Identifying Changes of Functional Brain Networks using Graph Theory

This thesis gives an overview on how to estimate changes in functional brain networks using graph theoretical measures. It explains the assessment and definition of functional brain networks derived from fMRI data. More explicitly, this thesis provides examples and newly developed methods on the measurement and visualization of changes due to pathology, external electrical stimulation or ongoing internal thought processes. These changes can occur on long as well as on short time scales and might be a key to understanding brain pathologies and their development. Furthermore, this thesis describes new methods to investigate and visualize these changes on both time scales and provides a more complete picture of the brain as a dynamic and constantly changing network.:1 Introduction 1.1 General Introduction 1.2 Functional Magnetic Resonance Imaging 1.3 Resting-state fMRI 1.4 Brain Networks and Graph Theory 1.5 White-Matter Lesions and Small Vessel Disease 1.6 Transcranial Direct Current Stimulation 1.7 Dynamic Functional Connectivity 2 Publications 2.1 Resting developments: a review of fMRI post-processing methodologies for spontaneous brain activity 2.2 Early small vessel disease affects fronto-parietal and cerebellar hubs in close correlation with clinical symptoms - A resting-state fMRI study 2.3 Dynamic modulation of intrinsic functional connectivity by transcranial direct current stimulation 2.4 Three-dimensional mean-shift edge bundling for the visualization of functional connectivity in the brain 2.5 Dynamic network participation of functional connectivity hubs assessed by resting-state fMRI 3 Summary 4 Bibliography 5. Appendix 5.1 Erklärung über die eigenständige Abfassung der Arbeit 5.2 Curriculum vitae 5.3 Publications 5.4 Acknowledgement

Differences in electric field strength between clinical and non-clinical populations induced by prefrontal tDCS: a cross-diagnostic, individual MRI-based modeling study

Introduction: Prefrontal cortex (PFC) regions are promising targets for therapeutic applications of non-invasive brain stimulation, e.g. transcranial direct current stimulation (tDCS), which has been proposed as a novel intervention for major depressive disorder (MDD) and negative symptoms of schizophrenia (SCZ). However, the effects of tDCS vary inter-individually, and dose-response relationships have not been established. Stimulation parameters are often tested in healthy subjects and transferred to clinical populations. The current study investigates the variability of individual MRI-based electric fields (e-fields) of standard bifrontal tDCS across individual subjects and diagnoses.Method: The study included 74 subjects, i.e. 25 patients with MDD, 24 patients with SCZ, and 25 healthy controls (HC). Individual e-fields of a common tDCS protocol (i.e. 2 mA stimulation intensity, bifrontal anode-F3/ cathode-F4 montage) were modeled by two investigators using SimNIBS (2.0.1) based on structural MRI scans.Result: On a whole-brain level, the average e-field strength was significantly reduced in MDD and SCZ compared to HC, but MDD and SCZ did not differ significantly. Regions of interest (ROI) analysis for PFC subregions showed reduced e-fields in Sallet areas 8B and 9 for MDD and SCZ compared to HC, whereas there was again no difference between MDD and SCZ. Within groups, we generally observed high inter-individual variability of e-field intensities at a higher percentile of voxels.Conclusion: MRI-based e-field modeling revealed significant differences in e-field strengths between clinical and non-clinical populations in addition to a general inter-individual variability. These findings support the notion that dose-response relationships for tDCS cannot be simply transferred from healthy to clinical cohorts and need to be individually established for clinical groups. In this respect, MRI-based e-field modeling may serve as a proxy for individualized dosing

Investigation of brain networks for personalized rTMS in healthy subjects and patients with major depressive disorder: A translational study

