Cüneyt Demiralay

Abnormal plasticity of the sensorimotor cortex to slow repetitive transcranial magnetic stimulation in patients with writer's cramp

Previous studies demonstrated functional abnormalities in the somatosensory system, including a distorted functional organization of the somatosensory cortex (S1) in patients with writers cramp. We tested the hypothesis that these functional alterations render S1 of these patients more susceptible to the “inhibitory” effects of subthreshold 1 Hz repetitive transcranial magnetic stimulation (rTMS) given to S1. Seven patients with writers cramp and eight healthy subjects were studied. Patients also received rTMS to the motor cortex hand area (M1). As an outcome measure, short‐latency afferent inhibition (SAI) was tested. SAI was studied in the relaxed first dorsal interosseous muscle using conditioning electrical stimulation of the index finger and TMS pulses over the contralateral M1. Baseline SAI did not differ between groups. S1 but not M1 rTMS reduced SAI in patients. rTMS had no effects on SAI in healthy subjects. Because SAI is mediated predominantly at a cortical level in the sensorimotor cortex, we conclude that there is an abnormal responsiveness of this area to 1 Hz rTMS in writers cramp, which may represent a trait toward maladaptive plasticity in the sensorimotor system in these patients.

Influence of religious aspects and personal beliefs on psychological behavior: focus on anxiety disorders

The current paper presents literature relevant to the relationship of religiosity, spirituality, and personal beliefs with mental health and, in particular, anxiety disorders as an empirical narrative review, providing an overview on the most important and clinically relevant research results on the topic. The relationship between religiosity/spirituality, personal beliefs (ie, magical ideation and paranormal beliefs), and mental health has lately been studied extensively, and results have indicated significant associations among these variables. However, scientific approaches to this field are complex and multidimensional, partly leading to poor operationalization, incomparable data, and contradictory results. Literature demonstrates that higher religiosity/spirituality and magical ideation scores have often been associated with increased obsessive–compulsive traits. Similar results could not be confidently replicated for other anxiety disorders. However, it is still unclear if these differences suggest a specific association with obsessive–compulsive traits and reflect deviating etiopathogenetic and cognitive aspects between obsessive–compulsive disorder and other anxiety disorders, or if these results are biased through other factors. Religiosity/spirituality and personal beliefs constitute important parameters of human experience and deserve greater consideration in the psychotherapeutic treatment of psychiatric disorders.

Genetic Risk Factors for Depression in Alzheimer´s Disease Patients

Objective: Alzheimer´s Disease (AD) is often associated with depressive symptoms developing at any time before and after AD onset. The aetiology of depression in AD has not sufficiently been characterized, but biological aspects due to neurodegeneration and/ or genetic risk factors may play a plausible role and may distinguish it from common depressive disorders. Method: To investigate the possible relationship between genetic risk factors and depression in AD, we assessed genetic polymorphisms reported to be associated with depression (MAOA VNTR, ACE 288bp Insertion/ Deletion, 5HTTLPR, COMT Val158Met, BDNF Val66Met, TPH1 A218C, HTR2A T102C, P2RX7 Q460R, FKBP5 rs1360780 and CRHR1 rs242941) in a cross-sectional study on 246 AD patients with or without clinically significant major depressive disorder (MDD) according to DSM-IV. Results: Significant associations between AD and MDD have been found for three polymorphisms mainly in females (TPH1 A218C, MAOA VNTR and BDNF Val66Met) and one polymorphism in the total population only (FKBP5 rs1360780). There was an increased risk of having MDD in homozygous female carriers of the TPH1 A-allele (odds ratio: 4.35) and homozygous carriers of the MAOA VNTR low activity allele 3R (odds ratio: 3.37). Conclusion: We detected allelic or genotypic associations of MAOA, TPH1, FKBP5 and BDNF in clinically significant MDD in AD. Odds-ratios were generally higher in female AD-patients, which might be due to the composition of the study population. Further studies on the neurotransmitter systems affected by the genetic polymorphisms found to be associated with MDD in AD may help to elucidate the underlying pathomechanisms of MDD.

The selective serotonin re-uptake inhibitor escitalopram modulates the panic response to cholecystokinin tetrapeptide in healthy men depending on 5-HTTLPR genotype.

