Dominique de Quervain




Prof. Dr. Dominique de Quervain, MD

Director

Professor at the Faculty of Psychology

and Faculty of Medicine

University of Basel

phone: +41 61 267 02 37

dominique.dequervain@unibas.ch









Biosketch


Dominique de Quervain (born December 8, 1968) studied medicine at the University of Berne, Switzerland, and was a Postdoctoral Fellow at the University of California Irvine, USA, and at the Universities of Basel and Zurich, Switzerland. Dominique de Quervain is interested in the effects of stress and stress hormones on memory in health and disease. In 1998 he found that glucocorticoids impair memory retrieval in animals and, together with his group, he translated these findings to healthy humans and is now investigating the clinical implications in patients with PTSD and phobias. Furthermore, Dominique de Quervain is interested in the identification of memory-related genes in humans using behavioral genetics approaches together with neuroimaging techniques. Dominique de Quervain received the Pfizer-Prize 2006 in Neuroscience, the Robert-Bing Prize of the Swiss Academy of Medical Sciences (2007) and has been elected a Fellow of the Association for Psychological Science.



Publications


in alphabetical order


Aerni, A., R. Traber, et al. (2004). "Low-dose cortisol for symptoms of posttraumatic stress disorder." Am J Psychiatry 161(8): 1488-90.

OBJECTIVE: Because elevated cortisol levels inhibit memory retrieval in healthy human subjects, the present study investigated whether cortisol administration might also reduce excessive retrieval of traumatic memories and related symptoms in patients with chronic posttraumatic stress disorder (PTSD). METHOD: During a 3-month observation period, low-dose cortisol (10 mg/day) was administered orally for 1 month to three patients with chronic PTSD in a double-blind, placebo-controlled, crossover design. RESULTS: In each patient investigated, there was a significant treatment effect, with cortisol-related reductions of at least 38% in one of the daily rated symptoms of traumatic memories, as assessed by self-administered rating scales. In accordance, Clinician-Administered PTSD Scale ratings assessed after each month showed cortisol-related improvements for reexperiencing symptoms and, additionally, in one patient for avoidance symptoms. CONCLUSIONS: The results of this pilot study indicate that low-dose cortisol treatment reduces the cardinal symptoms of PTSD.


Bentz, D., T. Michael, et al. (2009). "Enhancing exposure therapy for anxiety disorders with glucocorticoids: From basic mechanisms of emotional learning to clinical applications." J Anxiety Disord.

Current neurophysiological and psychological accounts view exposure therapy as the clinical analog of extinction learning that results in persistent modifications of the fear memory involved in the pathogenesis, symptomatology, and maintenance of anxiety disorders. Evidence from studies in animals and humans indicate that glucocorticoids have the potential to facilitate the processes that underlie extinction learning during exposure therapy. Particularly, glucocorticoids can restrict retrieval of previous aversive learning episodes and enhance consolidation of memory traces relating to non-fearful responding in feared situations. Thus, glucocorticoid treatment especially in combination with exposure therapy might be a promising approach to optimize treatment of anxiety disorders. This review examines the processes involved in aversive conditioning, fear learning and fear extinction, and how glucocorticoids might enhance restructuring of fear memories during therapy.


Buchmann, A., C. R. Mondadori, et al. (2008). "Prion protein M129V polymorphism affects retrieval-related brain activity." Neuropsychologia 46(9): 2389-402.

The prion protein Met129Val polymorphism has recently been related to human long-term memory with carriers of either the 129MM or the 129MV genotype recalling 17% more words than 129(VV) carriers at 24h following learning. Here, we sampled genotype differences in retrieval-related brain activity at 30min and 24h following learning. Furthermore, genotype groups were compared regarding grey matter concentrations and cognitive profiles. We used event-related functional magnetic resonance imaging (fMRI) during a word recognition task on 12 Met/Met carriers, 12 Val/Met carriers, and 12 Val/Val carriers. These groups were matched for retrieval performance, gender, age, education, and other memory-related genetic polymorphisms. Although retrieval performance was matched, Val carriers exhibited enhanced retrieval-related brain activity at 30min and 24h following learning. At both time lags, correlations between retrieval-related brain activity and retrieval success were negative for Val homozygotes (the more activity, the worse retrieval success), while correlations showed no significance or were positive for Met homozygotes and heterozygotes. These results suggest a less economic use of retrieval-related neural resources in Val relative to Met carriers. Furthermore, Val carriers exhibited higher neocortical grey matter concentrations compared to Met carriers. When controlling for grey matter concentration, genotype effects in retrieval-related brain activity remained significant. Val and Met carriers yielded comparable brain activations for correct rejections of non-studied words and for working memory, which speaks to the specificity of the genotype effect. Findings suggest that the prion protein Met129Val polymorphism affects neural plasticity following learning at a time-scale of minutes to hours.


Coluccia, D., O. T. Wolf, et al. (2008). "Glucocorticoid therapy-induced memory deficits: acute versus chronic effects." J Neurosci 28(13): 3474-8.

Conditions with chronically elevated glucocorticoid levels are usually associated with declarative memory deficits. Considerable evidence suggests that long-term glucocorticoid exposure may cause cognitive impairment via cumulative and long-lasting influences on hippocampal function and morphology. However, because elevated glucocorticoid levels at the time of retention testing are also known to have direct impairing effects on memory retrieval, it is possible that such acute hormonal influences on retrieval processes contribute to the memory deficits found with chronic glucocorticoid exposure. To investigate this issue, we examined memory functions and hippocampal volume in 24 patients with rheumatoid arthritis who were treated either chronically (5.3 +/- 1.0 years, mean +/- SE) with low to moderate doses of prednisone (7.5 +/- 0.8 mg, mean +/- SE) or without glucocorticoids. In both groups, delayed recall of words learned 24 h earlier was assessed under conditions of either elevated or basal glucocorticoid levels in a double-blind, placebo-controlled crossover design. Although the findings in this patient population did not provide evidence for harmful effects of a history of chronic prednisone treatment on memory performance or hippocampal volume per se, acute prednisone administration 1 h before retention testing to either the steroid or nonsteroid group impaired word recall. Thus, these findings indicate that memory deficits observed under chronically elevated glucocorticoid levels result, at least in part, from acute and reversible glucocorticoid effects on memory retrieval.


de Quervain, D. J. (2006). "Glucocorticoid-induced inhibition of memory retrieval: implications for posttraumatic stress disorder." Ann N Y Acad Sci 1071: 216-20.

