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P.1.i. Basic and clinical neuroscience − Brain imaging and neuro-modulation
P.1.i.019 Are the acute effects of citalopram mediated by the dopamine system? A. Dutta1 ° , S. McKie1 , J.F.W. Deakin1 1 University of Manchester, Neuroscience & Psychiatry Unit, Manchester, United Kingdom Introduction: Major Depressive Disorder is a chronic mental disorder with a high burden on society. Despite the development of newer antidepressants the mechanism of this illness is elusive. The objective in the current study was to determine the effects on functional magnetic resonance imaging blood oxygen level dependent signal produced by acute intravenous infusion of citalopram compared to placebo in current and remitted major depressive disorder and healthy controls. The plan is to compare this to the changes in resting state functional magnetic resonance imaging blood oxygen level dependent signal produced by novel N-methyl-D-aspartate receptor antagonist antidepressants. Citalopram is an effective selective serotonin reuptake inhibitor antidepressant commonly utilised in the management of Major Depressive Disorder. If the mechanisms of traditional antidepressants are elucidated the discoveries could allow testing of new compounds. Method: In the first citalopram study 67 unmedicated males and females with current or remitted Major Depressive Disorder and healthy controls were scanned on a Philips 1.5 tesla magnetic resonance imaging scanner. In citalopram study 1 all patients were infused citalopram 7.5 mg. In the second citalopram study 63 unmedicated males and females with current Major Depressive Disorder and healthy controls were scanned on a Philips 1.5 tesla magnetic resonance imaging scanner. They were infused with either placebo (0.5% saline) or citalopram 7.5 mg. Functional magnetic resonance imaging resting state data was compared for the final 12 12 minutes following drug infusion in both studies. Images were pre-processed using Statistical Parametric Mapping 8. Independent Component Analysis was performed using the Group ICA for fMRI toolbox and the resting component with the highest spatial correlation to the anterior cingulate cortex was used. This was due to due the effects of acute ketamine challenge which demonstrated effects in the anterior cingulate cortex [1]. Region of Interest analysis was performed using MarsBaR (Marseille Boite a Regions d’interet). Results: Citalopram study 1 revealed reduced mean Amplitude of Low Frequency Fluctuations in current Major Depressive Disorder compared to healthy controls in the precuneus but increases in the caudate. The pattern of response in the lentiform nucleus mimics that of the caudate. In contrast remitted Major Depressive Disorder patients had significantly reduced Amplitude of Low Frequency Fluctuations in both regions. In citalopram study 2following placebo infusion depressed individuals showed reduced default mode activity in precuneus. Citalopram infusion had no effect in controls but normalised default mode activity in the depressives producing a significant drug x group interaction. Conclusion: The acute antidepressant effects of citalopram are modulated by changes in the bilateral precuneus. The acute action on the caudate and lentiform suggests links to the dopamine system. The precuneus is central to connectivity with other regions in Major Depressive Disorder. Given its prominent role in the default mode network and its links to rumination this is an important finding. This discovery may help our understanding of the mechanism of antidepressant response and pathophysiology of Major Depressive Disorder. Future studies will examine the effects compared to novel antidepressants and the effects on functional connectivity of these compounds.
References [1] Deakin J.F.W., Lees J., McKie S., Hallak J.E.C., Williams S.R., Dursun S.M., 2008 Glutamate and the neural basis of the subjective effects of ketamine. Archives of General Psychiatry, 65, 154−64.
