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apl. Prof. Dr. Gabriele Ende

Schmahl C, Ende G. DFG - Deutsche Forschungsgemeinschaft KFO 256, 2nd funding period: TP 06 Tissue Damage and Pain - Modelling Cutting Behavior in BPD. 08/2015-07/2018.

1 Results of the first funding period To investigate the influence of tissue damage in the context of non-suicidal self-injury (NSSI), we first characterized nociceptive non-invasive stimuli and a mechanical stimulus associated with tissue injury (incision). Twenty healthy men and women each were investigated regarding pain intensity and affective/sensory characteristics of the stimuli. Affective scores were significantly lower than sensory scores for all modalities, including the incision. In women, affective scores were not different for blade, laser and incision stimuli. In a second step, a non-invasive mechanical “blade” stimulus was matched by means of pain intensity with the incision stimulus. Comparing time courses of blade and incision pain, the time course including the pain maximum was very similar (point-by-point comparison between p=0.8 and 1.0). In the ongoing second study, we were successful to induce stress in all groups (current BPD, remitted BPD, healthy controls), verified by significant increase of inner tension and heart rate. An interim analysis of the effects of incision, blade and sham treatment on stress levels in current BPD patients revealed a trend for stronger tension reduction following incision as compared to sham. A similar time course of tension reduction was observed following blade application which appears to be comparably successful to incision in reducing tension. Perception of mechanical pain was lower on both arms in current BPD patients compared to controls, as a sign of generalized hypoalgesia in these patients. Additionally conducted pilot studies investigated the influence of seeing artificial blood together with a pain stimulus on tension reduction and established MR spectroscopy to quantify glutamate and GABA levels in pain-processing brain regions. 2 New questions and work schedule Since the blade stimulus appears to have similar affective pain properties as well as similar influence on tension reduction, it will be used in the studies of the next funding period. The new project has two major objectives. First, we aim to further elucidate mechanisms related to reduced pain sensitivity in BPD using recently established neuroimaging methods. In the second part of the project, we will further disentangle mechanisms related to NSSI with a particular focus on the role of seeing blood and the perspective of the injury (self- vs. other-inflicted) regarding stress reduction. In the first part, we will acquire structural MRIs at 3T and assess morphological group differences in amygdala, anterior cingulate, anterior and posterior insula, and DLPFC as well as volumetric connectivity between these regions in 25 patients with current BPD and 25 healthy controls. Quantitative MRS measures of GABA and glutamate levels will be obtained from the insula and ACC, the glutamate/GABA ratio will be compared between groups, and the association of morphological differences with neurochemical alterations will be investigated. Pseudo-continuous arterial spin labelling (pCASL), which allows absolute quantification of blood flow in pain-processing regions following single stimuli, will be conducted before and after blade stimulation. In the second part, patients with current NSSI will be randomized into four groups of 25 patients each (a) blood, self-inflicted; b)blood, other-inflicted; c) no blood, self-inflicted; d) no blood, other-inflicted). For each patient, an individual stressful script will be prepared and presented while stress levels, and heart rate is 16 monitored. Immediately after the end of the script, the blade stimulus will be applied, either in conjunction with artificial blood or without and either self-inflicted or inflicted by the investigator. The third part is an ambulatory assessment study in which BPD patients carry mobile devices in combination with sensors for physiological signals such as heart rate. Here, we aim to monitor the natural time course of NSSI events in the daily life of BPD patients. Patients will regularly enter their level of subjective stress. In case of NSSI events, stress levels will be prompted more frequently; in addition, painfulness of the NSSI event as well as during the following time period will be closely monitored.

Schad LR, Ende G. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP Z03: DTI tractography, brain network analysis and advanced translational. 01/2012-12/2015.

As a core project Z03 will give methodological support to those studies within the SFB, that use diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), including real-time fMRI, and magnetic resonance spectroscopy (MRS) at 3.0T as well as advanced imaging and MRS methods at 9.4T. Methods to directly compare functional connectivity and spatiotemporal dynamics acquired with BOLD and regional cerebral blood volume (rCBV)-weighted fMRI in anesthetized rats at the 9.4T scanner will be established. Various MRS editing techniques will be optimized for glutamine, GABA, glutathione, and NAAG detection. Another goal of project Z03 is to combine structural connection maps determined by DTI tractography and/or diffusion spectrum imaging (DSI) with brain network analysis of fMRI data to gain insight into the patterning and dynamics of brain networks and to determine how structural connectivity relates to functional and effective connectivity of the brain. Concepts from graph theory will be used to analyze connection maps and brain network properties. These network properties such as clustering coefficients, characteristic path length or global efficiency can then be quantified and translated to clinical applications.

Mann KF, Ende G, Sommer WH. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP D07: Neuroplasticity of brain glutamate and glutamine and treatment. 01/2012-12/2015.