Posttraumatic stress disorder (PTSD) is characterized by traumatic memories that can manifest as daytime recollections, traumatic nightmares, or flashbacks in which components of the event are relieved. These symptoms reflect excessive retrieval of traumatic memories that often retain their vividness and power to evoke distress for decades or even a lifetime. We have reported previously that elevated glucocorticoid levels inhibit memory retrieval in animals and healthy human subjects. We therefore hypothesized that the administration of cortisol might also inhibit the retrieval of traumatic memories in patients with PTSD. In a recent pilot study, we found the first evidence to support this hypothesis. During a 3-month observation period, low-dose cortisol (10 mg/day) was administered orally for 1 month to three patients with chronic PTSD using a double-blind, placebo-controlled, crossover design. In each patient investigated, there was a significant treatment effect with cortisol-related reductions in one of the daily rated symptoms of traumatic memories without causing adverse side effects. Future studies with more patients and longer treatment periods are required to evaluate the efficacy of cortisol treatment for PTSD.


de Quervain, D. J. (2008). "Glucocorticoid-induced reduction of traumatic memories: implications for the treatment of PTSD." Prog Brain Res 167: 239-47.

Post-traumatic stress disorder (PTSD) is an anxiety disorder that can occur after a traumatic event such as military combat, terrorist attacks, or accidents. The disorder is characterized by traumatic memories that manifest as reexperiencing symptoms including daytime recollections, traumatic nightmares, or flashbacks in which components of the event are relived. These symptoms result from excessive retrieval of traumatic memories that often retain their vividness and power to evoke distress for decades or even a lifetime. We have reported previously that elevated glucocorticoid levels inhibit memory retrieval in animals and healthy human subjects. We therefore hypothesized that the administration of cortisol might also inhibit the retrieval of traumatic memories in patients with PTSD. In a recent pilot study we found the first evidence to support this hypothesis. During a 3-month observation period, low-dose cortisol (10 mg per day) was administered orally for 1 month to three patients with chronic PTSD using a double-blind, placebo-controlled, crossover design. In each patient investigated, there was a significant treatment effect with cortisol-related reductions in one of the daily-rated symptoms of traumatic memories without causing adverse side effects. Furthermore, we have reported evidence for a prolonged effect of the cortisol treatment. Persistent retrieval and reconsolidation of traumatic memories is a process that keeps these memories vivid and thereby the disorder alive. By inhibiting memory retrieval, cortisol may weaken the traumatic memory trace and thus reduce symptoms even beyond the treatment period. Future studies with more patients and longer treatment periods are required to evaluate the efficacy of cortisol treatment for PTSD.


de Quervain, D. J., A. Aerni, et al. (2007). "Preventive effect of beta-adrenoceptor blockade on glucocorticoid-induced memory retrieval deficits." Am J Psychiatry 164(6): 967-9.

OBJECTIVE: Elevated glucocorticoid levels impair retrieval of emotional information, and animal studies indicate that this effect depends on concurrent emotional arousal-induced increases in noradrenergic transmission within the brain. The authors investigated whether the beta-adrenoceptor antagonist propranolol blocks glucocorticoid-induced memory retrieval impairments in human subjects. METHOD: In a double-blind, placebo-controlled study, 42 healthy volunteers were presented a set of words with variable emotionality and asked to learn them for recall. A day later, cortisone (25 mg), propranolol (40 mg), or both drugs were administered orally 1 hour before a free-recall test. RESULTS: Cortisone selectively impaired the recall of emotionally arousing words by 42%. This impairment was blocked by the concurrent administration of propranolol. Propranolol alone did not affect recall of either emotional or neutral words. CONCLUSIONS: A pharmacological blockade of beta-adrenoceptors prevents glucocorticoid-induced memory retrieval deficits in human subjects. This finding may have important implications for the treatment of memory deficits in hypercortisolemic states, such as stress and depression.


de Quervain, D. J., A. Aerni, et al. (2009). "Glucocorticoids and the regulation of memory in health and disease." Front Neuroendocrinol 30(3): 358-70.

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.


de Quervain, D. J., U. Fischbacher, et al. (2004). "The neural basis of altruistic punishment." Science 305(5688): 1254-8.

Many people voluntarily incur costs to punish violations of social norms. Evolutionary models and empirical evidence indicate that such altruistic punishment has been a decisive force in the evolution of human cooperation. We used H2 15O positron emission tomography to examine the neural basis for altruistic punishment of defectors in an economic exchange. Subjects could punish defection either symbolically or effectively. Symbolic punishment did not reduce the defector's economic payoff, whereas effective punishment did reduce the payoff. We scanned the subjects' brains while they learned about the defector's abuse of trust and determined the punishment. Effective punishment, as compared with symbolic punishment, activated the dorsal striatum, which has been implicated in the processing of rewards that accrue as a result of goal-directed actions. Moreover, subjects with stronger activations in the dorsal striatum were willing to incur greater costs in order to punish. Our findings support the hypothesis that people derive satisfaction from punishing norm violations and that the activation in the dorsal striatum reflects the anticipated satisfaction from punishing defectors.


de Quervain, D. J., K. Henke, et al. (2003). "A functional genetic variation of the 5-HT2a receptor affects human memory." Nat Neurosci 6(11): 1141-2.

