Thematic Area C: Altered Multi-Site Communication in Brain Disorders

Projects in Thematic Area C focused on neurological and psychiatric disorders associated with pathological network alteration. The clinical conditions addressed in this thematic area included stroke, Parkinson’s disease and schizophrenia. Projects C1, C2 and C4 involved studies on stroke patients and healthy aged controls, focusing on the analysis of interactions between cortical motor regions, on mechanisms of large-scale functional regeneration and reorganization, and on modulation by non-invasive brain stimulation. Projects C5 and C8 addressed alterations of multi-site interactions in cortico-subcortical networks in patients with genetic and idiopathic forms of Parkinson’s disease. Projects C6 and C7 investigated changes in multi-site interactions occurring in patients with schizophrenia. In the second and third funding period, the Z area has been expanded by a third project (Z3) with focus on computational modeling, network statistics, and signal processing. In the third funding phase, we integrated project C9 which provided expertise on multi-scale models of network dynamics.

Thematic Area C – Projects of 3rd Funding Period (2019-2023)

Project C1: Encoding of kinematics and effector choice in reorganized brain networks after stroke

The results of the past funding periods point towards parieto-frontal connectivity as a crucial element in recovery of motor function after stroke. Now, we aim to apply our findings to more complex motor behavior and cognitive processes like decision making in stroke patients. To this end, we will combine kinematics, structurally informed EEG network metrics, virtual-reality based interventions and network modulation by transcranial AC stimulation. Moreover, for the first time the spinal motoneuron pool (measured by functional MRI) will be integrated into network models in order to improve their robustness and predictive properties. With this thematic continuation and extension towards behavioral relevance, targeted network modulation and improved modeling, the project will move on towards network-based therapeutic interventions in stroke.

Prof. Dr. Christian Gerloff – Dept. of Neurology, UKE

Project C2: Structural determinants of disturbed evidence accumulation in cortical decision networks after stroke 

The evidence accumulation process during decision making is distributed over a large-scale structural and functional network of cortical regions. However, fundamental questions concerning the organization and structural determinants of this network remain open. We will study stroke patients and patients with cerebral small vessel disease, providing models for focal and distributed brain lesions, by algorithmic modeling of behavior, structural MRI, EEG, and catecholaminergic pharmacologic intervention. By this, we aim at a better understanding of the structural underpinnings and organization of the cortical decision network in the healthy brain, and of cognitive impairments in patients with vascular brain lesions.

PD Dr. Bastian Cheng – Dept. of Neurology, UKE
Prof. Dr. Götz Thomalla – Dept. of Neurology, UKE

Project C5: Characterization of action control networks in genetically determined parkinsonism

In the first two funding periods, we found evidence for increased activity of action selection networks in patients with genetically undefined parkinsonism, Parkin- and PINK1-associated parkinsonism, L-dopa-responsive dystonia, and X-linked dystonia parkinsonism. We now focus on network-related processes leading to disease manifestation by comparing asymptomatic mutation carriers with symptomatic patients with Parkin- and PINK1-associated parkinsonism, X-linked dystonia parkinsonism, and GBA-associated parkinsonism. To this end, we will use behavioral tasks, EEG, TMS, pupillometry, and neuromelanin-sensitive high-resolution MRI.

Prof. Dr. Alexander Münchau – Dept. of Neurology, University of Lübeck
Prof. Dr. Christine Klein – Dept. of Neurology, University of Lübeck  

Project C6: Pharmacological and electrical modulation of disturbed networks in schizophrenia and the clinical high-risk state for psychosis

This project aims to investigate the effects of both pharmacological modulation and transcranial AC stimulation (tACS) on alterations of connectivity patterns in different stages of schizophrenia and in the ketamine model of schizophrenia using EEG and simultaneous EEG and fMRI. Theta-tACS will target disturbed patterns of functional brain connectivity within a working-memory network related to schizophrenia cognitive symptoms. The glutamatergic intervention at the NMDA-receptor using glycine will be used to modulate alterations of (1) the gamma-band connectivity between auditory cortices related to the occurrence of auditory hallucinations and (2) a gamma-band-specific network involved in deficits in attentional auditory information processing.

