1. High-field fMRI of thalamo-cortical circuits
    The aim of this project is to exploit the potential of high field fMRI at 7 Tesla, to measure task specific activations at the level of nuclear subunits in thalamus and basal ganglia. Taking the functional diversity of the different nuclei into account, we try to shed light on a cortico-striato-thalamo-cortical loop relevant for cognitive and affective processing.

    Selected publications:

    Walter, et al, 2008, High resolution fMRI of subcortical regions during visual erotic stimulation at 7 Tesla. MAGMA.
    Metzger, et al, 2013, Functional mapping of thalamic nuclei and their integration into cortico-striatal-thalamo-cortical loops via ultra-high resolution imaging - From animal anatomy to in vivo imaging in humans. Frontiers in Neuroscience.
    Kruschwitz JD, et al, 2015, 5-HTTLPR/rs25531 polymorphism and Neuroticism are linked by resting state functional connectivity of amygdala and fusiform gyrus. Brain Structure and Function.
    Bola M, et al, 2016, Cognitive processing involves dynamic reorganization of the whole-brain network's functional community structure. Journal of Neuroscience.
    Schmidt F, et al, 2017, Habenula volume increases with disease severity in unmedicated major depressive disorder as revealed by 7T MRI.European archives of psychiatry and clinical neuroscience.
    Sweeney-Reed CM, et al, 2017, Anterior Thalamic High Frequency Band Activity is Coupled with Theta Oscillations at Rest.Frontiers in Human Neuroscience.

  2. Network alterations under oral antidepressant treatment
    Collaborators: Birgit Abler and Heiko Graf, University of Ulm, Germany.
    Antidepressant treatment currently strongly focusses on noradrenergic and serotonergic drugs. In this project we try to understand, what neurobiological differences can be found on a circuit level.
    We therefore apply analyses of functional activations and connectivity to data of pharmacological challenges at 3 Tesla.

     

    Selected publication:
    Abler, et al, 2012, Modulation of frontostriatal interaction aligns with reduced primary reward processing under serotonergic drugs.Journal of Neuroscience. Metzger, et al, 2015, Local and global resting–state activity in the noradrenergic and dopaminergic pathway modulated by reboxetine and amisulpride in healthy subjects. International Journal of Neuropsychopharmacology.
    Graf H, et al, 2017, Noradrenergic modulation of neural erotic stimulus perception. European Neuropsychopharmacology.
    Graf H, et al, 2014, Erotic stimulus processing under amisulpride and reboxetine: a placebo controlled fMRI-study in healthy subjects. Int J Neuropsychopharmacol.

  3. Eating regulation and motivation disorders
    Collaborators: S. Ehrlich, Dresden and D.Tian, Tianjin.
    Psychiatric disorders are characterized by abnormal motivation and affect regulation, directly translating into deviant eating and reward seeking behavior. On the other hand, biological mechanisms primarily associated with pathologically increased or decreased body weight represent driving factors for neuronal changes which themselves are associated with affective and cognitive symptoms also observed in psychiatric patients. A further difficulty is incurred by the metabolic consequences of antidepressant or antipsychotic medication, which next to primary neuronal consequences directly affect insulin sensitivity or satiety. Our work here addresses the neuronal mechanisms mediating pathological behavior both as a cause and consequence of homeostatic dysregulation and ingestive behavior at the threshold between public health and core clinical populations.

     


    Selected publication:
    Walter M, et al, 2009, The relationship between aberrant neuronal activation patterns in the pregenual anterior cingulate, altered glutamatergic metabolism and anhedonia in Major Depression.JArchives of General Psychiatry.
    Steiner J, et al, 2010, Elevated S100B levels in schizophrenia are associated with insulin resistance. Molecular Psychiatry.
    Zhang, et al, 2015, Altered baseline brain activity differentiates regional mechanisms subserving biological and psychological alterations in obese men. Scientific Reports
    Zhang B, et al, 2015, Altered baseline brain activities before food intake in obese men: A resting state fMRI study. Neuroscience Letters.
    Ehrlich S, et al, 2015, Reduced functional connectivity in the thalamo-insular subnetwork in patients with acute anorexia nervosa. Human Brain Mapping.
    Deng Y, et al, 2018, Motivation but not valence modulates neuroticism dependent cingulate cortex and insula activity. Human Brain Mapping.
    Kroemer N, et al, 2018, Exaggerated Control Demands Over Reward-Related Behavior in Anorexia Nervosa. Biol Psychiatry.