Human memory capacity is highly variable across individuals and is influenced by both genetic and environmental factors. A roughly 50% heritability estimate indicates that naturally occurring genetic variations have an important impact on this cognitive ability. Therefore, we investigated a functional variation of a memory-related serotonin receptor in 349 healthy young volunteers, and found 21% poorer memory performance in subjects with the rare variant.


de Quervain, D. J., K. Henke, et al. (2003). "Glucocorticoid-induced impairment of declarative memory retrieval is associated with reduced blood flow in the medial temporal lobe." Eur J Neurosci 17(6): 1296-302.

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 H(2)(15)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.


de Quervain, D. J., I. T. Kolassa, et al. (2007). "A deletion variant of the alpha2b-adrenoceptor is related to emotional memory in Europeans and Africans." Nat Neurosci 10(9): 1137-9.

Emotionally arousing events are recalled better than neutral events. This phenomenon, which helps us to remember important and potentially vital information, depends on the activation of noradrenergic transmission in the brain. Here we show that a deletion variant of ADRA2B, the gene encoding the alpha2b-adrenergic receptor, is related to enhanced emotional memory in healthy Swiss subjects and in survivors of the Rwandan civil war who experienced highly aversive emotional situations.


de Quervain, D. J. and J. Margraf (2008). "Glucocorticoids for the treatment of post-traumatic stress disorder and phobias: a novel therapeutic approach." Eur J Pharmacol 583(2-3): 365-71.

Post-traumatic stress disorder (PTSD) and phobias belong to the most common anxiety disorders and to the most common psychiatric illnesses in general. In both disorders, aversive memories are thought to play an important role in the pathogenesis and symptomatology. Previously, we have reported that elevated glucocorticoid levels inhibit memory retrieval in animals and healthy humans. We therefore hypothesized that the administration of glucocorticoids might also inhibit the retrieval of aversive memory, thereby reducing symptoms in patients with PTSD and phobias. In recent clinical studies, we found first evidence to support this hypothesis. In patients with PTSD, low-dose cortisol treatment for one month reduced symptoms of traumatic memories without causing adverse side effects. Furthermore, we found evidence for a prolonged effect of the cortisol treatment. Persistent retrieval and reconsolidation of traumatic memories is a process that keeps these memories vivid and thereby the disorder alive. By inhibiting memory retrieval, cortisol may weaken the traumatic memory trace, and thus reduce symptoms even beyond the treatment period. In patients with social phobia, we found that a single oral administration of cortisone 1 h before a socio-evaluative stressor significantly reduced self-reported fear during the anticipation-, exposure-, and recovery phase of the stressor. In subjects with spider phobia, repeated oral administration of cortisol 1 h before exposure to a spider photograph induced a progressive reduction of stimulus-induced fear. This effect was maintained when subjects were exposed to the stimulus again two days after the last cortisol administration, indicating that cortisol facilitated the extinction of phobic fear. In conclusion, by a common mechanism of reducing the retrieval of aversive memories, glucocorticoids may be suited for the treatment of PTSD as well as phobias. More studies are needed to further evaluate the therapeutic efficacy of glucocorticoids in the treatment of anxiety disorders and to explore the potential of combining glucocorticoid treatment with psychotherapy.


de Quervain, D. J. and A. Papassotiropoulos (2006). "Identification of a genetic cluster influencing memory performance and hippocampal activity in humans." Proc Natl Acad Sci U S A 103(11): 4270-4.

Experimental work in animals has shown that memory formation depends on a cascade of molecular events. Here we show that variability of human memory performance is related to variability in genes encoding proteins of this signaling cascade, including the NMDA and metabotrobic glutamate receptors, adenylyl cyclase, CAMKII, PKA, and PKC. The individual profile of genetic variability in these signaling molecules correlated significantly with episodic memory performance (P < 0.00001). Moreover, functional MRI during memory formation revealed that this genetic profile correlated with activations in memory-related brain regions, including the hippocampus and parahippocampal gyrus. The present study indicates that genetic variability in the human homologues of memory-related signaling molecules contributes to interindividual differences in human memory performance and memory-related brain activations.


de Quervain, D. J., R. Poirier, et al. (2004). "Glucocorticoid-related genetic susceptibility for Alzheimer's disease." Hum Mol Genet 13(1): 47-52.

Because glucocorticoid excess increases neuronal vulnerability, genetic variations in the glucocorticoid system may be related to the risk for Alzheimer's disease (AD). We analyzed single-nucleotide polymorphisms in 10 glucocorticoid-related genes in a population of 814 AD patients and unrelated control subjects. Set-association analysis revealed that a rare haplotype in the 5' regulatory region of the gene encoding 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) was associated with a 6-fold increased risk for sporadic AD. Results of a reporter-gene assay indicated that the rare risk-associated haplotype altered HSD11B1 transcription. HSD11B1 controls tissue levels of biologically active glucocorticoids and thereby influences neuronal vulnerability. Our results indicate that a functional variation in the glucocorticoid system increases the risk for AD, which may have important implications for the diagnosis and treatment of this disease.


de Quervain, D. J., B. Roozendaal, et al. (1998). "Stress and glucocorticoids impair retrieval of long-term spatial memory." Nature 394(6695): 787-90.

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.


de Quervain, D. J., B. Roozendaal, et al. (2000). "Acute cortisone administration impairs retrieval of long-term declarative memory in humans." Nat Neurosci 3(4): 313-4.


Hock, C., U. Konietzko, et al. (2003). "Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease." Neuron 38(4): 547-54.

To test whether antibodies against beta-amyloid are effective in slowing progression of Alzheimer's 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 Alzheimer's disease.


Hoerndli, F. J., M. Walser, et al. (2009). "A conserved function of C. elegans CASY-1 calsyntenin in associative learning." PLoS One 4(3): e4880.

