Projekte: Neuropsychologie und Klinische Psychologie

The body image, which is often taken for granted, is disrupted in patients with chronic back pain. Patients are unable to clearly delineate the outline of their trunk and state that they cannot “find it”. The back is normally a rather unknown area of the body. The reason is that in everyday life the own back is not seen. Although pain leads to an increased attention to their backs in patients with chronic back pain (CBP), it also changes the perception of the trunk. Despite there was no difference in reduction of pain intensity between healthy controls and patients with chronic back pain I showed in previous work that visual feedback during painful stimulation of the back led to reduced pain intensity ratings compared to visual feedback of the dorsum of the hand. However, the supraspinal mechanism behind pain reduction induced by seeing one’s own back is currently unknown. Therefore, we will use functional magnetic resonance imaging (fMRI) to measure brain activation in 20 healthy controls (HC) during painful electrical stimuli of the back while subjects receive visual feedback of a) the dorsum of the hand, b) the site on the back were the stimuli are applied and c) a video of a third person’s back. Participants will rate pain intensity during the measurement.

Mit einem kombiniert respondent-operanten Lernparadigma soll untersucht werden, ob akute und remittierte depressive Patienten gegenüber Gesunden verändertes appetitives und aversives Lernen unter wahrgenommener Kontrolle vs. Nichtkontrolle zeigen. Wir erwarten differenzielle Gruppeneffekte in Abhängigkeit vom Kontrollstatus. Mittels funktioneller Magnetresonanztomographie möchten wir neuronale Korrelate und Netzwerke identifizieren, die mit verändertem Lernen bei Depression assoziiert sind, und Zusammenhänge mit genetischen, endokrinologischen und kognitiven Variablen analysieren. Mögliche störungsübergreifende Pathomechanismen sollen durch Einschluss von Angstpatienten untersucht werden.

The overarching aim of the SFB Graduate Program "Translational Neuroscience" is to enable transfer of knowledge between basic and clinical sciences. All of our PhD and MD students shall gain insight into both areas of research by attending an interdisciplinary teaching program including electives in different interacting groups. We also provide a framework for regular advice to the students and individual support wherever techniques or knowledge are lacking. The international and interdisciplinary program accepts students from a wide variety of natural and social sciences as well as medical students. Much of the translational work within SFB 636 is done by junior scientists, mostly MD and/or PhD students. During the current funding period, the graduate program was instrumental in cross-linking different approaches and system levels within the SFB. All students were provided with a common knowledge base allowing them to understand the translational aspects of their own projects and to interact successfully with colleagues from other disciplines. The Graduate Program pursues its goals by offering a compact course (60 hours) in neurosciences which covers a large variety of relevant topics and methods (qualification concept). This core curriculum is taught on a regular basis and covers 4 hours/week (usually on Friday, with social events to follow). This introductory course ends with a written exam, ensuring a common knowledge base for all students. It is important that the program does not distract students from their own research projects. Therefore, the second part of the curriculum is individual, i.e. specifically adapted to the needs of individual students. This is supported by several measures: students have regular meetings with the members of the student advisory board; they can visit German and foreign laboratories, including those in industry, in order to acquire specific techniques; they can invite guest scientists. Most importantly, each student has to choose two special topics (major and minor) for extended studies throughout the PhD or MD course. Students with projects rooted in basic sciences chose a clinical minor and have to visit a clinical unit for an elective. Conversely, students with a clinical focus stay for some time in a laboratory. In-depth education in the major continues with courses of 2 hours/week throughout the entire period of the PhD or MD thesis work. In addition, we offer regular autumn schools focussed on selected topics in translational neuroscience. In order to represent the students' interests and to train their rganizational skills, these courses have been organized by the students themselves (with help of the board members of the Integrated Graduate Program). In addition, students have been offered specific training courses in “soft skills” such as presentation techniques or group work in cooperation with the Graduate Academy of Heidelberg University. The students choose one main laboratory and advisor with whom they are affiliated at the very beginning of the program. In order to foster the idea of translational research we have also encouraged the possibility to split the dissertation work between a basic/preclinical laboratory and a clinical unit. Accepted students thus chose one main laboratory and advisor and two additional advisors who have had regular meetings twice a year with the student and follow the progress of his or her work. We are strongly encouraging first-author publications by the students and allow for a short, cumulative version of the dissertation script after 1 or 2 articles have been accepted (depending on the extent of the work invested) and one additional article has been submitted at the time of the completion of the degree. The Graduate Program is run by a governing board that also involves student representatives. From our experience with the program so far, we found that both the scientists within SFB 636 and the students greatly profit from this structured program in advanced neuroscience teaching. It increases the students´ professional prospects in the growing area of translational neurosciences and it creates a platform for interdisciplinary dialogue within the SFB, thus fostering preclinical-clinical cooperations. In the new funding period we have kept the basic structure of the program but have added additional offers: mentoring can now be done by our international collaborators; there is more career counselling; recruitment efforts for medical students will be intensified; and additional self-organized activities of the students have been included.