Depression is a complex psychiatric disorder with emotional dysregulation at its core. The first line of treatment includes cognitive behaviour therapy and pharmacological antidepressants. However, up to one third of patients with depression fail to respond to these treatment interventions. The past decades have seen an increasing use of repetitive Transcranial Magnetic Stimulation (rTMS) in clinical studies, as an alternative treatment for depression. Several large-scale, multicentre randomized controlled trials have led the Food and Drugs Administration (FDA), USA to approve two rTMS protocols for clinical application in the treatment of depression - 10 Hz rTMS and intermittent Theta Burst Stimulation (iTBS). However, only 30-50% of patients receiving rTMS respond to the treatment. The large variability in response to rTMS likely stems from multiple reasons, one being the targeting method currently employed for delivering rTMS at the left dorsolateral prefrontal cortex (DLPFC). Previous functional connectivity studies have shown that stimulation at left DLPFC targets with larger negative correlation to the subgenual anterior cingulate cortex (sgACC) may result in greater therapeutic response than those with lower negative correlation. However, current use of rTMS ignores functional connectivity in choosing the left DLPFC target, thus largely discarding functional architectural differences of the brain across subjects. Furthermore, despite widespread clinical use of rTMS, the basic network mechanisms behind these rTMS protocols remain elusive. This work presents a novel personalization method of left DLPFC target selection based on their negative functional connectivity to the sgACC. The default mode network (DMN) is a large-scale brain network commonly involved in self-referential thought processing and plays an essential role in the pathophysiology of depression. I use the novel personalization method and identical study designs to delineate DMN mechanisms from a single session of 10 Hz rTMS and iTBS in healthy subjects. Arguably, an understanding of basic mechanisms of clinically relevant rTMS protocols in healthy subjects will help improve the current therapeutic effect of rTMS, and possibly expand the therapeutic role of rTMS. My work shows, for the first time, strong but different modulations of DMN connectivity by single personalized sessions of 10 Hz rTMS and iTBS. Such modulations can be predicted using the personality trait harm avoidance (HA). Given that initial results show that the method is robust and reproducible, its adaptation to patient cohorts is likely to result in improved therapeutic benefits. Therefore, the novel method of personalization is translated to clinical setting by using accelerated iTBS (aiTBS) in patients with depression. Additionally, a comparison is made between effects resulting from personalized and nonpersonalized (10-20 EEG system F3 position) aiTBS in patients with depression. By evaluating the DMN, and heart rate variability, I show precise modulatory effects of personalized aiTBS, which is not seen in the standard aiTBS group. The work presented here introduces an important method to reduce variability and increase precision in rTMS modulation by personalizing the left DLPFC target selection. Even though DMN and cardiac effects already point towards the advantage of personalization, the still preliminary analysis fails to show significant differences in treatment response. Lack of greater therapeutic benefits viii from personalized aiTBS in this ongoing study probably stems from a still limited sample size. In case personalization proves clinically advantageous to standard iTBS by the final sample size, this work can sediment the first step towards systems medicine in the field of psychiatry.2022-02-0

Investigating the Cortical, Metabolic and Behavioral Effects of Transcranial Direct Current Stimulation in Preparation for Combined Rehabilitation

The goal of this thesis was to determine the cortical reorganization that occurs in patients with cervical spondylotic myelopathy (CSM) after surgical decompression and to implement this knowledge into a new rehabilitation strategy. Transcranial direct current stimulation (tDCS) is a non-invasive technique to modulate human behavior. Due to the novel electrode montage used, it was first pertinent that we determine how tDCS would modulate cortical, metabolic and motor behavior in healthy individuals. We observed the longitudinal functional adaptations that occur in patients with CSM using functional MRI. Enhanced excitation of supplementary motor area (SMA) was observed following surgical decompression and associated with increased function following surgery. This novel finding of enhanced excitation of motivated us to use a bihemispheric tDCS protocol, exciting bilateral motor areas to provide optimal motor enhancement. This novel tDCS electrode montage, targeting the SMA and primary motor cortex (M1) was implemented in healthy older adults to determine its effects on enhancing manual dexterity. Furthermore, to determine the frequency with which to apply tDCS, a single and tri session protocol was used. We observed a differential pattern of action with anti-phase and in-phase motor tasks during multisession tDCS. We used ultra-high field (7T) MRI to examined the metabolic changes that occur following tDCS. After the stimulation period we observed no significant metabolite modulation. A trend towards an increase in the NAA/tCr ratio, with a concomitant decrease in the absolute concentration of tCr was observed. Finally, we examined the functional connectivity before, during and after tDCS with the use of resting-state fMRI at 7T. We observed enhanced connectivity within right sensorimotor area after stimulation compared to during stimulation. This result confirmed that cortical modulations differ during versus after tDCS, signifying that optimal modulation of behaviour may be after the stimulation period. Furthermore, we observed an enhanced correlation between motor regions and the caudate, both during and after stimulation. In conclusion, we observed novel cortical adaptations in CSM patients after surgical decompression, which led us to believe that bihemispheric tDCS of M1-SMA network would result in optimal motor enhancement and warrants further investigation in CSM and other neurological disorders