P.1.i.020 A 3T functional magnetic resonance imaging study with N-back task to assess working memory activation in euthymic bipolar I and II patients L. Cremaschi1 ° , M.C. Palazzo1 , A. Di Giorgio2 , M. Cristoffanini3 , L. Fazio2 , C. Cinnante3 , S. Avignone3 , C. Dobrea1 , F. Triulzi3 , A. Bertolino2 , B. Dell’Osso1 , A.C. Altamura1 1 Fondazione IRCCS C`a Granda Ospedale Maggiore Policlinico Milano, Dipartimento di Salute Mentale, Milano, Italy; 2 Universit`a Aldo Moro, Dipartimento di Scienze Mediche di Base Neuroscienze e Organi di senso, Bari, Italy; 3 Fondazione IRCCS C` a Granda Ospedale Maggiore Policlinico Milano, Dipartimento di Neuroscienze e Salute Mentale U.O. di Neuroradiologia, Milano, Italy Introduction: Bipolar disorder (BD) is a chronic mood disorder included among the leading worldwide causes of disability, given its recurrency, morbidity and high suicide rates. Among symptom domains, neurocognitive impairment represents a major source of burden for patient functioning, often persisting during euthymia. In particular, Working Memory (WM) is one of the most impaired area, also beyond acute phases of illness, thus often allowing only a partial interepisodic functional recovery [1]. For this reason, WM appears to be a candidate endophenotype of illness, being potentially considered as a trait biomarker rather than a state variable of illness [2,3]. The purpose of the present study was to assess potential differences in terms of brain activation elicited by a WM task, between euthymic bipolar patients and healthy controls. Methods: Fifty-five subjects, including 28 euthymic bipolar patients (15 BD I, 13 BD II) and 27 healthy controls, underwent a 3T fMRI exam with one of the most extensively used paradigm for the assessment of WM, the N-back task (0-, 2- and 3-back conditions, characterized by increasing cognitive load and arranged as a block design). During its performance, participants were required to monitor a series of stimuli appearing on a screen; at the baseline condition (0-back), they were asked to respond as soon as the ‘X’ letter appeared on the screen, whereas in 2- and 3-back condition, the target was defined as any letter that appeared 2 or 3 items before, respectively (2- and 3-back). Functional images and behavioural data, including reaction times and accuracy, were recorded. SPSS and SPM5 softwares were used to assess statistical differences between groups. Results: As regards behavioural data (accuracy and reaction time), no significant differences were reported between two groups in all three N-back conditions. With respect to fMRI data, second level analyses investigating effect of diagnosis between groups reported a significant hyperactivation at the level of dorsolateralprefrontal cortex (DLPFC; BA 10, Z=4.72, k=344, p = 0.000 corrected, x 34 y 42 z 10), with the following pattern of activation in the whole sample: BD I > BD II > healthy controls. Furthermore, no significant interactions were observed between WM load and diagnosis, nor between signal distribution and behavioural performance. Conclusions: Results seem consistent with the pattern of alteration reported in neuroimaging studies investigating neurofunc-
P.1.i. Basic and clinical neuroscience − Brain imaging and neuro-modulation tional substrates of WM, while performing the N-back task. This pattern may be interpreted in light of patients’ increased effort in recruiting networks and/or involvement of alternative circuits, with a compensatory effect aimed to support cognitive performance. The role of bias potentially influencing cognitive functioning, particularly some clinical variables (e.g., age of onset, duration of illness, psychiatric comorbidity, predominant polarity, history of psychosis) and concomitant pharmacological treatment, deserves further investigation. Moreover, larger samples may allow more reliable comparison data between BD I and II patients. References [1] Thermenos, H.W., Goldstein, J.M., Milanovic, S.M., WhitfieldGabrieli, S.M., Makris, N., LaViolette, P., Koch, J.K., Faraone, S.V., Tsuang, M.T., Buka, S.L., Seidman, L.J., 2010. An f MRI study of working memory in persons with bipolar disorder or at genetic risk for bipolar disorder. American Journal of Medical Genetics B, Neuropsychiatric Genetics 153, 120–131. [2] Drapier, D., Surguladze, S., Marshall, N., Schulze, K., Fern, A., Hall, M.H., Walshe, M., Murray, R.M., McDonald, C., 2008. Genetic liability for bipolar disorder is characterized by excess frontal activation in response to a working memory task. Biological Psychiatry 64, 513−20. [3] Lagopoulos, J., Ivanovski, B., Malhi, G.S., 2007. An event-related functional MRI study of working memory in euthymic bipolar disorder. Journal of Psychiatry & Neuroscience 32, 174−84.