The goal of this study is the analysis of learning processes and plastic brain changes in the development and maintenance of posttraumatic stress disorder (PTSD). We hypothesize that enhanced cue and deficient context conditioning along with high stress sensitivity lead to an enhanced risk to develop PTSD after traumatic experience and suggest that these alterations in associative and non-associative learning are accompanied by enhanced amygdalar and reduced hippocampal activation during acquisition and deficient midfrontal-amygdalar and midfrontal-hippocampal connectivity during extinction. In addition, we believe that traumatic stress, which alters the brain structure in these regions and leads to altered stress reactivity of the ypothalamus-pituitary-adrenal axis (HPA), contributes to the occurrence of PTSD along with peritraumatic factors. In the last funding period we continued the longitudinal study and added another 125 students in schools for rescue workers to the original 120 subjects (we plan to have 300 complete cases by the end of 2011) and characterized them with psychometric, psychophysiological, neuroimaging, endocrine and genetic methods. Since we do not yet have enough subjects who converted to PTSD we focused on predictors of cue and context conditioning in this sample. We found that hippocampal volume predicts context conditioning and that larger amygdala volume is associated with better cue conditioning, whereas cue conditioning is reduced with larger hippocampal volume. We also found that polymorphisms related to the minor alleles of HPA axis-related genes predict enhanced amygdala activation during cue conditioning and reduced prefrontal activation and prefrontal-amygdala connectivity during extinction. A polymorphism on the neurogranin gene, which has been associated with high risk for schizophrenia and memory disturbance, was found to predict hippocampal activation during context conditioning. In addition, traumatized persons with and without PTSD and healthy controls participated in cross-sectional neuroimaging studies. We found enhanced stress sensitivity as indexed by higher stress analgesia in the patients with PTSD and this was linked to enhanced activation in the rostral anterior cingulate. We also observed better second order conditioning with trauma cues as unconditioned stimuli in the PTSD patients accompanied by amygdala deactivation, which was associated with delayed extinction and abnormal dorsolateral prefrontal activation. In the PTSD group renewal was enhanced and associated with reduced hippocampal activation. A study on reinstatement is still ongoing as is the assessment of the effects of exposure treatment on renewal and einstatement. We also observed enhanced hippocampal activation during simple contextual conditioning in the PTSD group. These data are in line with our hypothesis of deficient context conditioning as a core pathological factor in PTSD. In the new funding period we will complete the longitudinal study by adding another 150 subjects to arrive at a total of 450, will retest persons who developed PTSD symptoms and compare them to persons who were traumatized without developing the disorder and matched controls from the rescue worker samples. In addition to retesting these predefined subjects we will use regression analyses to predict symptoms from the baseline tests in the entire sample. In the cross-sectional study we will expand the analysis of the role of deficient contextual processing in PTSD. Study 1 will test the hypothesis that PTSD patients focus their attention more on emotional cues at the expense of contexts compared to traumatized persons without PTSD and controls and that this is an early attentional process related to the perception rather than the evaluation of the stimuli that also determines that cues are better remembered than contexts. The study combines electroencephalographic recordings and eye tracking. A second study will examine the relationship of cued and contextual fear by combining differential fear conditioning to cues and contexts in one study. The contexts will be more complex than previous contexts in order to be able to model configural versus single item processing. Extinction to cues, contexts and their combination will be tested on a separate day and in a third session the response to the cues and contexts will be reversed (the previous danger cue/context will signal safety and vice versa) and tested with and without a retrieval cue. This will permit to test the role of inhibitory mechanisms and safety signals and will provide the possibility to determine how easily aversive memories can be updated. Functional magnetic resonance imaging will be employed to study the role of medial prefrontal and orbitofrontal circuits in this task. In these studies the effects of exposure treatment will also be examined to test if the deficient processing of cue-context interactions is an enduring deficit or can be reversed by effective treatment. Finally, we will address the specificity of the altered onditioning mechanisms and the brain correlates by using comorbidity, medication effects and trauma load as covariates and by comparing our patient group to others in and outside the collaborative research center with respect to the specificity of alterations in context conditioning.