  4. Neuroinflammation Networks in depression, obesity and schizophrenia
    Collaborators: Lucile Capuron, Bordeaux, Johan Steiner, Magdeburg , B. Pichler, Tübingen
    Neuroinflammation findings prevail in many psychiatric diagnostic groups however until recently their etiological involvement remained poorly understood. Recent evidence has shown differential profiles for inflammatory affection in subtypes of depression. In the same line, phenomenological characteristics arise for patients classically diagnosed as psychotic particularly in the presence of NMDA receptor antibodies. While a differentiated clinical expression cannot be drawn from certain inflammatory patterns themselves, knowledge on functional and receptor architectonics in key networks underlying MDD and psychosis may allow a more direct link between peripheral signs of inflammation and deviant brain function. We try to shed light on this complex relationship by integrating molecular and functional brain imaging such as PET, MRS and fMRI with blood assessments in patients and patient subgroups.

     


    Selected publication:
    Steiner J*, Walter M*, et al, 2011, Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission?Journal of Neuroinflamation.
    Walter M, et al, 2011,Aberant resting state mechanisms in major depression - converging evidence from histopathology and non invasive imaging reveal the importance of glial dysfunction. Nervenheilkunde
    Steiner J*, Walter M*, et al, 2013, Increased Prevalence of Diverse N -Methyl-D-Aspartate Glutamate Receptor Antibodies in Patients With an Initial Diagnosis of Schizophrenia: Specific Relevance of IgG NR1a Antibodies for Distinction From N -Methyl-D-Aspartate Glutamate Receptor Encephalitis. JAMA Psychiatry.
    Woelfer M, et al, 2018, The role of depressive subtypes within the neuroinflammation hypothesis of Major Depressive Disorder. Neuroscience.

  5. Systems neuroscience integration of histopathology in neuropsychiatric disorders
    Collaborators: Anke Henning, Greifswald, Oliver Speck Magdeburg, HG Bernstein Magdeburg
    Post mortem assessment of patient brains has revealed a large set of evidence for individual cellular aberrations in depression or schizophrenia. As a major drawback, their functional relevance has not been investigated directly. Furthermore, subtle whole brain functional architecture and connectomic perspectives, which dominate non-invasive brain imaging seem to stand separate to the findings e.g. revealed by immunehistochemistry, even if whole brain specimen is available. In this project we develop methods for a cross-linkage of non-invasive and postmortem findings based on direct and data based fusion of modalities. We make explicit use of the new means provided by improved spectral resolutions of ultra-high field spectroscopy and spatial resolutions of up to 150 microns at magnetic fields of 7 and 9.4 Tesla.

     



    Selected publication:
    6. Bernstein H-G, et al, 2015, Reduced density of glutamine synthetase immunoreactive astrocytes in different cortical areas in major depression but not in bipolar I disorder. Frontiers in cellular neuroscience.
    Li M*, et al, 2014, Dissociation of glutamate and cortical thickness is restricted to regions subserving trait but not state markers in major depressive disorder. Journal of Affective Disorders.
    Metzger CD, van der Werf Y, Walter M 2013, Functional mapping of thalamic nuclei and their integration into cortico-striatal-thalamo-cortical loops via ultra-high resolution imaging - From animal anatomy to in vivo imaging in humans. Frontiers in Neuroscience.
    Dou W, et al, 2013, Systematic regional variations of GABA, Gln and Glu concentrations follow receptor fingerprints of human cingulate cortex. Journal of Neuroscience,
    Yang S*, et al, 2013, Integration of ultra-high field MRI and histology for connectome based research of brain disorders. Frontiers in Neuroanatomy,
    Amidfar M, et al, 2017, Increased levels of 5HT2A receptor mRNA expression in peripheral blood mononuclear cells of patients with major depression: correlations with severity and duration of illness. Nordic Journal of Psychiatry.
    Colic,,et al, 2018, A GAD65 promoter polymorphism rs2236418 modulates harm avoidance in women via inhibition/excitation balance in the rostral ACC. Journal of Neuroscience.

