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PD Dr. rer. nat. Frauke Nees

Nees F. SFB 1158: B03 - The role of learning, stress and underlying brain circuits involving prefrontal-limbic interactions in the development of chronic back pain . 07/2019-06/2023.

Previous research led to the assumption that chronic pain may be related to emotional learning, however, little is known about the associated changes in brain structure and function that might predict persistent pain. This project seeks to determine brain circuits related to learning mechanisms in pain such as aversive and appetitive, operant and respondent learning as well as the role of stress to predict the transition from acute to chronic back pain and to identify risk and resilience factors.

BMBF - Bundesministerium für Bildung und Forschung : IMAC-Mind: Improving Mental Health and Reducing Addiction in Childhood and Adolescence through Mindfulness: Mechanisms, Prevention and Treatment. Project TP2 “Translation of neurobehavioral risk profiles into the development of screening and prevention . 10/2017-09/2021.

BMBF - Bundesministerium für Bildung und Forschung : IMAC-Mind: Improving Mental Health and Reducing Addiction in Childhood and Adolescence through Mindfulness: Mechanisms, Prevention and Treatment. Project TP1 “Identification of early bio-psycho-social risks and resilience factors and etiological pathway. 10/2017-09/2021.

Nees F. DFG - Deutsche Forschungsgemeinschaft NE 1383/14-1: Heisenberg-Stelle. 02/2018-01/2021.

Muster des aversiven u. appetiven Pavlovschen-Instrumentellen Transfers und die Rolle von Stress über die Lebensspanne

Flor H. DFG - Deutsche Forschungsgemeinschaft FL 156/41-1: Reinhart Koselleck Projekt: "Körperrepräsentation und sensomotorische Funktionen modulieren die Reorganisation des Gehirns und Verhaltensänderungen: Vom chronischen Schmerz zur lmmobilität und Demenz ". 07/2015-06/2020.

Brain circuits involved in pain processing and body representation are closely connected and interact more than previously thought. Somatosensory, visual, interoceptive and motor processes contribute to the formation of body perception and can be combined in treatments designed to reestablish normal body representation. Based on the development of novel psychological interventions targeting body representation in phantom limb pain, we devise new virtual and augmented reality-based training pro-cedures to reestablish normal body representation and improve sensory, motor and cognitive function. We apply these interventions in post-injury pain and motor dysfunction, where the counteracting of long-term immobility by feedback of movement should shorten recovery times and preserve muscle function. Another novel application is in chronic musculoskeletal pain, where the systematic shaping of intact body representation including interoception, should reduce pain and pain behaviors and alter maladaptive brain circuits. We expand this approach to early dementia, where the breakdown of sen-sorimotor processing and immobility may be important in disease progression. We employ novel im-plicit and explicit assessment methods of these perceptual and neuronal changes involving psycho-physics, computational modeling, physiological recordings and brain imaging methods. These studies are the basis for mechanistic treatment approaches and also advance basic research on body repre-sentation and multisensory integration.

Flor H. BMBF - Bundesministerium für Bildung und Forschung 01EE1406C, AERIAL: Addiction: Early Recognition and Intervention Across the Lifespan . 02/2015-01/2019.

Addictive disorders are among the most frequent and costly disorders in industrialized countries. While substantial research focused on treatment of single substance use disorders (SUDs), most interventions do not sufficiently address comorbid disorders, are provided too late, do not reach the majority of addicted subjects and are not adjusted with respect to environmental stressors, affective comorbidity, gender and age-specific contexts. Focusing on alcohol use disorders (AUD), the main aim of the consortium is to improve the health care system by 1) assessing new access pathways including a wider range of healthcare professionals, and 2) evaluating existing and developing novel early assessment and intervention tools including e-health applications (computer/internet/smart phone-based). We will address patients suffering from the most prevalent SUDs, particularly alcohol, across the lifespan. We will use state-of-the-art basic science approaches to assess social stressors and comorbid affective disorders and we will adapt our approach to age-related differences in treatment needs. To adapt early interventions to modify risk and resilience factors across the lifespan, we will use existing cohorts such as the longitudinal IMAGEN sample of (now) young adults, representative data across the lifespan and from a systematic assessment of adolescent psychiatry, community and hospital general medical settings as well as observational data from studies on the mechanisms of addictive behavior. We will focus on proactive approaches for all primary medical care patients including general practices and hospitals. In all settings, we will assess comorbid mental disorders and gender and migration-specific factors such as social exclusion and discrimination.

Nees F. DFG - Deutsche Forschungsgemeinschaft NE 1383/9-1: Scientific network for a better understanding of the neuroplasticity and associated functions following hemispherectomy. 01/2016-12/2018.

Nees F. DFG - Deutsche Forschungsgemeinschaft NE 1383/6-1: Annäherung und Vermeidung bei chronischem Schmerzsyndrom der Skelettmuskulatur: Die Rolle des Transfers von Pavlovschem zu instrumentellem Verhalten. 01/2015-12/2017.