BACKGROUND: Whole-genome association studies in humans have enabled the unbiased discovery of new genes associated with human memory performance. However, such studies do not allow for a functional or causal testing of newly identified candidate genes. Since polymorphisms in Calsyntenin 2 (CLSTN2) showed a significant association with episodic memory performance in humans, we tested the C. elegans CLSTN2 ortholog CASY-1 for possible functions in the associative behavior of C. elegans. METHODOLOGY/PRINCIPAL FINDINGS: Using three different associative learning paradigms and functional rescue experiments, we show that CASY-1 plays an important role during associative learning in C. elegans. Furthermore, neuronal expression of human CLSTN2 in C. elegans rescues the learning defects of casy-1 mutants. Finally, genetic interaction studies and neuron-specific expression experiments suggest that CASY-1 may regulate AMPA-like GLR-1 glutamate receptor signaling. CONCLUSION/SIGNIFICANCE: Our experiments demonstrate a remarkable conservation of the molecular function of Calsyntenins between nematodes and humans and point at a role of C. elegans casy-1 in regulating a glutamate receptor signaling pathway.


Huentelman, M. J., A. Papassotiropoulos, et al. (2007). "Calmodulin-binding transcription activator 1 (CAMTA1) alleles predispose human episodic memory performance." Hum Mol Genet 16(12): 1469-77.

Little is known about the genes and proteins involved in the process of human memory. To identify genetic factors related to human episodic memory performance, we conducted an ultra-high-density genome-wide screen at > 500 000 single nucleotide polymorphisms (SNPs) in a sample of normal young adults stratified for performance on an episodic recall memory test. Analysis of this data identified SNPs within the calmodulin-binding transcription activator 1 (CAMTA1) gene that were significantly associated with memory performance. A follow up study, focused on the CAMTA1 locus in an independent cohort consisting of cognitively normal young adults, singled out SNP rs4908449 with a P-value of 0.0002 as the most significant associated SNP in the region. These validated genetic findings were further supported by the identification of CAMTA1 transcript enrichment in memory-related human brain regions and through a functional magnetic resonance imaging experiment on individuals matched for memory performance that identified CAMTA1 allele-specific upregulation of medial temporal lobe brain activity in those individuals harboring the 'at-risk' allele for poorer memory performance. The CAMTA1 locus encodes a purported transcription factor that interfaces with the calcium-calmodulin system of the cell to alter gene expression patterns. Our validated genomic and functional biological findings described herein suggest a role for CAMTA1 in human episodic memory.


Kolassa, I. T., C. Eckart, et al. (2007). "Lack of cortisol response in patients with posttraumatic stress disorder (PTSD) undergoing a diagnostic interview." BMC Psychiatry 7: 54.

BACKGROUND: According to DSM-IV, the diagnosis of posttraumatic stress disorder (PTSD) requires the experience of a traumatic event during which the person's response involved intense fear, helplessness, or horror. In order to diagnose PTSD, clinicians must interview the person in depth about his/her previous experiences and determine whether the individual has been traumatized by a specific event or events. However, asking questions about traumatic experiences can be stressful for the traumatized individual and it has been cautioned that subsequent "re-traumatization" could occur. This study investigated the cortisol response in traumatized refugees with PTSD during a detailed and standardized interview about their personal war and torture experiences. METHODS: Participants were male refugees with severe PTSD who solicited an expert opinion in the Psychological Research Clinic for Refugees of the University of Konstanz. 17 patients were administered the Vivo Checklist of War, Detention, and Torture Events, a standardized interview about traumatic experiences, and 16 subjects were interviewed about absorption behavior. Self-reported measures of affect and arousal, as well as saliva cortisol were collected at four points. Before and after the experimental intervention, subjects performed a Delayed Matching-to-Sample (DMS) task for distraction. They also rated the severity of selected PTSD symptoms, as well as the level of intrusiveness of traumatic memories at that time. RESULTS: Cortisol excretion diminished in the course of the interview and showed the same pattern for both groups. No specific response was detectable after the supposed stressor. Correspondingly, ratings of subjective well-being, memories of the most traumatic event(s) and PTSD symptoms did not show any significant difference between groups. Those in the presumed stress condition did not perform worse than persons in the control condition after the stressor. However, both groups performed poorly in the DMS task, which is consistent with memory and concentration problems demonstrated in patients with PTSD. CONCLUSION: A comprehensive diagnostic interview including questions about traumatic events does not trigger an HPA-axis based alarm response or changes in psychological measures, even for persons with severe PTSD, such as survivors of torture. Thus, addressing traumatic experiences within a safe and empathic environment appears to impose no unacceptable additional load to the patient.


Kolassa, I. T., S. Kolassa, et al. (2009). "The Risk of Posttraumatic Stress Disorder After Trauma Depends on Traumatic Load and the Catechol-O-Methyltransferase Val(158)Met Polymorphism." Biol Psychiatry.

BACKGROUND: The risk for posttraumatic stress disorder (PTSD) depends on the number of traumatic event types experienced in a dose-response relationship, but genetic factors are known to also influence the risk of PTSD. The catechol-O-methyltransferase (COMT) Val158Met polymorphism has been found to affect fear extinction and might play a role in the etiology of anxiety disorders. METHODS: Traumatic load and lifetime and current diagnosis of PTSD and COMT genotype were assessed in a sample of 424 survivors of the Rwandan Genocide living in the Nakivale refugee camp in southwestern Uganda. RESULTS: Higher numbers of different lifetime traumatic event types led to a higher prevalence of lifetime PTSD in a dose-response relationship. However, this effect was modulated by the COMT genotype: whereas Val allele carriers showed the typical dose-response relationship, Met/Met homozygotes exhibited a high risk for PTSD independently of the severity of traumatic load. CONCLUSIONS: The present findings indicate a gene-environment interaction between the human COMT Val158Met polymorphism and the number of traumatic event types experienced in the risk of developing PTSD.


Lutz, J., L. Jager, et al. (2008). "White and gray matter abnormalities in the brain of patients with fibromyalgia: a diffusion-tensor and volumetric imaging study." Arthritis Rheum 58(12): 3960-9.

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.


Mathis, J., D. de Quervain, et al. (1998). "Dependence of the transcranially induced silent period on the 'instruction set' and the individual reaction time." Electroencephalogr Clin Neurophysiol 109(5): 426-35.