Selective serotonin re-uptake inhibitors, such as escitalopram, are currently the treatment of choice for patients with panic disorder. The panic response to intravenous cholecystokinin tetrapeptide, a potentially useful paradigm for volunteer translational studies, has so far not been investigated in healthy man after respective pre-treatment. In a double-blind, placebo-controlled, randomized, within subject cross-over design 30 healthy young men, 15 each with the long/long or short/short genotype for the serotonin transporter linked polymorphic region, were pre-treated with 10mg/d of escitalopram orally for six weeks and then challenged with 50 microg of cholecystokinin tetrapeptide. The primary outcome measure was the increase of Acute Panic Inventory ratings by cholecystokinin tetrapeptide. The increase of anxiety, tension and stress hormone secretion were secondary outcome measures. A significant treatment by genotype effect on the increases of Acute Panic Inventory ratings emerged. Panic induced by cholecystokinin tetrapeptide was significantly more pronounced in the short/short genotype subjects under escitalopram vs. placebo pre-treatment. With the exception of significantly elevated serum prolactin after escitalopram, no effects in the secondary outcome measures were detected. Contrary to our expectation, no inhibitory effect of escitalopram upon panic symptoms elicited by choleystokinin tetrapeptide could be demonstrated in healthy men. These findings do not support the potential usefulness of this panic model for proof-of-concept studies. The biological underpinnings of the increased panic symptoms after escitalopram in our volunteers with short/short genotype need further research.

Decreased recognition of negative affect after selective serotonin reuptake inhibition is dependent on genotype.

Selective serotonin reuptake inhibitors (SSRIs) are known to influence the information processing of emotional material in depressed patients and healthy controls. The functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) has been shown to interact with the effectiveness of serotonin reuptake inhibitors. It is not known whether 5-HTTLPR has an influence on emotional processing in healthy controls. We report first data with long-term SSRI administration after genetic characterization of 5-HTTLPR in a randomized, double-blind, placebo-controlled, crossover design. In 30 healthy controls, 15 homozygous for the long and 15 for the short allele of 5-HTTLPR, emotionally valent images were used to elicit positive or negative emotions. We found a diminished perception of sad and fearful information under SSRI which was significant in the long allele group. These findings emphasize the importance of genetic variance in emotion processing research.

No effect of six weeks of treatment with escitalopram on mood in healthy volunteers — Irrespective of genotype for the promoter of the serotonin transporter

Data on emotional effects of chronic antidepressants in normal subjects are scarce and contradictory. Thirty healthy men were given 10 mg/day of escitalopram for 6 weeks in a double-blind, placebo-controlled, within-subject cross-over study. No significant effect on negative affect, positive affect, or state anxiety was detected, irrespective of serotonin transporter gene-linked polymorphism.

Differential effects to CCK-4-induced panic by dexamethasone and hydrocortisone

Abstract Objectives. Peripheral administration of the cholecystokinin (CCK) receptor agonist CCK-4 generates panic and activates the hypothalamic–pituitary–adrenal (HPA) axis. Direct effects at the pituitary and CCK-HPA interactions at higher regulatory sites have been suggested. According to preliminary data, ACTH response to CCK receptor agonists may differ from its response to exogenous CRH by its resistance to cortisol feedback inhibition. To further explore this resistance and to better characterize CCK-4 sites of action, the effects of different glucocorticoid pretreatments on CCK-4-induced panic were compared. Methods. Using a double-blind placebo-controlled design we pretreated healthy males with either dexamethasone (peripheral action) or hydrocortisone (central-peripheral action) each followed by a CCK-4 challenge. Blood levels of ACTH and cortisol were analyzed and panic symptoms were assessed. Results. We found a blunted response of ACTH release following CCK-4 injection only after hydrocortisone pretreatment. Dexamethasone however did not affect CCK-4-induced ACTH release relative to baseline. In contrast to dexamethasone, hydrocortisone reduced the severity of CCK-4-induced panic as measured by the Acute Panic Inventory on a trend level. Conclusions. Findings suggest that CCK-4-induced stress hormone release seems susceptible to cortisol-feedback inhibition and argues for a suprapituitary site of CCK action. Effects on panic anxiety were weak but congruent with studies showing that CCK-4-induced HPA axis inhibition is accompanied by a reduction of anxiety after CCK-4.

Copeptin – A potential endocrine surrogate marker of CCK-4-induced panic symptoms?