The glutamate hypothesis of alcoholism posits that chronic alcohol intake leads to an enhanced activity of the glutamate system. As soon as alcohol is discontinued, withdrawal develops with marked brain hyperexcitability. Under abstinent conditions this hyperglutamatergic state could be reinstated by stress or alcohol cues and precipitate relapse. Anti-glutamatergic compounds are effective in preventing relapse and potentially also in alleviation of withdrawal. Effect sizes of this pharmacotherapy are moderate, a fact which may be accounted for by individual differences in the extent of neuroplastic changes of the glutamate system. Thus, we predict that antiglutamatergic medications work primarily in individuals who develop a pronounced hyperglutamatergic state, a condition that can be identified and monitored by magnetic resonance spectroscopy (MRS). We previously found that alcohol withdrawal is reflected by increased central glutamate levels. A new measure to be studied in the coming funding period is the glutamate/glutamine ratio which we now can also measure reliably in humans. This ratio will be tested as a potential biomarker for monitoring alcoholism, which may lay the grounds for a personalized treatment approach of this condition. We believe that a translational approach involving human patients and “alcohol dependent rats” serves the purpose of our research best. In both species prefrontal cortex changes in metabolite concentrations during acute withdrawal and into several weeks of abstinence are measured with and without pharmacological interference targeting the glutamatergic system. In the last funding period we developed methods for absolute quantification of metabolites in the human and rat brain. Under control conditions glutamate concentrations in the human anterior cingulate cortex (ACC) and the rat medial prefrontal cortex (mPFC) were highly similar. Thus, for the first time direct evidence for increased central glutamate levels during acute alcohol withdrawal in both species was provided. In the animal experiments, we will induce alcohol dependence through chronic, intermittent, ethanol-vapor exposure. Rats will be assessed repeatedly, over the course of acute alcohol withdrawal into abstinence, for neurometabolic changes in the medial-prefrontal cortex, using MRS at 9.4T. In the new funding period we shall concentrate on the effects of experimental pharmacotherapies for alcohol detoxification (glutamate modulators, such as acamprosate, memantine and lamotrigine) on neurometabolic profiles and on alcohol-related behaviors, comparing these therapies to standard treatments (GABAergic: diazepam). We will also compare neurometabolic profiles to in vivo, microdialysis measurements of extracellular glutamate release from parallel groups of rats. In the human study, we will continue to assess the effects of alcohol withdrawal. As a new element, alcohol cues and pharmacological intervention on levels of glutamate, glutamine and GABA in the prefrontal cortices of treatment-seeking alcoholics will be studied. Alcohol dependent inpatients (n=60) will undergo three combined measurements of MRS and fMRI cue reactivity. The first MR session will take place during acute withdrawal (without medication). The second group of measurements will be taken after five days of abstinence, in order to monitor the glutamate/glutamine ratio over time, and to what extent this ratio is affected by the diazepam that will at this point have been administered for withdrawal-symptom relief. The third MR session will take place on day 14 to monitor the effects of abstinence, both for patients under treatment with acamprosate (which will have been initiated as an open-label treatment following the second MR session) and for patients not being treated with medication. Relapse behavior will be monitored in follow-up assessments, and correlated to MRS metabolites. A control group of n=20 healthy subjects will undergo combined MRS and fMRI twice, two weeks apart.

Ende G, Schmahl C. DFG - Deutsche Forschungsgemeinschaft EN 361/13-1, SCHM 1526/14-1: KFO 256 TP 5: Characteristics and Training of Neural Responding in BPD . 01/2012-12/2014.

Schmahl C, Ende G. DFG - Deutsche Forschungsgemeinschaft EN 361/12-1, SCHM 1526/13-1: Impulsivität und Stress - behaviorale und MR-spektroskopische Untersuchungen bei der Boderline-Persönlichkeitsstörung und der Aufmerksamheitsdefizit-Hyperaktivitäts-Störung. 09/2011-08/2013.

Impulsivität wird als ein Kernmerkmal vieler psychiatrischer Erkrankungen wie der Borderline-Persönlichkeitsstörung (BPS) und des Aufmerksamkeits-Defizit-Hyperaktivitäts-Syndroms (ADHS) diskutiert. Der Begriff Impulsivität ist jedoch unscharf und umfasst ein komplexes mehrdimensionales Konstrukt. Auf der Verhaltensebene lässt sich Impulsivität als verminderte Reaktionshemmung in Verbindung mit Schwierigkeiten bei der Aufmerksamkeitsfokussierung und einer unsorgfältigen Informationsverarbeitung operationalisieren. Hinzu kommen Schwierigkeiten beim Belohnungsaufschub, stärkere Bevorzugung unmittelbar wirksamer Vermeidungsstrategien auf Kosten langfristig wirksamer Bewältigungsstrategien und reduzierte Handlungskontrolle bei intensivem Ärger und Wut („Impulsive Aggressivität“). Auf neurobiologischer Ebene weisen aktuelle Forschungsbefunde auf eine Beteiligung frontaler Bereiche an der Impulskontrolle sowie auf eine wichtige Rolle des glutamatergen (und evtl. auch des GABAergen) Systems insbesondere im Bereich des anterioren cingulären Kortex hin. Der Zusammenhang zwischen neurochemischen und Verhaltensmaßen ist bislang jedoch noch wenig untersucht. Zudem fehlen bislang noch experimentelle Studien zum Einfluss von Stress auf subjektive und behaviorale Maße der Impulsivität. Das Ziel des geplanten Forschungsprojekts ist es, 1. eine mehrdimensionale Untersuchung von Impulsivität auf Verhaltensebene bei der BPS und ADHS durch den Einsatz mehrerer behavioraler Paradigmen vorzunehmen, 2. diese behavioralen Maße mit neurobiologischen Parametern (Magnetresonanz-Spektroskopie und funktionelle Magnetresonanztomographie) und subjektiven Selbsteinschätzungen (Fragebögen) zu korrelieren, und 3. diese behavioralen Maße in Zusammenhang mit emotionalem Stress zu untersuchen. Dazu sollen 30 Patientinnen mit BPS, 30 Patientinnen mit ADHS und 30 gesunde Probandinnen mit Bildgebung, mehreren psychometrischen Verfahren sowie verschiedenen Verhaltenstests vor und nach einer Stressinduktion untersucht werden.

Ende G, Mann KF. BMBF - Bundesministerium für Bildung und Forschung 01GS08152: NGFN Plus GENALC TP14: Endophenotyping with soectroscopy: Genetic modulation and treatment response. 06/2011-05/2013.

Zentralinstitut für Seelische Gesundheit (ZI) - https://www.zi-mannheim.de