OBJECTIVES AND METHODS: We looked for influences of the experimental condition on the silent period (SP) from transcranial motor cortex stimulation and analyzed how the instruction given to the subject, as well as the individual reaction time, might affect the duration of the SP in the biceps brachii muscle. RESULTS: The duration of the SP was found to critically depend on the subject's voluntary reaction of the target muscle immediately after the stimulus. With low stimulus intensity and low background force, the duration of the silent period was significantly longer in 10 of 13 subjects (P = 0.002) when they were instructed to relax quickly after the stimulus rather than to maintain the the force at a constant level. A significant shortening of the SP (P = 0.02) was observed when the subjects were instructed to perform a rapid contraction of the target muscle in reaction to the cortical stimulus. With low stimulus intensity and high background force, the same influence of the instruction set was found in 6 of 13 subjects. When the subjects were left without precise instruction, the SP duration was unpredictable. In 10 subjects, the SP corresponded to that obtained with the instruction to maintain the force at a constant level. However, in 3 subjects it was prolonged to the value observed in the 'relax' instruction. With greater stimulus intensities, the effect of the instruction set on the SP duration was generally smaller. A significant prolongation was nevertheless found at low background forces with rapid relaxation (P < 0.001), and a significant shortening was found at high background forces with rapid contraction (P < 0.001) after the stimulus. The SP duration observed with 20% of maximal voluntary contraction (MVC) significantly correlated with the individual reaction time. No such correlation was found for the SP obtained with 80% MVC. The SP was slightly longer at 20% MVC, as compared to 80% MVC within each instruction group. This effect was significant (P < 0.05) at low stimulus intensities. CONCLUSIONS: Therefore, when assessing the SP duration for diagnostic purposes, not only the stimulus intensity but also the background force and the voluntary reaction must be standardized. Furthermore, great stimulus intensities and high background forces should be used to minimise the effects of instruction set and individual reaction time.


Mathis, J., D. de Quervain, et al. (1999). "Task-dependent effects on motor-evoked potentials and on the following silent period." J Clin Neurophysiol 16(6): 556-65.

The silent period (SP) after transcranial stimulation is used as a diagnostic tool in various central nervous system disorders although no standardized experimental setup has been established. The aim of this study was to demonstrate the influence of an isotonic compared to an isometric experimental condition. The SP after transcranial magnetic brain stimulation in the biceps brachii and brachioradialis muscle was up to 130% longer when elicited during a maintain-position (isotonic) task as compared to a maintain-force task (isometric) when stimulus intensities of 5% to 25% above threshold were used. The mean SP duration in these muscles was positively correlated to the mean contraction time in both tasks. However, no such relationship was observed for the trials within the individual subjects. We speculate that the invariably longer SP of the maintain-position task was due to the different "motor set" which predictively determined the muscle behavior after the stimulus. In the maintain-position trials, the stimulus-induced long-lasting flexion movement is counteracted by a motor set aiming to relax the elbow flexors immediately after the stimulus. In the maintain-force task the contraction twitch is short and a force drop below the preset level must be prevented by a motor set aiming to contract the elbow flexors immediately after the stimulus. The latter may increase the synaptic input to the motoneuron pool and facilitate the reoccurrence of the electromyogram terminating the SP. At high-stimulus intensities the SP duration increased in both tasks, and the task-dependent differences disappeared. Therefore, when using the SP duration for diagnostic purposes, isometric conditions and high-stimulus intensities should be used.


Mondadori, C. R., D. J. de Quervain, et al. (2007). "Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers." Cereb Cortex 17(8): 1934-47.

The apolipoprotein E (APOE) epsilon4 allele is the major genetic risk factor for Alzheimer's disease, but an APOE effect on memory performance and memory-related neurophysiology in young, healthy subjects is unknown. We found an association of APOE epsilon4 with better episodic memory compared with APOE epsilon2 and epsilon3 in 340 young, healthy persons. Neuroimaging was performed in a subset of 34 memory-matched individuals to study genetic effects on memory-related brain activity independently of differential performance. E4 carriers decreased brain activity over 3 learning runs, whereas epsilon2 and epsilon3 carriers increased activity. This smaller neural investment of epsilon4 carriers into learning reappeared during retrieval: epsilon4 carriers exhibited reduced retrieval-related activity with equal retrieval performance. APOE isoforms had no differential effects on cognitive measures other than memory, brain volumes, and brain activity related to working memory. We suggest that APOE epsilon4 is associated with good episodic memory and an economic use of memory-related neural resources in young, healthy humans.


Papassotiropoulos, A., K. Henke, et al. (2005). "Age-dependent effects of the 5-hydroxytryptamine-2a-receptor polymorphism (His452Tyr) on human memory." Neuroreport 16(8): 839-42.

A polymorphism (His452Tyr) of the 5-hydroxytryptamine (5-HT)2a receptor is associated with episodic memory in healthy young humans. Because 5-HT2a-receptor density decreases with increasing age, we tested whether the 5-HT2a receptor genotype effect on memory is influenced by age. We investigated the association of the His452Tyr genotype with memory performance in 622 healthy study participants aged from 18 to 90 years. In young to middle-aged participants, age significantly influenced genotype effects on episodic memory: the His452Tyr genotype exerted a significant influence on memory only in young participants. In the group of elderly cognitively healthy participants, the His452Tyr genotype did not affect memory performance. We conclude that age strongly modulates the effect of the 5-HT2a receptor polymorphism at residue 452 on episodic memory.


Papassotiropoulos, A., K. Henke, et al. (2009). "A genome-wide survey of human short-term memory." Mol Psychiatry.

