Dominique J.-F. de Quervain

Stress and glucocorticoids impair retrieval of long-term spatial memory

Extensive evidence from animal and human studies indicates that stress and glucocorticoids influence cognitive function. Previous studies have focused exclusively on glucocorticoid effects on acquisition and long-term storage of newly acquired information. Here we report that stress and glucocorticoids also affect memory retrieval. We show that rats have impaired performance in a water-maze spatial task after being given footshock 30 min before retention testing but are not impaired when footshock is given 2 min or 4 h before testing. These time-dependent effects on retention performance correspond to the circulating corticosterone levels at the time of testing, which suggests that the retention impairment is directly related to increased adrenocortical function. In support of this idea, we find that suppression of corticosterone synthesis with metyrapone blocks the stress-induced retention impairment. In addition, systemic corticosterone administered to non-stressed rats 30 min before retention testing induces dose-dependent retention impairment. The impairing effects of stress and glucocorticoids on retention are not due to disruption of spatial navigation per se. Our results indicate that besides the well described effects of stress and glucocorticoids on acquisition and consolidation processes, glucocorticoids also affect memory retrieval mechanisms.

Antibodies against β-Amyloid Slow Cognitive Decline in Alzheimer's Disease

To test whether antibodies against beta-amyloid are effective in slowing progression of Alzheimers disease, we assessed cognitive functions in 30 patients who received a prime and a booster immunization of aggregated Abeta(42) over a 1 year period in a placebo-controlled, randomized trial. Twenty patients generated antibodies against beta-amyloid, as determined by tissue amyloid plaque immunoreactivity assay. Patients who generated such antibodies showed significantly slower rates of decline of cognitive functions and activities of daily living, as indicated by the Mini Mental State Examination, the Disability Assessment for Dementia, and the Visual Paired Associates Test of delayed recall from the Wechsler Memory Scale, as compared to patients without such antibodies. These beneficial clinical effects were also present in two of three patients who had experienced transient episodes of immunization-related aseptic meningoencephalitis. Our results establish that antibodies against beta-amyloid plaques can slow cognitive decline in patients with Alzheimers disease.

Acute cortisone administration impairs retrieval of long-term declarative memory in humans

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Glucocorticoids and the regulation of memory in health and disease

Over the last decades considerable evidence has accumulated indicating that glucocorticoids - stress hormones released from the adrenal cortex - are crucially involved in the regulation of memory. Specifically, glucocorticoids have been shown to enhance memory consolidation of emotionally arousing experiences, but impair memory retrieval and working memory during emotionally arousing test situations. Furthermore, growing evidence indicates that these different glucocorticoid effects all depend on emotional arousal-induced activation of noradrenergic transmission within the basolateral complex of the amygdala (BLA) and on interactions of the BLA with other brain regions, such as the hippocampus and neocortical regions. Here we review findings from both animal and human experiments and present an integrated perspective of how these opposite glucocorticoid effects might act together to serve adaptive processing of emotionally significant information. Furthermore, as intense emotional memories also play a crucial role in the pathogenesis and symptomatology of anxiety disorders, such as posttraumatic stress disorder (PTSD) or phobias, we discuss to what extent the basic findings on glucocorticoid effects on emotional memory might have implications for the understanding and treatment of these clinical conditions. In this context, we review data suggesting that the administration of glucocorticoids might ameliorate chronic anxiety by reducing retrieval of aversive memories and enhancing fear extinction.

Glucocorticoids interact with emotion-induced noradrenergic activation in influencing different memory functions

Extensive evidence from rat and human studies indicates that glucocorticoid hormones influence cognitive performance. Posttraining activation of glucocorticoid-sensitive pathways dose-dependently enhances the consolidation of long-term memory. Glucocorticoid effects on memory consolidation rely on noradrenergic activation of the basolateral amygdala and interactions of the basolateral amygdala with other brain regions. Glucocorticoids interact with the noradrenergic system both at a postsynaptic level, increasing the efficacy of the beta-adrenoceptor-cyclic AMP/protein kinase A system, as well as presynaptically in brainstem noradrenergic cell groups that project to the basolateral amygdala. In contrast, memory retrieval and working memory performance are impaired with high circulating levels of glucocorticoids. Glucocorticoid-induced impairment of these two memory functions also requires the integrity of the basolateral amygdala and the noradrenergic system. Such critical interactions between glucocorticoids and noradrenergic activation of the basolateral amygdala have important consequences for the role of emotional arousal in enabling glucocorticoid effects on these different memory functions.