Der Einfluss von präfrontaler Gleichstromstimulation (tDCS) auf EEG- und fMRT-Ruhenetzwerke

Das Hauptziel der vorliegenden Dissertation war die Untersuchung des Einflusses der präfrontalen Gleichstromstimulation (tDCS) auf die mögliche Modulation kortikaler Netzwerke. Grundlage dieser kumulativen Dissertation sind die Publikationen: - Keeser D, Padberg F, Reisinger E, Pogarell O, Kirsch V, Palm U, Karch S, Möller HJ, Nitsche MA, Mulert C. Prefrontal direct current stimulation modulates resting EEG and event-related potentials in healthy subjects: a standardized low resolution tomography (sLORETA) study. Neuroimage. 2011 Mar 15;55(2):644-57. - Keeser D, Meindl T, Bor J, Palm U, Pogarell O, Mulert C, Brunelin J, Möller HJ, Reiser M, Padberg F. Prefrontal Transcranial Direct Current Stimulation Changes Connectivity of Resting-State Networks during fMRI. Journal of Neuroscience. 2011 Oct 26;31(43):15284-93. Beide Studien wurden doppelt-verblindet und plazebo-kontrolliert durchgeführt. In den Arbeiten wird mit zwei unterschiedlichen Verfahren, einem neurophysiolo-gischen Ruhe- und einem aktiven Gedächtnistestparadigma (EEG), sowie mit einer funktionellen Konnektivitäts-Magnetresonanztomographie (fcMRT) nachgewiesen, dass präfrontale tDCS kortikale Netzwerke moduliert. Diese Ergebnisse sollen hier wiedergegeben und diskutiert werden. Die Verteilung, Ausrichtung und das Aus-maß der auf tDCS beruhenden Effekte auf die Gehirnphysiologie sind bisher wenig erforscht. Die Erarbeitung weiterer spezifischer Hypothesen bezüglich der neuro-physiologischen Wirkung von präfrontaler tDCS ist entscheidend, um Hinweise auf künftige experimentelle und therapeutische tDCS-Anwendungen zu erhalten.The principal purpose of the present thesis was to investigate the influence of prefrontal direct current stimulation (tDCS) on the modulation of cortical networks. The bases of this cumulative thesis are the two publications: - Keeser D, Padberg F, Reisinger E, Pogarell O, Kirsch V, Palm U, Karch S, Möller HJ, Nitsche MA, Mulert C. Prefrontal direct current stimulation modulates resting EEG and event-related potentials in healthy subjects: a standardized low resolution tomography (sLORETA) study. Neuroimage. 2011 Mar 15;55(2):644-57. - Keeser D, Meindl T, Bor J, Palm U, Pogarell O, Mulert C, Brunelin J, Möller HJ, Reiser M, Padberg F. Prefrontal Transcranial Direct Current Stimulation Changes Connectivity of Resting-State Networks during fMRI. Journal of Neuroscience. 2011 Oct 26;31(43):15284-93. Both studies were carried out in a double-blinded, placebo-controlled manner. In the studies two different procedures, a neurophysiological electroencephalog-raphy (EEG) resting-state and an active EEG memory task paradigm, as well as a functional connectivity magnetic resonance imaging (fcMRI) procedure were used. Both studies proved that prefrontal tDCS modulates cortical networks. These results are presented and discussed. The distribution, direction, and extent of tDCS mediated effects on brain physiology are not well understood. The development of further hypotheses with regard to the neurophysiological effects of prefrontal tDCS is crucial to obtain informations for future experimental and therapeutic tDCS applica-tions