Recent advances in the development of high-throughput genotyping platforms allow for the unbiased identification of genes and genomic sequences related to heritable traits. In this study, we analyzed human short-term memory, which refers to the ability to remember information over a brief period of time and which has been found disturbed in many neuropsychiatric conditions, including schizophrenia and depression. We performed a genome-wide survey at 909 622 polymorphic loci and report six genetic variations significantly associated with human short-term memory performance after genome-wide correction for multiple comparisons. A polymorphism within SCN1A (encoding the alpha subunit of the type I voltage-gated sodium channel) was replicated in three independent populations of 1699 individuals. Functional magnetic resonance imaging during an n-back working memory task detected SCN1A allele-dependent activation differences in brain regions typically involved in working memory processes. These results suggest an important role for SCN1A in human short-term memory.Molecular Psychiatry advance online publication, 29 December 2009; doi:10.1038/mp.2009.133.


Papassotiropoulos, A., D. A. Stephan, et al. (2006). "Common Kibra alleles are associated with human memory performance." Science 314(5798): 475-8.

Human memory is a polygenic trait. We performed a genome-wide screen to identify memory-related gene variants. A genomic locus encoding the brain protein KIBRA was significantly associated with memory performance in three independent, cognitively normal cohorts from Switzerland and the United States. Gene expression studies showed that KIBRA was expressed in memory-related brain structures. Functional magnetic resonance imaging detected KIBRA allele-dependent differences in hippocampal activations during memory retrieval. Evidence from these experiments suggests a role for KIBRA in human memory.


Papassotiropoulos, A., M. A. Wollmer, et al. (2005). "The prion gene is associated with human long-term memory." Hum Mol Genet 14(15): 2241-6.

Human cognitive processes are highly variable across individuals and are influenced by both genetic and environmental factors. Although genetic variations affect short-term memory in humans, it is unknown whether genetic variability has also an impact on long-term memory. Because prion-like conformational changes may be involved in the induction of long-lasting synaptic plasticity, we examined the impact of single-nucleotide polymorphisms (SNPs) of the prion protein gene (PRNP) on long-term memory in healthy young humans. SNPs in the genomic region of PRNP were associated with better long-term memory performance in two independent populations with different educational background. Among the examined PRNP SNPs, the common Met129Val polymorphism yielded the highest effect size. Twenty-four hours after a word list-learning task, carriers of either the 129MM or the 129MV genotype recalled 17% more information than 129VV carriers, but short-term memory was unaffected. These results suggest a role for the prion protein in the formation of long-term memory in humans.


Rasch, B., K. Spalek, et al. (2009). "A genetic variation of the noradrenergic system is related to differential amygdala activation during encoding of emotional memories." Proc Natl Acad Sci U S A 106(45): 19191-6.

Emotionally arousing events are typically well remembered, but there is a large interindividual variability for this phenomenon. We have recently shown that a functional deletion variant of ADRA2B, the gene encoding the alpha2b-adrenergic receptor, is related to enhanced emotional memory in healthy humans and enhanced traumatic memory in war victims. Here, we investigated the neural mechanisms of this effect in healthy participants by using fMRI. Carriers of the ADRA2B deletion variant exhibited increased activation of the amygdala during encoding of photographs with negative emotional valence compared with noncarriers of the deletion. Additionally, functional connectivity between amygdala and insula was significantly stronger in deletion carriers. The present findings indicate that the ADRA2B deletion variant is related to increased responsivity and connectivity of brain regions implicated in emotional memory.


Roozendaal, B. and D. J. de Quervain (2005). "Glucocorticoid therapy and memory function: lessons learned from basic research." Neurology 64(2): 184-5.


Roozendaal, B., D. J. de Quervain, et al. (2001). "Basolateral amygdala-nucleus accumbens interactions in mediating glucocorticoid enhancement of memory consolidation." J Neurosci 21(7): 2518-25.

Systemic or intracerebral administration of glucocorticoids enhances memory consolidation in several tasks. Previously, we reported that these effects depend on an intact basolateral nucleus of the amygdala (BLA) and efferents from the BLA that run through the stria terminalis (ST). The BLA projects directly to the nucleus accumbens (NAc) via this ST pathway. The NAc also receives direct projections from the hippocampus and, therefore, may be a site of convergence of BLA and hippocampal influences in modulating memory consolidation. In support of this view, we found previously that lesions of either the NAc or the ST also block the memory-modulatory effect of systemically administered glucocorticoids. The present experiments examined the effects of lesions of the NAc or the ST on the memory-modulatory effects of intracerebral glucocorticoids on inhibitory avoidance training. Microinfusions of the specific glucocorticoid receptor agonist 11beta,17beta-dihydroxy-6,21-dimethyl-17alpha-pregna-4,6-trien-20yn-3-one (RU 28362; 1.0 or 3.0 ng) into either the BLA or the hippocampus of male Sprague Dawley rats administered immediately after training enhanced the 48 hr retention performance in a dose-dependent manner. Bilateral lesions of the NAc or the ST alone did not affect retention performance but blocked the memory enhancement induced by intra-BLA or intrahippocampal glucocorticoid receptor agonist administration. These findings indicate that the BLA-NAc pathway plays an essential role in mediating glucocorticoid effects on memory consolidation and suggest that the BLA interacts with hippocampal effects on memory consolidation via this pathway.


Roozendaal, B., D. J. de Quervain, et al. (2004). "A systemically administered beta-adrenoceptor antagonist blocks corticosterone-induced impairment of contextual memory retrieval in rats." Neurobiol Learn Mem 81(2): 150-4.

Several studies have reported that glucocorticoids impair memory retrieval. The present study examined in male Sprague-Dawley rats the effects of systemically administered corticosterone on retrieval of memory for inhibitory avoidance training. Corticosterone (3.0mg/kg, s.c.) injected 30min before retention testing, 48h after training, significantly impaired retention performance, as compared to vehicle treatment, of rats tested in the training context. In contrast, corticosterone administration did not impair retrieval when rats were tested for retention in a different context. Corticosterone did also not impair retention performance of rats given a mild-intensity footshock that resulted in only weak, non-contextual memory. These findings strongly suggest that corticosterone selectively impaired retrieval of contextual information associated with the training context. The centrally acting beta-adrenoceptor antagonist propranolol (2.0mg/kg), co-administered in a dose that did not affect retention performance alone, blocked the impairment in contextual memory retrieval induced by corticosterone. These findings provide evidence for the view that glucocorticoids interact with noradrenergic mechanisms in influencing memory retrieval.