Intravenous cholecystokinin-tetrapeptide (CCK-4) administration reliably and dose-dependently provokes panic anxiety in man, accompanied by adrenocorticotropic hormone (ACTH) and cortisol release. Preclinical findings suggest that behavioral and endocrine effects of CCK-4 are mediated via corticotropin-releasing hormone (CRH) release. Anxiogenic stimulation of the central CCK-receptors in man was shown to increase as well vasopressin (AVP), which acts synergistically with CRH as pituitary-adrenocortical axis stimulator during stress. Copeptin (CoP), the C-terminal part of pre-pro-AVP, is released in an equimolar ratio to AVP. It is more stable in the circulation and easier to determine than AVP and it was found to closely mirror the production of AVP. So far, CoP secretion has not been characterized during panic provocation. In 30 healthy male human subjects, we repeatedly measured CoP in plasma during a panic challenge and studied its correlation to Acute Panic Inventory (API) ratings and plasma ACTH and cortisol. CoP levels correlated positively with the increase in API ratings (r=0.41, p=0.03), while ACTH or cortisol did not (r=0.08, p=0.68 and r=0.12, p=0.53, respectively). CoP levels correlated also positively with ACTH (r=0.48, p=0.009) and cortisol (r=0.48, p=0.01) concentrations throughout the CCK-4 challenge. As expected, we found a positive correlation between plasma ACTH and cortisol levels (r=0.57, p=0.001). A vasopressinergic activation during CCK-4 induced panic was demonstrated, which was correlated positively to panic symptoms and pituitary-adrenocortical release. Our findings suggest a role of CoP as a potential surrogate marker of CCK-4 panic symptoms. Further studies are needed to replicate our results and to further clarify the role of CoP as a stress-sensitive hormone in different panic paradigms as well as in panic patients.

Blunted autonomic reactivity to pharmacological panic challenge under long-term escitalopram treatment in healthy men

Background: Central serotonergic pathways influence brain areas involved in vagal cardiovascular regulation and, thereby, influence sympathetic efferent activity. Selective serotonin reuptake inhibitors (SSRIs) affect multiple serotonergic pathways, including central autonomic pathways. However, only a few studies have assessed SSRI-mediated effects on autonomic reactivity in healthy individuals using heart rate variability (HRV). Methods: The present study assessed the influence of long-term treatment with escitalopram (ESC) on autonomic reactivity to an intravenous application of 50 µg cholecystokinin tetrapeptide (CCK-4) in 30 healthy young men using a double-blind, placebo (PLA)-controlled, randomized, within-subject cross-over design. Main outcome measures were time- and frequency-domain HRV parameters, assessed at both baseline and immediately after CCK-4 application. Results: Results showed substantial effects for the treatment × CCK-4 challenge interaction with respect to heart rate (p < 0.001; pη2 = 0.499), SDNN (p < 0.001; pη2 = 576), RMSSD (p = 0.015; pη2 = 194), NN50% (p = 0.008; pη2 = 0.224), and LF% (p = 0.014; pη2 = 0.196), and moderate effects with respect HF% (p = 0.099; pη2 = 0.094), with PLA subjects showing a higher increase in HR and SDNN and a higher decrease in RMSSD, NN50, LF and HF than subjects in the ESC condition. Thus, ESC treatment significantly blunted the autonomic reactivity to CCK-4. Secondary analysis indicated no effect of the 5-HTTLPR polymorphism on CCK-4-induced autonomic response. Conclusions: Our results support findings suggesting an effect of SSRI treatment on autonomic regulation and provide evidence that ESC treatment is associated with blunted autonomic reactivity in healthy men.

Influence of exogenous atrial natriuretic peptide on the nocturnal hypothalamic-pituitary-adrenal axis and sleep in healthy men

Atrial natriuretic peptide (ANP), originally found in the cardiac atria, is also widely distributed in the central nervous system (CNS) and has been predominantly found in the hypothalamus and the pituitary gland. Previous in vitro and in vivo studies have provided evidence for an inhibitory control of ANP at all regulatory levels of the hypothalamo-pituitary-adrenocortical (HPA) system. In vivo studies in man demonstrated that ANP inhibits stimulated pituitary-adrenal secretion during wakefulness. On the other hand, it has been reported that various neuropeptides not only influence the neuroendocrine compound of sleep, but also exert specific effects on the sleep electroencephalogram (EEG). To further characterize the role of ANP in the regulation of the nocturnal HPA axis activity and consecutive sleep regulation, we investigated sleep-endocrine effects of intravenously administered ANP in healthy men during nocturnal sleep. Eight volunteers underwent three trial conditions in random order and in a single-blind design receiving ANP infusion at the beginning of the 1st or the 2nd half of the night, or placebo. Sleep was assessed by polysomnography and blood samples were drawn in 30-min intervals for determination of adrenocorticotrophic hormone (ACTH) and cortisol during the entire night. While the ACTH and cortisol secretion during ANP infusions remained unchanged, an immediate increase of ACTH and cortisol secretion occurred after each infusion period for approximately 2h without changing basal levels and the circadian course of both hormones. Sleep EEG parameters were neither directly affected by ANP infusions nor by the following ANP-induced ACTH and cortisol secretion. The presence of such clear-cut enhancement of the pituitary-adrenal release indicates a rebound effect of ANP on HPA secretory activity and supports the idea that ANP acts as corticotropin-releasing hormone (CRH)-inhibiting factor.