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.

  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.
  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 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, 2015 et al 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 2011Aberant 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,

  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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