P.1.i.021 EMDR efficacy on characteristic posttraumatic stress disorder neurobiological alterations C. Caterini1 ° , L. Bossini1 , I. Casolaro1 , D. Koukouna1 , E. Santernecchi2 , I. Fernandez3 , A. Fagiolini1 1 AOUS Siena, Molecular Medicine and Development Psychiatry Section, Siena, Italy; 2 AOUS Siena, Department of Medicine Surgery and Neuroscience, Siena, Italy; 3 Private Practice, Private Practice, Milan, Italy Post-Traumatic Stress Disorder (PTSD) is characterized by dysfunction and structural alteration of several discrete brain regions. Eye Movement Desensitization and Reprocessing (EMDR) is a psychotherapy that has been found to effectively resolve the effects of traumatic experiences and it is recognized as a first-line treatment for PTSD; moreover, in recent research, fundamental and structural neurobiological changes after successful treatment of PTSD with EMDR were proven [1]. We proposed to evaluate the neurobiological effects of EMDR on 14 patients (age 18−65 years) with drug-na¨ıve PTSD without comorbidity, matched with 14 untreated healthy controls. Patients and control participants underwent a complete Psychiatric evaluation and were assessed with Clinical Administered PTSD Scale (CAPS) for PTSD diagnosis; psychiatric comorbidity was excluded by administration of Structured Clinical Interview for DSM-IV (SCID-I). Brain magnetic resonance imaging (MRI) measurements, with Optimized Voxel-Based Morphometry, were conducted to find out characteristic neurobiological alterations. The patients received 3 months of EMDR treatment according to the guidelines by Shapiro [2], and then were evaluated posttreatment with MRI and CAPS, while the healthy controls were re-evaluated with MRI at 3 months after baseline acquisition. We applied one-way Analysis of CoVariance (ANCOVA) models for cross-sectional comparisons between PTSD and control groups at baseline and repeated measure ANCOVA (RM ANCOVA) for longitudinal evaluation of brain morphology changes comparing the Time 1 and Time 2 images of patients and controls.
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Patients and controls did not differ for demographic data. From a clinical point of view, the diagnosis of PTSD was effectively eliminated in 11 of 14 patients, reflected in a significant improvement in CAPS scores (p < 0.004). At baseline, gray matter volume (GMV) differed significantly between patients and controls: the Analyses revealed a region of significantly decreased GMV in patients’ left parahippocampal region, supplementary motor area, lingual gyrus, and both left and right superior frontal gyrus (p = 0.008). Patients with PTSD also showed a significant increase in GMV corresponding to right angular gyrus, inferior parietal lobule and left inferior temporal gyrus. Analyses of 3-month scans showed no changes for controls, while significant changes were highlighted for patients post-EMDR, with a significant increase in GMV in left parahippocampal gyrus and a significant decrease in GMV in the left thalamus region. Our results confirmed EMDR clinical efficacy on PTSD and highlighted post-EMDR changes in brain morphology. Although to date, we are still far from matching symptoms and single alterations, work with PTSD has suggested that many symptoms and/or psychopathological characterizations appear to be closely related to some specific neurobiological alterations. Future research in this direction is recommended so that we can better understand the mechanisms that underlie both etiopathogenesis and then the maintenance of the disorder. Such insights could be used to select treatments which could target specific neurobiological alterations, with the goal of achieving resolution of biological damage and, subsequently the disorder. References [1] Bossini L., Casolaro I., Santarnecchi E., Caterini C., Koukouna D., Fernandez I., Fagiolini A., 2012. Evaluation study of clinical and neurobiological efficacy of EMDR in patients suffering from PostTraumatic Stress Disorder. Rivista di psichiatria. 47(2), 12−15. [2] Shapiro F., 1995. Eye Movement Desensitization and Reprocessing: Basic Principles, Protocols, and Procedures. New York: Guilford.
P.1.i.022 Neural activity during the “n-back” working memory task predicts relapse risk in alcohol dependence K. Charlet1 ° , A. Beck1 , A. Jorde2 , S. Vollst¨adt-Klein2 , J. Gallinat3 , H. Walter4 , F. Kiefer2 , A. Heinz5 1 Charit´e − Universit¨atsmedizin Berlin Campus Mitte, Dept of Psychiatry and Psychotherapy, Berlin, Germany; 2 Central Institute of Mental Health Medical Faculty Mannheim Heidelberg University, Department of Addictive Behavior and Addiction Medicine, Mannheim, Germany; 3 St Hedwig Krankenhaus, Charit´e − Department of Psychiatry and Psychotherapy, Berlin, Germany; 4 Charit´ e-Universit¨atsmedizin Berlin Campus Mitte, Division of Mind and Brain Research, Berlin, Germany; 5 Charit´eUniversit¨atsmedizin Berlin Campus Mitte, Department of Psychiatry and Psychotherapy, Berlin, Germany Introduction: Addictive behavior can be understood as a dysbalance between drug craving and reduced control of drug consumption on the one hand and impaired ability for executive behavior control on the other. Here, working memory deficits are often found in alcohol-dependent individuals, especially in early abstinence, which may contribute to an increased relapse risk after detoxification. Previous studies on visuospatial working memory using brain imaging techniques in alcohol-dependent patients compared to controls indicate that adequate information