  6. Investigation of pharmacological side effects and their prediction by passive MRI assessment
    Next to their primary therapeutic effect, the choice of antidepressant treatment and compliance currently is strongly dependent on the extent and type of side effects. We therefore try to understand, which brain systems are mostly affected for certain cognitive or vegetative unfavorable effects which often result in discontinuation of treatment. Resting-state fMRI, in contrast to active task paradigms, can be conveniently acquired in patients without a need for cooperation which would exceed that of structural MRI scans. We try to use the rich information provided by this technique to reveal brain biomarkers which can reveal information about a patients individual vulnerability to develop certain side effects even before initiation of pharmacotherapy.

     

    Selected publications:
    Graf, et al, 2012, Modulation of attention network activation under antidepressant agents in healthy subjects.International Journal of Neuropharmacology.
    Metzger et al, 2013, SSRI-related modulation of sexual functioning is predicted by pre-treatment resting state functional connectivity in healthy men.Archives of Sexual Behavior.
    Liebe T, et al, 2017, Factors influencing the cardiovascular response to sub-anesthetic ketamine – a randomized, placebo-controlled trial. Int J Neuropsychopharmacol.
    Lehmann M, et al, 2016,Differential effects of rumination and distraction on ketamine induced modulation of resting state functional connectivity and reactivity of regions within the default-mode network.Social cognitive and affective neuroscience.
    Graf H, et al, 2016,Serotonergic antidepressants decrease hedonic signals but leave learning signals in the nucleus accumbens unaffected.NeuroReport.

  7. Expectancy, recollection and perception of affective stimuli in major depression
    According to current theories of depression, a cognitive bias influences patients memory of the past, the attention towards and processing of current stimuli as well as anticipation and concepts about future events. Application of established fMRI paradigms and behavioral tasks, we investigate the neural basis of such mechanisms. Specifically, we try to understand, which brain networks mediate, either by integration or in interaction with other functional systems, are involved in generating and shaping stable concepts about the internal and external world as well the integration of such information on the subjective level.


    Selected publications:
    Walter, et al, 2009, Preceding attention and the dorsomedial prefrontal cortex: Process specificity versus domain dependence.Human Brain Mapping.
    Metzger, et al, 2010, High Field fMRI Reveals Thalamocortical Integration of Segregated Cognitive and Emotional Processing in Mediodorsal and Intralaminar Thalamic Nuclei.Frontiers in Neuroanatomy.
    Li S, et al, 2017, Novelty seeking and reward dependence related large-scale brain networks functional connectivity variation during salience expectancy.Human Brain Mapping.
    Götting FN, et al, 2017, Higher interference susceptibility in reaction time task is accompanied by weakened functional dissociation between salience and default mode network.Neuroscience Letters.
    Borchardt V, et al, 2017, Echoes of Affective Stimulation in Brain Connectivity Networks.Cerebral Cortex.
    Zhang, et al, 2017, Altered task-specific deactivation in the default mode network depends on valence in patients with major depressive disorderJournal of affective disorders.

  8. Resting-state alterations by visual salient stimulation in fMRI and EEG
    Collaboration with Harold Mouras, Amiens, France.
    Combining advantages for high spatial and temporal resolution as well as susceptibility for different biological mechanisms, we use parallel EEG-fMRI to discern sub-processes of mutual cognitive - affective regulation. Erotic stimuli have been found to represent strong primary rewards whose behavioral relevance is also changed during episodes of depressive and bipolar depression, and thus are used next to other stimuli to investigate effects of vigilance and salience processing in healthy controls and depressed patients.


    Selected publications:
    Walter, et al, 2008, Distinguishing sexual and emotional effects during erotic picture viewing in subcortical and cortical regions. NeuroImage.
    van der Meer J, et al, 2067, "Eyes Open - Eyes Closed" EEG/fMRI data set for evaluating hardware motion sensors (Carbon-Wire Loops) with respect to corretion of the Helium pump artefact.Data in Brief.
    van der Meer J, et, 2016, Carbon-wire loop based artefact correction outperforms post-processing EEG/fMRI corrections—A validation of a real-time simultaneous EEG/fMRI correction method.Neuroimage.