Prof. Dr. Christoph Mulert – Center of Psychiatry, Justus-Liebig University, Giessen 
PD Dr. Gregor Leicht – Dept. of Psychiatry and Psychotherapy, UKE

Project C7: Effects of virtual reality in the augmentation of neuronal network plasticity

A main finding of the previous funding period was that brain-plasticity effects in the hippocampal-prefrontal network in response to a video game intervention are primarily induced by demanding spatial navigation (training of a 3D versus 2D version of the same video game). Clinical data of schizophrenia patients show a significant decrease in general psychopathology in the 3D training condition. Based on this encouraging evidence our goal for the next funding period is to (1) maximize the plasticity effects by using virtual-reality technology in the game, (2) unravel the time course and sequence of network plasticity effects and (3) to search for predictors of long-term plasticity in functional connectivity measures prior to training.

Prof. Dr. Jürgen Gallinat – Dept. of Psychiatry, UKE
Prof. Dr. Simone Kühn – Dept. of Psychiatry, UKE

Project C8: Cognitive and motor networks as a basis of mobility in patients with Parkinson´s disease 

The aim of this project is to advance multi-scale assessments of functional connectivity of cognitive and motor neuronal circuits to daily relevant tasks related to mobility in Parkinson´s disease patients, driving and walking. Intraoperative and postoperative recordings of neuronal network activities will be performed under realistic conditions, combining a driving simulator setup, virtual reality, mobile EEG, wearable movement-tracking sensors and eye-tracking techniques. Modulation of network activities will be performed by applying novel algorithms of deep brain stimulation such as patterned stimulation with evaluation of its impact on behavioral performance and assessment of reshaped subcortico-cortical network activity.

PD Dr. Monika Poetter-Nerger – Dept. of Neurology, UKE
PD Dr. Christian Moll – Dept. of Neurophysiology and Pathophysiology, UKE

Project C9: Multiscale modeling of network dynamics: from multimodal data to biophysical mechanisms and individual predictions 

This project develops and applies a computational framework that will enable the integration of neuroscience data across multiple scales to identify general principles of their interactions. We propose an approach using multiscale analyses of empirical neuroimaging data available from the SFB projects and large-scale brain simulations with TheVirtualBrain (TVB). We will decompose complex brain dynamics into probabilistic functional modes and mathematically operationalize them as manifolds along which trajectories evolve as the dynamics unfold.

Prof. Dr. Petra Ritter – Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neurology, Berlin Institute of Health (BIH), Bernstein Center for Computational Neuroscience, Berlin
Thematic Area C – Projects of 2nd Funding Period (2015-2019)

Project C1: Analysis, modeling, and modulation of the human motor network during recovery from motor strokes

The overall goal of this project is to understand adaptive changes of the cerebral motor network after stroke. In the first funding period, a central multimodal stroke database has been created and various network analyses have been implemented (DCM for fMRI/EEG, graph and game theory, machine learning, oscillator models). In the second funding period, different types of network characterization will be compared and related to clinical parameters. To move on towards causal relations between network dynamics and behavior, we will modulate networks with non-invasive brain stimulation, measure the effects, and apply modeling to predict them. With this thematic continuation and extension into modeling, modulation, and simulation, the project will move towards network-based, individualized outcome prediction and therapeutical applications.

Prof. Dr. Christian Gerloff – Dept. of Neurology, UKE

Project C2: Impact of alterations and therapeutic modulation of brain perfusion on structural and functional brain connectivity

The impact of both alterations as well as therapeutic modulation of brain perfusion on brain connectivity is poorly understood. We will use structural and functional magnetic resonance imaging, perfusion imaging, and EEG to characterize the interaction of brain perfusion, structural and functional brain connectivity in patients with cerebral small vessel disease and healthy control subjects. We will further study the impact of therapeutic modulation of brain perfusion in patients with high-grade carotid artery stenosis by serial measurements before and after revascularization. 