Roozendaal, B., Q. K. Griffith, et al. (2003). "The hippocampus mediates glucocorticoid-induced impairment of spatial memory retrieval: dependence on the basolateral amygdala." Proc Natl Acad Sci U S A 100(3): 1328-33.

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 11beta, 17beta-dihydroxy-6,21-dimethyl-17alpha-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.


Roozendaal, B., E. L. Hahn, et al. (2004). "Glucocorticoid effects on memory retrieval require concurrent noradrenergic activity in the hippocampus and basolateral amygdala." J Neurosci 24(37): 8161-9.

Previous findings indicate that administration of abeta-adrenoceptor antagonist systemically blocks glucocorticoid impairment of memory retrieval. Here, we report that beta-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 11beta,17beta-dihydroxy-6,21-dimethyl-17alpha-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 beta1-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 beta-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 beta1-adrenoceptor antagonist atenolol into either the hippocampus (1.25 microg in 0.5 microl) or the BLA (0.5 microg in 0.2 microl) 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.


Roozendaal, B., S. Okuda, et al. (2006). "Glucocorticoids interact with emotion-induced noradrenergic activation in influencing different memory functions." Neuroscience 138(3): 901-10.

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.


Schelling, G., E. Kilger, et al. (2004). "Stress doses of hydrocortisone, traumatic memories, and symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized study." Biol Psychiatry 55(6): 627-33.

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.


Schelling, G., B. Roozendaal, et al. (2004). "Can posttraumatic stress disorder be prevented with glucocorticoids?" Ann N Y Acad Sci 1032: 158-66.

Patients with critical illness who are treated in an intensive care unit (ICU) often report traumatic memories from ICU treatment, receive exogenously administered glucocorticoids for medical reasons, and have a relatively high incidence of chronic stress symptoms and posttraumatic stress disorder (PTSD) during follow-up. ICU therapy could therefore represent a useful model for investigating glucocorticoid effects on traumatic memories and PTSD development. Studies in long-term survivors of ICU treatment demonstrated a clear and vivid recall of different categories of traumatic memory such as nightmares, anxiety, respiratory distress, or pain. The incidence and intensity of PTSD symptoms increased with the number of categories of traumatic memory present. The prolonged administration of glucocorticoids (stress doses of hydrocortisone) to critically ill patients resulted in a significant reduction of PTSD symptoms measured after recovery without influencing the number of categories of traumatic memory. This protective effect of cortisol can possibly be explained by a cortisol-induced temporary impairment in traumatic memory retrieval which has previously been demonstrated in both rats and humans. Therefore, stress doses of hydrocortisone could be useful for prophylaxis and treatment of PTSD.


Schmidt, C., P. Peigneux, et al. (2006). "Encoding difficulty promotes postlearning changes in sleep spindle activity during napping." J Neurosci 26(35): 8976-82.

Learning-dependent increases in sleep spindle density have been reported during nocturnal sleep immediately after the learning session. Here, we investigated experience-dependent changes in daytime sleep EEG activity after declarative learning of unrelated word pairs. At weekly intervals, 13 young male volunteers spent three 24 h sessions in the laboratory under carefully controlled homeostatic and circadian conditions. At approximately midday, subjects performed either one of two word-pair learning tasks or a matched nonlearning control task, in a counterbalanced order. The two learning lists differed in the level of concreteness of the words used, resulting in an easier and a more difficult associative encoding condition, as confirmed by performance at immediate cued recall. Subjects were then allowed to sleep for 4 h; afterward, delayed cued recall was tested. Compared with the control condition, sleep EEG spectral activity in the low spindle frequency range and the density of low-frequency sleep spindles (11.25-13.75 Hz) were both significantly increased in the left frontal cortex after the difficult but not after the easy encoding condition. Furthermore, we found positive correlations between these EEG changes during sleep and changes in memory performance between pre-nap and post-nap recall sessions. These results indicate that, like during nocturnal sleep, daytime sleep EEG oscillations including spindle activity are modified after declarative learning of word pairs. Furthermore, we demonstrate here that the nature of the learning material is a determinant factor for sleep-related alterations after declarative learning.


Sigmund, J. C., C. Vogler, et al. (2008). "Fine-mapping at the HTR2A locus reveals multiple episodic memory-related variants." Biol Psychol 79(2): 239-42.

A functional polymorphism (His452Tyr) in the gene encoding the serotonin 2A receptor (HTR2A) has been previously associated with human episodic memory performance and with differences in brain volume in memory-related brain regions. Here we present data obtained through imputation and fine-mapping showing that multiple loci within HTR2A are significantly associated with human memory performance independently of the His452Tyr polymorphism. Our data support the existence of multiple memory-related loci within HTR2A.


Soravia, L. M., D. J. de Quervain, et al. (2009). "Glucocorticoids do not reduce subjective fear in healthy subjects exposed to social stress." Biol Psychol 81(3): 184-8.

BACKGROUND: Previous experiments in patients with phobia have shown that the administration of glucocorticoids reduces fear in phobic situations. Extensive evidence indicates that elevated glucocorticoid levels inhibit memory retrieval processes. In patients with phobia, exposure to a phobic stimulus (socio-evaluative stress test) provokes retrieval of stimulus-associated fear memory that leads to a fear response. It is therefore possible that glucocorticoids reduce phobic fear by inhibiting retrieval of the previously acquired fear memory. Whether glucocorticoids reduce subjective fear also in healthy subjects exposed to a socially fearful situation is not known. METHOD: In a double-blind, placebo-controlled study, 50 healthy subjects underwent the same socio-evaluative stress test as used in a previous study in patients with social phobia. One hour before the stress test, subjects received 25mg cortisone or placebo orally. Psychological anxiety measures were repeatedly assessed. RESULTS: Although the stress situation robustly increased fear in this population of healthy subjects, cortisone treatment did not reduce subjective fear, physical discomfort or avoidance behavior when compared to placebo-treated subjects. CONCLUSION: The present study did not find evidence indicating that glucocorticoids reduce subjective fear in healthy subjects exposed to a socially fearful situation.