Aims of this research are (a) the determination of pain-related approach and avoidance behavior and their neural correlates in chronic musculoskeletal pain, and (b) more specifically the interaction of pavlovian and instrumental conditioning processes in the development and maintenance of chronic musculoskeletal pain, involving (classical) reward and pain relief processing and the analysis of prediction error signaling. Hypotheses: We expect patients with chronic back pain to be characterized by reduced appetitive approach and enhanced avoidance as well as by reduced pavlovian and instrumental reward- and pain-relief-related conditioning and reduced approach-related PIT effect. These should be represented by decreased muscle tension levels and increased skin conductance responses, increased response times and frequency and, for the central measures, enhanced activation in the amygdala, insula and orbitofrontal cortex, but reduced activation in the striatal and prefrontal activation and deficient amygdala-prefrontal, amygdala-PAG and amygdala-striatal connectivity. Additionally, learning-related aversive prediction error signaling in reward (pain relief) related brain regions is expected to be reduced in chronic back pain, reflected by a decreased activation of the striatum, especially the nucleus accumbens, in pain patients compared to healthy subjects.

Szabo K, Nees F. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP C07: Implicit and explicit learning and memory processes in acute and chronic. 01/2012-12/2015.

The aim of this project is to investigate the effect of stress and hypothalamus-pituitary-adrenal (HPA) axis function on implicit and explicit learning and memory processes in states of acute and chronic hippocampal impairment in a cohort of patients with transient global amnesia (TGA). TGA is a neurological disorder characterized by the acute onset of severe anterograde memory loss that usually resolves within 24 hours. In up to 90% of cases, an emotionally or physically charged event precedes the onset of TGA. By using magnetic resonance imaging (MRI) following a TGA episode, we have observed small lesions in the hippocampus and hence hypothesize that the disorder is caused by the stress-related transient inhibition of memory formation in the hippocampus. To test this assumption, we will determine the effect of experimental exposure to stress (socially evaluated cold pressor test) on cortisol levels and on hippocampal activation patterns in implicit and explicit memory and learning paradigms by functional MRI in the following three cohorts: patients with acute TGA, patients who suffered a TGA in the previous 2 years, and healthy control subjects. We will analyze cortisol levels during and after TGA, in response to the dexamethasone suppression test, as well as under experimental stress conditions. We expect TGA patients to exhibit an altered HPA axis reactivity resulting in increased cortisol values. To show that changes in brain activation patterns during memory formation and retrieval are a pathophysiological correlate of TGA, we will employ fMRI measurements based on two different approaches to assess hippocampal function. In a recognition memory paradigm, we expect only the performance in the recollection aspect (hippocampal memory) to be affected in TGA patients (with a specific reduction in hippocampal activation in contrast to healthy controls), while extra-hippocampal memory processes (familiarity) should remain intact. We will additionally employ a contextual fear conditioning fMRI task that has been shown to lead to significant hippocampal activation. We assume that the activation produced by this paradigm will also be reduced and that extinction processes will be differentially affected in TGA patients as compared to controls. In addition to understanding the pathophysiology of TGA, the results of this study may aid to understand the development and maintenance of anxiety disorders and depression, in which altered hippocampus-related learning processes play a crucial role.

Flor H. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP C01: Learning and brain plasticity in posttraumatic stress disorder:. 01/2012-12/2015.

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.

Flor H, Mann KF. EU - Europäische Union 037286: IMAGEN WP6: Reinforcement-related behaviour in normal brain function and psychopathology: Neuroimaging adolescents. 02/2007-07/2012.

To acquire a large integrated structural and functional MRI dataset to allow analysis of the structural-functional correlations within the dataset. Analysis will be conducted in cooperation with WP 07. This data will be acquired in an identical fashion from multiple sites and will require explicit standardization with the input of WP 05. Participants will be recruited in conjunction with WP 04. To relate findings in this dataset to external measures of adolescent development, environmental exposure (WP 04) and current neuropsychological performance on tasks which relate to impulsivity (WP 02) To relate findings to genetic information in a coordinated hypothesis testing approach using candidate genes identified from strategies developed in WP 01, 03, 08. Activities in this workpackage are also linked to training activities coordinated in WP 10. Initially each site will implement a comparable pulse sequence for BOLD sensitive functional imaging, for diffusion weighted imaging and for structural T1 weighed imaging. In addition each site will implement the agreed battery of tasks for fMRI scanning and test this set of paradigms. On this basis each site will conduct functional, structural and diffusion weighted imaging at a rate of approximately 100 subjects per year. This data will be analysed individually and then correlated with personality and genetic markers.

Flor H. EU - Europäische Union 037286: IMAGEN WP2: Reinforcement-related behaviour in normal brain function and psychopathology: Behavioural tasks in humans. 02/2007-07/2012.

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.

Flor H. EU - Europäische Union 037286: IMAGEN WP2: Reinforcement-related behaviour in normal brain function and psychopathology: Behavioural tasks in humans. 02/2007-07/2012.

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.


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