Prof. Dr. Götz Thomalla – Dept. of Neurology, UKE
Prof. Dr. Jens Fiehler – Dept. of Neuroradiology, UKE  

Project C5: Modulation of the action selection and error processing networks in genetic parkinsonism using rTMS and DBS

In the first funding period, we delineated neurophysiological abnormalities in the action selection network in genetically undefined, Parkin- and PINK1-associated parkinsonism, and dopa-responsive dystonia as a function of the dopaminergic state. In X-linked dystonia-parkinsonism, characterised by neurodegeneration in parts of the error processing network, intracortical inhibition was increased. We now propose to modulate the action selection and error processing network with repetitive TMS and deep brain stimulation to explore network dynamics in these patients using EEG.

Prof. Dr. Alexander Münchau – Dept. of Neurology, University of Lübeck
Prof. Dr. Christine Klein – Dept. of Neurology, University of Lübeck  

Project C6: Modulation of disturbed networks in schizophrenia with transcranial electrical stimulation

This project aims at modulating neural mechanisms involved in the pathophysiology of schizophrenia by means of non-invasive brain stimulation. Here, patients will be investigated with EEG, MEG, fMRI and DTI. Simultaneous EEG-fMRI will help characterizing the effects of frontal tDCS. Moreover, we will use a task requiring interhemispheric information transfer which is related to gamma-band phase coupling and auditory verbal hallucinations. During the task we will apply in-phase and anti-phase gamma-band tACS to left and right auditory cortex in order to manipulate interhemispheric gamma-band coupling. EEG will be recorded at the same time. In a similar way, brain function during cognitive tasks will be investigated.

Prof. Dr. Christoph Mulert – Dept. of Psychiatry, UKE

Project C7: Augmentation of neuronal network plasticity in schizophrenia

Current pathophysiological models of schizophrenia focus on dysconnectivity of distributed neuronal systems to explain the multitude of psychic symptoms. However, therapeutic strategies targeting this specific pathobiology are lacking. Our recent work provides strong evidence that complex video-game training interventions facilitate fronto-hippocampal structural and functional connectivity within 2 months in healthy subjects. The planned project transfers this knowledge into a training study in schizophrenic patients to counteract disease-related dysconnectivity. Underlying mechanisms and behavioral effects are extensively parametrized by resting state fMRI, DTI, MRS, MEG and clinical short- and long-term outcome.

Prof. Dr. Jürgen Gallinat
Prof. Dr. Simone Kühn – Dept. of Psychiatry, UKE

Project C8: Multi-scale assessment and modulation of cortico-subcortical networks in Parkinson´s disease

The aim of this project is to assess and modulate human motor and associative-limbic networks in patients with Parkinson´s disease undergoing deep brain stimulation. A motor task consisting of stepping movements and a cognitive task comprising an auditory gambling paradigm will be performed during and following deep brain surgery. Multi-site activity will be measured in subcortico-cortical networks by intraoperative microelectrode recordings, as well as postoperative EEG, MEG, EMG and pupillometry. The identified networks will be modulated by high-frequency stimulation of the subthalamic area. We expect to find task-related changes of coherent oscillations between cortico-subcortical sites which might be differentially modulated by deep brain stimulation.

PD Dr. Monika Poetter-Nerger – Dept. of Neurology, UKE
Dr. Christian Moll – Dept. of Neurophysiology and Pathophysiology, UKE
Thematic Area C – Projects of 1st Funding Period (2011-2015)

Project C4: The functional role of altered multisite interactions between primary and secondary motor areas after stroke and in healthy ageing

This project is geared at understanding multisite interactions between primary and secondary motor cortices during complex sensorimotor behaviour and learning in chronic stroke patients and in healthy aged individuals. The emphasis is on the role of these interactions for functional reorganisation and recovery after focal brain lesions and maintainance of complex sensorimotor functioning during healthy ageing. A multimodal approach with transcranial magnetic stimulation, multichannel electroencephalography, structural brain imaging and functional behavioural testing will be used. The long-term goal is to provide a basis for innovative interventions (e.g., non-invasive brain stimulation) enhancing functional recovery and supporting motor function during healthy aging by optimizing connectivity in the central motor control network.

Prof. Dr. Friedhelm Hummel – Dept. of Neurology, UKE