Stress doses of hydrocortisone, traumatic memories, and symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized study.

BACKGROUND Traumatic experiences associated with cardiac surgery (CS) can result in traumatic memories and posttraumatic stress disorder (PTSD). Because it is known that subjects who develop PTSD often show sustained reductions in circulating cortisol concentrations, we performed a prospective, randomized study to examine whether exogenously administered stress doses of hydrocortisone during the perioperative period of CS reduces the long-term incidence of chronic stress and PTSD symptoms. METHODS Patients (n = 91) were prospectively randomized to receive either stress doses of hydrocortisone or standard treatment during the perioperative period of CS. Of 48 available patients at 6 months after CS, 26 had received stress doses of hydrocortisone and 22 standard treatment. Traumatic memories and PTSD symptoms were diagnosed with previously validated questionnaires. RESULTS As compared with patients after standard therapy, patients from the hydrocortisone group had significantly lower chronic stress symptom scores (p <.05). There was no significant difference regarding the number or type of traumatic memories between the hydrocortisone and the standard treatment groups. CONCLUSIONS Stress doses of hydrocortisone in patients undergoing CS are associated with a lower intensity of chronic stress and PTSD symptoms at 6 months after CS.

Glucocorticoid-induced impairment of declarative memory retrieval is associated with reduced blood flow in the medial temporal lobe

Previous work indicates that stress levels of circulating glucocorticoids can impair retrieval of declarative memory in human subjects. Several studies have reported that declarative memory retrieval relies on the medial temporal lobe. The present study used \mathrm{H}^{15}_{2}O‐positron emission tomography to investigate whether acutely elevated glucocorticoid levels affect regional cerebral blood flow in the medial temporal lobe, as well as in other brain regions, during declarative memory retrieval in healthy male human subjects. When measured over four different declarative memory retrieval tasks, a single, stress‐level dose of cortisone (25 mg) administered orally 1 h before retention testing, induced a large decrease in regional cerebral blood flow in the right posterior medial temporal lobe, the left visual cortex and the cerebellum. The decrease in the right posterior medial temporal lobe was maximal in the parahippocampal gyrus, a region associated with successful verbal memory retrieval. Cortisone administration also significantly impaired cued recall of word pairs learned 24 h earlier, while drug effects on performance in the other tasks (verbal recognition, semantic generation and categorization) were not significant. The present results provide further evidence that acutely elevated glucocorticoid levels can impair declarative memory retrieval processes and suggest that such impairments may be related to a disturbance of medial temporal lobe function.

The hippocampus mediates glucocorticoid-induced impairment of spatial memory retrieval: Dependence on the basolateral amygdala

Previous studies have indicated that stress-activated glucocorticoid hormones induce temporary memory retrieval impairment. The present study examined whether adrenal steroid receptors in the hippocampus mediate such glucocorticoid effects on spatial memory retrieval. The specific glucocorticoid receptor (GR) agonist 11β, 17β-dihydroxy-6,21-dimethyl-17α-pregna-4,6-trien-20yn-3-one (RU 28362; 5 or 15 ng) infused into the hippocampus of male Sprague–Dawley rats 60 min before water-maze retention testing, 24 h after training, dose-dependently impaired probe-trial retention performance, as assessed both by time spent in the training quadrant and initial latency to cross the platform location. The GR agonist did not affect circulating corticosterone levels immediately after the probe trial, indicating that RU 28362 infusions did not influence retention by altering glucocorticoid feedback mechanisms. As infusions of the GR agonist into the hippocampus 60 min before training did not influence water-maze acquisition or immediate recall, the findings indicated that the GR agonist-induced retention impairment was induced selectively by an influence on information retrieval. In contrast, pretest infusions of the GR agonist administered into the basolateral complex of the amygdala (BLA; 2 or 6 ng) did not alter retention performance in the water maze. However, N-methyl-d-aspartate-induced lesions of the BLA, made 1 week before training, blocked the memory retrieval impairment induced by intrahippocampal infusions of RU 28362 given 60 min before the retention test. These findings indicate that the effects of glucocorticoids on retrieval of long-term spatial memory depend on the hippocampus and, additionally, that neuronal input from the BLA is critical in enabling hippocampal glucocorticoid effects on memory retrieval.

