response to a well-validated psychosocial stressor. Thirty participants (63% female; mean ± SEM age 45.4 ± 2.12 years) were exposed to the Trier Social Stress Test (TSST) consisting of a public speech and mental arithmetic. Ten salivary cortisol samples and systolic and diastolic blood pressure recordings were collected at time points spanning 50 min before and up to 50 min after stress exposure. These data were transformed into parameters representing stress reactivity (area under the curve) and stress recovery (percent change). The Primary Appraisal Secondary Appraisal scale assessed anticipatory stress before exposure to the TSST. Our results revealed that increased anticipatory stress predicted increased stress reactivity for cortisol (p = 0.009) but not blood pressure. For stress recovery, increased anticipatory stress predicted greater decrements of cortisol concentration (p = 0.015) and blood pressure (p = 0.039), even when controlling for total systemic “output” by incorporating baseline activity. This efficient shutdown of stress responses would have otherwise been ignored by solely investigating reactive increases. These findings underscore the importance of measuring multiple dynamic parameters such as recovery when investigating physiological stress response patterns as a function of psychosocial factors.

Acute Stress Contributes to Individual Differences in Pain and Pain-Related Brain Activity in Healthy and Chronic Pain Patients

Individual differences in pain sensitivity and reactivity are well recognized but the underlying mechanisms are likely to be diverse. The phenomenon of stress-induced analgesia is well documented in animal research and individual variability in the stress response in humans may produce corresponding changes in pain. We assessed the magnitude of the acute stress response of 16 chronic back pain (CBP) patients and 18 healthy individuals exposed to noxious thermal stimulations administered in a functional magnetic resonance imaging experiment and tested its possible contribution to individual differences in pain perception. The temperature of the noxious stimulations was determined individually to control for differences in pain sensitivity. The two groups showed similar significant increases in reactive cortisol across the scanning session when compared with their basal levels collected over 7 consecutive days, suggesting normal hypothalamic–pituitary–adrenal axis reactivity to painful stressors in CBP patients. Critically, after controlling for any effect of group and stimulus temperature, individuals with stronger cortisol responses reported less pain unpleasantness and showed reduced blood oxygenation level-dependent activation in nucleus accumbens at the stimulus onset and in the anterior mid-cingulate cortex (aMCC), the primary somatosensory cortex, and the posterior insula. Mediation analyses indicated that pain-related activity in the aMCC mediated the relationship between the reactive cortisol response and the pain unpleasantness. Psychophysiological interaction analysis further revealed that higher stress reactivity was associated with reduced functional connectivity between the aMCC and the brainstem. These findings suggest that acute stress modulates pain in humans and contributes to individual variability in pain affect and pain-related brain activity.

Metyrapone Administration Reduces the Strength of an Emotional Memory Trace in a Long-Lasting Manner

CONTEXT It has recently been demonstrated that the process of memory retrieval serves as a reactivation mechanism whereby the memory trace that is reactivated during retrieval is once again sensitive to modifications by environmental or pharmacological manipulations. Recent studies have shown that glucocorticoids (GCs) have the capacity to modulate the process of memory retrieval. This suggests that GCs could be an interesting avenue to investigate with regard to reduction of emotional memory. OBJECTIVE The current study assessed whether a pharmacological decrease in GC levels, induced by metyrapone, a potent inhibitor of GC secretion, would affect retrieval of emotional and neutral information in an acute and/or long-lasting manner. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION To do so, 1 × 750 mg dose of metyrapone, 2 × 750 mg dose of metyrapone, or placebo was administered to young normal participants 3 d after the encoding of a slide show having neutral and emotional segments. The experiment took place in a university and a hospital setting. MAIN OUTCOME MEASURE Memory performance was assessed after treatment and 4 d later. RESULTS RESULTS showed that retrieval of emotional information was acutely impaired in the double-dose metyrapone group and that this effect was still present 4 d later, when GC levels were not different between groups. CONCLUSIONS These results show that decreasing GC levels via metyrapone administration is an efficient way to reduce the strength of an emotional memory in a long-lasting manner.

Stress, PTSD, and dementia *

The physiological consequences of acute and chronic stress on a range of organ systems have been well documented after the pioneering work of Hans Selye more than 70 years ago. More recently, an association between exposure to stressful life events and the development of later‐life cognitive dysfunction has been proposed. Several plausible neurohormonal pathways and genetic mechanisms exist to support such an association. However, many logistical and methodological barriers must be overcome before a defined causal linkage can be firmly established. Here the authors review recent studies of the long‐term cognitive consequences of exposures to cumulative ordinary life stressors as well as extraordinary traumatic events leading to posttraumatic stress disorder. Suggestive effects have been demonstrated for the role of life stress in general, and posttraumatic stress disorder in particular, on a range of negative cognitive outcomes, including worse than normal changes with aging, Alzheimers disease, and vascular dementia. However, given the magnitude of the issue, well‐controlled studies are relatively few in number, and the effects they have revealed are modest in size. Moreover, the effects have typically only been demonstrated on a selective subset of measures and outcomes. Potentially confounding factors abound and complicate causal relationships despite efforts to contain them. More well‐controlled, carefully executed longitudinal studies are needed to confirm the apparent association between stress and dementia, clarify causal relationships, develop reliable antemortem markers, and delineate distinct patterns of risk in subsets of individuals.