  9. Resting-state Dynamics and their changes in depressed patients
    Collaboration with Catherine E. Chang, Stanford, CA, USA.
    It has been shown that functional connectivity, revealed by temporal correlation of spontaneous low frequency signal at rest, is not stable, even across a short time window of 5-10 TR. To understand the functional meaning of resting state dynamics of connectivity, we use novel analysis methods to manipulate connectivity brain states, and explore their interrelation to other state markers of the autonomous nervous system. Secondly we explore these markers for relevant disease related information which could not be extracted by current observations of mean resting state connectivity.

    Selected publications:
    Chang, et al, 2012, Association between heart rate variability and fluctuations in resting-state functional connectivity.NeuroImage.
    Hutchison RM, et al, 2013, Dynamic functional connectivity: promise, issues, and interpretations.NeuroImage.

  10. Metabolism-BOLD-interaction during task- and restingstate fMRI
    Multimodal investigations allow us to go further when interpreting the neurobiological meaning of observed effects in BOLD Signal changes or functional connectivity. We use combinations of Magnetic Resonance Spectroscopy (MRS) and fMRI from 3T to 7T which allow us to compare the inter-individual variation in classical fMRI markers with changes in concentrations of GABA, Glutamate or Glutamine. In healthy controls this helps to define physiological mechanisms of inter-regional integration while in patients, we can get closer to potential cellular origins of abnormal fMRI findings.


    Selected publications:
    Northoff, et al, 2007, GABA concentration in the human anterior cingulate cortex predicts negative BOLD response in fMRI.Nature Neuroscience.
    Walter, et al, 2009, The relationship between aberrant neuronal activation patterns in the pregenual anterior cingulate, altered glutamatergic metabolism and anhedonia in Major Depression. Archives of General Psychiatry.
    Horn DI, et al, 2010, Glutamatergic and resting-state functional connectivity correlates of severity in major depression - the role of pregenual anterior cingulate cortex and anterior insula.Frontiers in Systems Neuroscience.
    Demenescu LR,et al, 2017, A Spectroscopic Approach towards Depression Diagnosis: Local Metabolism Meets Functional Connectivity. European Archives of Psychiatry and Clinical Neuroscience.
    Colic L, et al, 2016, Metabolic mapping reveals sex dependent involvement of default mode and salience network in alexithymia. Social cognitive and affective neuroscience.
    Li M, et al, 2014, Dissociation of glutamate and cortical thickness is restricted to regions subserving trait but not state markers in major depressive disorder.Journal of Affective Disorders.

  11. Abnormal brain network behavior in major depression
    Collaboration with Michael Breakspear, Brisbane, Queensland, Australia.
    The network disorder, underlying pathological processing of internal and external stimuli in affective disorders can also be investigated on a whole network level. Advantages include that also regions, for which currently no strong relationship with clinical or psychological markers had been established, may be revealed, if functionally altered. Also understand the brain as a functional network, state of the art graph network approaches can help to define, which specific aspect of network dysfunction prevails at the levels of a single region or of a functional module or at whole brain level.


    Selected publications:
    Lord A, et al, 2012, Changes in community structure of resting state brain networks in unipolar depression. PLoS ONE.
    Bogerts B and Walter M, 2010, MöllerLaux Psychiatrie.
    Walter, 2013, in Systemische Neurowissenschaften in der Psychiatrie, Falkai & Gruber, Kohlhammer Verlag.
    Liu C-H, et al, 2017, Decreased resting-state activity in the precuneus is associated with depressive episodes in recurrent depression. The Journal of clinical psychiatry.
    Kambeitz J, et al, 2017, Detecting neuroimaging biomarkers for depression: A meta-analysis of multivariate pattern recognition studies Biological Psychiatry.
    Krause AL, et al , 2018, Functional connectivity changes following interpersonal reactivity. Human Brain Mapping
    Borchardt V, 2018, Exposure to attachment narratives dynamically modulates cortical arousal during the resting state in the listener. Brain and Behavior.
    Zhang B, et al, 2016, Altered functional connectivity density in major depressive disorder at rest. European archives of psychiatry and clinical neuroscience.
    Yang CC, et al, 2016, State and Training Effects of Mindfulness Meditation on Brain Networks Reflect Neuronal Mechanisms of Its Antidepressant Effect.Neural plasticity.
    Borchardt V, et al, 2015, Graph Theory reveals hyper-functionality in visual cortices of Seasonal Affective Disorder patients. The World Journal of Biological Psychiatry.