Glucocorticoid Effects on Memory Retrieval Require Concurrent Noradrenergic Activity in the Hippocampus and Basolateral Amygdala

Previous findings indicate that administration of aβ-adrenoceptor antagonist systemically blocks glucocorticoid impairment of memory retrieval. Here, we report that β-adrenoceptor activation in the hippocampus and the basolateral complex of the amygdala (BLA) is implicated in the impairing effects of glucocorticoids on memory retrieval. The specific glucocorticoid receptor (GR) agonist 11β,17β-dihydroxy-6,21-dimethyl-17α-pregna-4,6-trien-20yn-3-one (RU 28362) (15 ng) infused into the hippocampus of male Sprague Dawley rats 60 min before water maze retention testing, 24 hr after training, impaired probe trial retention performance, as assessed by quadrant search time and initial latency to cross the platform location. Because we found previously that RU 28362 infused into the hippocampus does not affect water maze acquisition or immediate recall, the findings suggest that the GR agonist-induced retention impairment was attributable to a selective influence on long-term memory retrieval. Likewise, systemic injections of the β1-adrenoceptor partial agonist xamoterol (3.0 or 10.0 mg/kg, s.c.) 60 min before the probe trial dose-dependently impaired retention performance. The β-adrenoceptor antagonist propranolol (2.0 mg/kg) administered subcutaneously before retention testing did not affect retention performance alone, but blocked the memory retrieval impairment induced by concurrent intrahippocampal infusions of RU 28362. Pretest infusions of the β1-adrenoceptor antagonist atenolol into either the hippocampus (1.25 μg in 0.5 μl) or the BLA (0.5 μg in 0.2 μl) also prevented the GR agonist-induced memory retrieval impairment. These findings suggest that glucocorticoids impair retrieval of long-term spatial memory by facilitating noradrenergic mechanisms in the hippocampus, and additionally, that norepinephrine-mediated BLA activity is critical in enabling hippocampal glucocorticoid effects on memory retrieval.

White and gray matter abnormalities in the brain of patients with fibromyalgia: A diffusion‐tensor and volumetric imaging study

OBJECTIVE To use a combination of magnetic resonance diffusion-tensor imaging (MR-DTI) and MR imaging of voxel-based morphometry (MR-VBM) in patients with fibromyalgia syndrome (FMS) to determine microstructural and volume changes in the central neuronal networks involved in the sensory-discriminative and affective-motivational characteristics of pain, anxiety, memory, and regulation of the stress response. METHODS Thirty female patients with FMS and 30 healthy female control subjects were studied. Predefined areas of the brain were measured for volume of gray matter by MR-VBM and for diffusivity and fractional anisotropy (FA) by MR-DTI. Higher FA values and reduced diffusivity are thought to reflect increased complexity of brain-tissue microstructure. RESULTS MR-VBM and MR-DTI demonstrated a striking pattern of changes in brain morphology in patients with FMS. Both thalami, the thalamocortical tracts, and both insular regions showed significant decreases in FA. In contrast, increases in FA and decreases in gray matter volume were seen in the postcentral gyri, amygdalae, hippocampi, superior frontal gyri, and anterior cingulate gyri. Increased pain intensity scores were correlated with changes in MR-DTI measurements in the right superior frontal gyrus. Increased fatigue was correlated with changes in the left superior frontal and left anterior cingulate gyrus, and self-perceived physical impairment was correlated with changes in the left postcentral gyrus. Higher intensity scores for stress symptoms were correlated negatively with diffusivity in the thalamus and FA in the left insular cortex. No relationship was found between MR-VBM measurements and symptom intensity scores. CONCLUSION MR-DTI allows the visualization of microstructural changes in the brain of patients with FMS, appears to be more sensitive than MR-VBM, and may serve as an additional diagnostic technique in FMS and probably other dysfunctional pain syndromes.