Soravia, L. M., M. Heinrichs, et al. (2006). "Glucocorticoids reduce phobic fear in humans." Proc Natl Acad Sci U S A 103(14): 5585-90.

Phobias are characterized by excessive fear, cued by the presence or anticipation of a fearful situation. Whereas it is well established that glucocorticoids are released in fearful situations, it is not known whether these hormones, in turn, modulate perceived fear. As extensive evidence indicates that elevated glucocorticoid levels impair the retrieval of emotionally arousing information, they might also inhibit retrieval of fear memory associated with phobia and, thereby, reduce phobic fear. Here, we investigated whether acutely administrated glucocorticoids reduced phobic fear in two double-blind, placebo-controlled studies in 40 subjects with social phobia and 20 subjects with spider phobia. In the social phobia study, cortisone (25 mg) administered orally 1 h before a socio-evaluative stressor significantly reduced self-reported fear during the anticipation, exposure, and recovery phase of the stressor. Moreover, the stress-induced release of cortisol in placebo-treated subjects correlated negatively with fear ratings, suggesting that endogenously released cortisol in the context of a phobic situation buffers fear symptoms. In the spider phobia study, repeated oral administration of cortisol (10 mg), but not placebo, 1 h before exposure to a spider photograph induced a progressive reduction of stimulus-induced fear. This effect was maintained when subjects were exposed to the stimulus again 2 days after the last cortisol administration, suggesting that cortisol may also have facilitated the extinction of phobic fear. Cortisol treatment did not reduce general, phobia-unrelated anxiety. In conclusion, the present findings in two distinct types of phobias indicate that glucocorticoid administration reduces phobic fear.


Vogler, C., K. Spalek, et al. (2009). "CPEB3 is associated with human episodic memory." Front Behav Neurosci 3: 4.

Cytoplasmic polyadenylation element-binding (CPEB) proteins are crucial for synaptic plasticity and memory in model organisms. A highly conserved, mammalian-specific short intronic sequence within CPEB3 has been identified as a ribozyme with self-cleavage properties. In humans, the ribozyme sequence is polymorphic and harbors a single nucleotide polymorphism that influences cleavage activity of the ribozyme. Here we show that this variation is related to performance in an episodic memory task and that the effect of the variation depends on the emotional valence of the presented material. Our data suggest a role for human CPEB3 in human episodic memory.


Weis, F., E. Kilger, et al. (2006). "Stress doses of hydrocortisone reduce chronic stress symptoms and improve health-related quality of life in high-risk patients after cardiac surgery: a randomized study." J Thorac Cardiovasc Surg 131(2): 277-82.

OBJECTIVES: Improvement in health-related quality of life is a major object of cardiac surgery. However, high stress exposure during the perioperative period of cardiac surgery can result in the formation of traumatic memories and symptoms of chronic stress or even posttraumatic stress disorder, which can have negative effects on health-related quality-of-life outcome. In this controlled study we examined whether exogenously administered stress doses of hydrocortisone during cardiac surgery reduce perioperative stress exposure and the long-term incidence of chronic stress symptoms and improve health-related quality of life after cardiac surgery. METHODS: Thirty-six high-risk patients undergoing cardiac surgery were prospectively randomized to receive either stress doses of hydrocortisone or placebo. Of 28 available patients at 6 months after cardiac surgery, 14 had received hydrocortisone, and 14 had received placebo. Traumatic memories, chronic stress symptoms (posttraumatic stress disorder scores), and health-related quality of life were measured by using validated questionnaires. RESULTS: Compared with patients from the placebo group, patients from the hydrocortisone group had a significantly shorter duration of intensive care unit treatment, required lower doses of the stress hormone norepinephrine during cardiac surgery, and had significantly fewer stress symptoms and a better health-related quality of life regarding physical function, chronic pain, general health, vitality, and mental health during follow-up. The groups did not differ with regard to the number or type of intensive care unit-related traumatic memories. CONCLUSIONS: The use of stress doses of hydrocortisone in high-risk cardiac surgical patients reduces perioperative stress exposure, decreases chronic stress symptoms, and improves health-related quality of life at 6 months after cardiac surgery.


Wollmer, M. A., A. Papassotiropoulos, et al. (2002). "Genetic polymorphisms and cerebrospinal fluid levels of tissue inhibitor of metalloproteinases 1 in sporadic Alzheimer's disease." Psychiatr Genet 12(3): 155-60.

Tissue inhibitor of metalloproteinases 1 (TIMP-1) inhibits several proteinases including a disintegrin and metalloproteinase 10 (ADAM10), a major alpha-secretase that cleaves the beta-amyloid precursor protein within its amyloidogenic Abeta domain. The gene encoding TIMP-1 (TIMP 1) maps to the short arm of the X chromosome, in a region previously suggested as conferring genetic susceptibility for Alzheimer's disease (AD). To determine whether genetic variability of TIMP 1 contributes to the pathogenesis of AD, we analysed one single nucleotide polymorphism within TIMP 1 and one single nucleotide polymorphism in the 5'-untranslated region of TIMP 1 in patients with AD and control subjects from two independent and ethnically different populations. We did not observe any association between TIMP 1 genotypes and the diagnosis of AD in men or women. We also measured TIMP-1 protein levels in the cerebrospinal fluid of patients with AD, healthy control subjects, and patients with other neurological disorders. TIMP-1 levels were similar in all groups. In addition, no significant differences were observed after stratification for TIMP 1 genotypes. Our data show that neither genetic variability nor protein levels of TIMP-1 are associated with AD.






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Division of Cognitive Neuroscience

University of Basel