  12. Ketamine in treatment resistant depression
    This projects investigates neural mechanisms of action of the recently described antidepressant substance ketamine. Parts of this project are done in collaboration in a multidisciplinary research group at the Leibniz Institute for Neurobiology. Here we investigate the mechanisms of synaptic plasticity from the molecular to the whole brain systems level in healthy controls. Using combined imaging modalities at 7T , we try to shed light on glutamatergic modulation of learning processes and plasticity, in systems with specific sensitivity to NMDAergic modulation. These brain systems are further investigated for their contribution of other symptoms associated with intravenous application of NMDA antagonists. In treatment resistant patients, we try to reveal markers of clinical change as well as predictors of treatment outcome which might, in the future guide clinical decisions in these severely affected patients.


    Selected publications:
    Scheidegger M and Walter M, et al, 2012, Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action.PLoS ONE.
    Steiner J and Walter M, et al, 2013, Increased Prevalence of Diverse N -Methyl-D-Aspartate Glutamate Receptor Antibodies in Patients With an Initial Diagnosis of Schizophrenia: Specific Relevance of IgG NR1a Antibodies for Distinction From N -Methyl-D-Aspartate Glutamate Receptor Encephalitis.JAMA Psychiatry.
    Scheidegger M, et al, 2016, Effects of Ketamine on Cognition-Emotion Interaction in the Brain.Neuroimage.
    Scheidegger M,et al, 2016, Ketamine administration reduces amygdalo-hippocampal reactivity to emotional stimulation.Human brain mapping.
    Li M, et al, 2017, Temporal Dynamics of Antidepressant Ketamine Effects on Glutamine Cycling Follow Regional Fingerprints of AMPA and NMDA Receptor Densities.Neuropsychopharmacology.
    Colic L, et al, 2018, Delayed increase of thrombocyte levels after a single sub–anesthetic dose of ketamine – a randomized trial. European Neuropharmacology.
    Walter M,et al, 2014, Multistage drug effects of ketamine in the treatment of major depression. Eur Arch Psychiatry Clin Neurosci.

  13. Influence of structural network variability on affect regulation in healthy subjects and depression
    Transient functional connectivities, which change during contextual demands or as a function of ongoing state changes, are thought to follow a backbone of structural connectivity. In the same line, the extent of functional activations is thought to rely heavily on structural integrity of region. While these relationships are ideal for a complex understanding of neurobiological origins of abnormal network properties in disease, covariation in structure across regions or fiber tracks across regions can also be utilized to contribute to understanding the functional neuroanatomy in humans. We therefore use DTI and cortical thickness measurements, including longitudinal observations at field different field strengths, to generate a link of abnormal structural, histological, functional and metabolic evidence in depression.


    Selected publications:
    Walter M, et al, 2011, Aberant resting state mechanisms in major depression - converging evidence from histopathology and non invasive imaging reveal the importance of glial dysfunction. Nervenheilkunde.
    Eckert U, et al, 2011, Preferential networks of the mediodorsal nucleus and centromedian-parafascicular complex of the thalamus-A DTI tractography study.Human Brain Mapping.
    Osoba A, et al, 2013, Disease severity is correlated to tract specific changes of fractional anisotropy in MD and CM thalamus - A DTI study in major depressive disorder.Journal of Affective Disorders.
    Li W and van Tol M-J et al, 2012, Regional Specificity of Sex Effects on Subcortical Volumes Across the Lifespan in Healthy Aging.Human Brain Mapping.
    Lord A, et al, 2017, Richness in Functional Connectivity Depends on the Neuronal Integrity within the Posterior Cingulate Cortex .Frontiers in Neuroscience.
    Teipel S, et al, 2017, Robust detection of impaired resting state functional connectivity networks in Alzheimer’s disease using elastic net regularized regression.Frontiers in Aging Neuroscience.
    Teipel S, et al, 2017, Multicenter stability of resting state fMRI in the detection of Alzheimer's disease and amnestic MCI.NeuroImage: Clinical.