The goal of this workpackage is the development, implemenatation and evaluation of behavioral tasks for functional magnatic resoance imaging as well as additional behavioral tasks and neuropsychological tests that capture the key constructs that will be addressed in the project. These include sensitivity to reward and punishment, impulsivity, novelty seeking, attentional capture, risk taking, reversal learning and pavlovian conditioning. The tasks have been closely modeled after the animal tasks used in workpackage 1 in order to permit a translational approach.

This project aims to study the representation of pain in the somatosensory cortex and elucidate neural circuit activity involved in nociceptive processing in humans using a combination of high resolution functional and structural magnetic resonance imaging at 7 Tesla and multivariate pattern analysis. We further plan to examine to what extent these somatosensory circuits are altered in neuropathic pain and in musculoskeletal back pain states and further extend these analyses to study neurochemical changes, such as GABAergic and glutamatergic modulation, using magnetic resonance spectroscopy. This interactive approach will unravel causal mechanisms in structural and functional plasticity by combining complementary studies in humans and animal models.

Die transiente globale Amnesie (TGA) ist eine schwere anterograde Gedächtnisstörung, der eine emotionale oder physische Belastungssituation vorausgeht und die sich innerhalb von 24 Stunden zurückbildet. Wir haben mittels Magnetresonanztomographie (MRT) nach TGA kleine Läsionen im Hippokampus beobachtet und die Hypothese aufgestellt, dass die Erkrankung durch eine transiente Stress-assoziierte Hemmung der Gedächtnisbildung im Hippokampus verursacht wird. Um diese Annahme zu testen, werden wir die Wirkung von experimentellem Stress auf die Kortisolspiegel und auf die mit Hilfe von funktioneller MRT ermittelten hippokampalen Aktivierungsmuster impliziter und expliziter Lern- und Gedächtnisprozesse in den folgenden drei Kohorten bestimmen: i) Patienten mit akuter TGA, ii) Patienten, die in den vorausgegangenen 2 Jahren eine TGA erlitten haben, und iii) gesunde Kontrollpersonen.

Nach Amputation eines Körperglieds leidet die Mehrheit aller Patienten unter Phantomschmerzen und den damit einhergehenden erheblichen psychosozialen Folgen. Die neurobiologischen Grundlagen des Phantomschmerzes sind bisher nur in Ansätzen verstanden, man weiß jedoch, dass zentralnervösen Prozessen eine große Bedeutung zukommt. Die Erforschung des Phantomschmerzes hat unmittelbare klinische Bedeutung und ist auch ein Zugang zur Untersuchung der generellen neurobiologischen Grundlagen der Wahrnehmung des eigenen Körpers. Human- und Tierstudien weisen darauf hin, dass genetische Faktoren für die Entstehung von Phantomschmerzen bedeutsam sind, bislang stehen für die Erforschung der molekulargenetischen Grundlagen aber keine ausreichend großen und gut charakterisierten Patientenkollektive zur Verfügung. In dieser Situation bietet nun das im 7. Rahmenprogramm vom Europäischen Forschungsrat (ERC) geförderte „PHANTOMMIND“ Projekt (Leitung: Prof. Flor), in dem 6.000 Patienten mit Amputationen untersucht werden, eine einmalige Chance. Ziel des hier vorgeschlagenen „PHANTOMGENE“ Projektes ist die Erweiterung des PHANTOMMIND Projektes um den Aufbau einer DNA-Bank als nationaler Forschungsressource. Im Rahmen der Rekontaktierung der Patienten soll u.a. auch eine vertiefende Phänotypisierung erfolgen. Anschließend sind genomweite Untersuchungen zu den molekularen Ursachen von Phantomschmerzen geplant.