Predicting Response to Brain Stimulation in Depression: a Roadmap for Biomarker Discovery

Abstract: Purpose of Review: Clinical response to brain stimulation treatments for depression is highly variable. A major challenge for the field is predicting an individual patient’s likelihood of response. This review synthesises recent developments in neural predictors of response to targeted brain stimulation in depression. It then proposes a framework to evaluate the clinical potential of putative ‘biomarkers’. Recent Findings: Largely, developments in identifying putative predictors emerge from two approaches: data-driven, including machine learning algorithms applied to resting state or structural neuroimaging data, and theory-driven, including task-based neuroimaging. Theory-driven approaches can also yield mechanistic insight into the cognitive processes altered by the intervention. Summary: A pragmatic framework for discovery and testing of biomarkers of brain stimulation response in depression is proposed, involving (1) identification of a cognitive-neural phenotype; (2) confirming its validity as putative biomarker, including out-of-sample replicability and within-subject reliability; (3) establishing the association between this phenotype and treatment response and/or its modifiability with particular brain stimulation interventions via an early-phase randomised controlled trial RCT; and (4) multi-site RCTs of one or more treatment types measuring the generalisability of the biomarker and confirming the superiority of biomarker-selected patients over randomly allocated groups

Adaptability and reproducibility of a memory disruption rTMS protocol in the PharmaCog IMI European project

Transcranial magnetic stimulation (TMS) can interfere with cognitive processes, such as transiently impairing memory. As part of a multi-center European project, we investigated the adaptability and reproducibility of a previously published TMS memory interfering protocol in two centers using EEG or fMRI scenarios. Participants were invited to attend three experimental sessions on different days, with sham repetitive TMS (rTMS) applied on day 1 and real rTMS on days 2 and 3. Sixty-eight healthy young men were included. On each experimental day, volunteers were instructed to remember visual pictures while receiving neuronavigated rTMS trains (20 Hz, 900 ms) during picture encoding at the left dorsolateral prefrontal cortex (L-DLPFC) and the vertex. Mixed ANOVA model analyses were performed. rTMS to the L-DLPFC significantly disrupted recognition memory on experimental day 2. No differences were found between centers or between fMRI and EEG recordings. Subjects with lower baseline memory performances were more susceptible to TMS disruption. No stability of TMS-induced memory interference could be demonstrated on day 3. Our data suggests that adapted cognitive rTMS protocols can be implemented in multi-center studies incorporating standardized experimental procedures. However, our center and modality effects analyses lacked sufficient statistical power, hence highlighting the need to conduct further studies with larger samples. In addition, inter and intra-subject variability in response to TMS might limit its application in crossover or longitudinal studies

Predicting Response to Brain Stimulation in Depression: a Roadmap for Biomarker Discovery

Abstract: Purpose of Review: Clinical response to brain stimulation treatments for depression is highly variable. A major challenge for the field is predicting an individual patient’s likelihood of response. This review synthesises recent developments in neural predictors of response to targeted brain stimulation in depression. It then proposes a framework to evaluate the clinical potential of putative ‘biomarkers’. Recent Findings: Largely, developments in identifying putative predictors emerge from two approaches: data-driven, including machine learning algorithms applied to resting state or structural neuroimaging data, and theory-driven, including task-based neuroimaging. Theory-driven approaches can also yield mechanistic insight into the cognitive processes altered by the intervention. Summary: A pragmatic framework for discovery and testing of biomarkers of brain stimulation response in depression is proposed, involving (1) identification of a cognitive-neural phenotype; (2) confirming its validity as putative biomarker, including out-of-sample replicability and within-subject reliability; (3) establishing the association between this phenotype and treatment response and/or its modifiability with particular brain stimulation interventions via an early-phase randomised controlled trial RCT; and (4) multi-site RCTs of one or more treatment types measuring the generalisability of the biomarker and confirming the superiority of biomarker-selected patients over randomly allocated groups