  14. Optimisation of image acquisition and procesing for large scale data
    Analyses of MRI data fundamentally rely on sufficient data quality and robust control of potential confounders. This requirement can be approached by determination of optimized and standardized imaging protocols. Furtheron, inclusion of additional information and development of new online measures of data accuracy and subject compliance are important means, by which future clinical and basic neuroscientific applications can yield improved insights via non-invasive imaging of the brains neurocircuitry. We develop such methods especially for large scale data initiatives and current work focussed on the rescue of large data which had been acquired with subotimal or incomplete datasets, including estimation of physiological noise contributions.


    Selected publications:
    Ash, et al, 2011, Detection of physiological noise in resting state fMRI using machine learning.Human Brain Mapping.
    Li M, et al, 2013, Fast online analysis of resting-state 'performance' using dynamic time wrapping.Human Brain Mapping.
    15. Kambeitz J, et al, 2018, Importance of statistical methods for assessing performance and moderator effects in neuroimaging-based classification models.Biological Psychiatry.
    Dou W, et al, 2015, Automatic Voxel Positioning for MRS at 7T.Magn Reson Mater Phy.
    Borchardt V, et al, 2016, Preprocessing strategy influences graph-based exploration of altered functional networks in Major Depression. Human brain mapping.
    Lord A, et al, 2016, Brain parcellation choice affects disease-related topology differences increasingly from global to local network levels.Psychiatry Research: Neuroimaging.

  15. Non-invasive interventions and Neurofeedback
    Next to psychotherapy and neuropsychopharmacology, a whole set of alternative treatment options has been developed to address deviant brain function in depression. Alteration of brain states by specific manipulation of subnetworks is thus a major field of current research in our group. While some networks could be affected by training of focussed attention or mindfullnes, more specific targeting could be reached via direct neurofeedback of regional signals or EEG network configuration. We use parallel EEG-fMRI and novel features of brain function during real-time fMRI to determine the additional potential of such methods, given that neurofeedback already has seen a history across several modalities. Other mechanisms include self monitoring such as during meditation and inclusion of EMG signatures of mimic expressions.


    Selected publications:
    Van der Meer Johan, et al, 2016, Carbon-wire loop based artefact correction outperforms post-processing EEG/fMRI corrections—A validation of a real-time simultaneous EEG/fMRI correction method.Neuroimage

  16. Neurobiology of deviant sexual desire
    Sexual desire and orientation, seem to be rooted deep in our brains development. In depression, desire strongly varies as incdreased (or decreased in hypoania) libido. In another neuropsychiatric disorder, sexual orientation is shifted towards prepubescent children. Patients clinically diagnosed with pedophilia were shown to have structural and functional brain abnormalities congruent with emotional immaturity and cognitive distortions. We investigate this disorder in a national research project NeMUP, which also focusses on deviant sexual orientation in subjects with no pedosexual behavior. In this reseach alliance, many of the diagnostic and evaluatory analysis methods and the expertise on large scale data management from CANLAB is shared with the collaborating partners across germany. This research is closely related to our investigations of specific monoaminergic modulation of specific subfunctions and neurocircuits during sexual arousal and performance mainly in depressive patients.


    Selected publications:
    Walter M, et al, 2007, Pedophilia is linked to reduced activation in hypothalamus and lateral prefrontal cortex during visual erotic stimulation. Biological Psychiatry.
    Walter M et al, 2010, Neurobiological markers for the diagnosis and treatment of pedophiliacs and their role in prevention of sexual abuse of children.Psychology andPsychotherapie.
    Metzger C et al, 2013, SSRI-related modulation of sexual functioning is predicted by pre-treatment resting state functional connectivity in healthy men. Archives of Sexual Behavior.
    Ristow I, et al, 2018, Pedophilic sex offenders are characterised by reduced GABA concentration in dorsal anterior cingulate cortex. NeuroImage.
    Kneer J, et al, 2018, Diminished fronto-limbic functional connectivity in child sexual offenders. Journal of Psychiatric Research.
    Safron A, et al, 2017, Neural Correlates of Sexual Orientation in Heterosexual, Bisexual, and Homosexual Men.Scientific Reports.