Daniel Keeser

YNICL Journal 2025 Journal Article

Brain age gap reduction following exercise mirrors clinical improvements in schizophrenia spectrum disorders

• Deniz Yilmaz
• Sergi Papiol
• Daniel Keeser
• James H. Cole
• Berend Malchow
• Henrik Walter
• Andreas Meyer-Lindenberg
• Dusan Hirjak

Schizophrenia spectrum disorders (SSD) are associated with accelerated brain aging, reflected in an increased brain age gap. This gap serves as a biomarker, indicating poorer brain health, cognitive deficits, and greater severity in specific symptom domains. Exercise holds promise as an adjunct therapy to mitigate these deficits by potentially promoting brain recovery. However, the extent of overall improvements in brain health following exercise, along with their predictors and relationships to symptom clusters, are yet to be determined. This study examined the brain age gap metric as a quantitative indicator of brain recovery in response to exercise. To achieve this, we aggregated data from two randomized controlled trials, analyzing baseline (n = 134) and 3- or 6-month post-exercise (n = 46) data from individuals with SSD. Our findings revealed that patients with a higher baseline body mass index (BMI) demonstrated greater brain recovery, as evidenced by a reduced brain age gap post-exercise. Furthermore, changes in the brain age gap were associated with improvements in negative symptoms and cognition, suggesting that reductions in brain-predicted age may reflect symptom relief, particularly in domains beyond positive symptoms. These results underscore the importance of BMI in brain health, support using the brain age gap as a surrogate marker for tracking clinically relevant brain recovery, and highlight the need for stratified interventions and combined lifestyle modifications to enhance outcomes in SSD.

YNICL Journal 2025 Journal Article

Contralateral prefrontal and network engagement during left DLPFC 10 Hz rTMS: an interleaved TMS-fMRI study in healthy adults

• Timo van Hattem
• Kai-Yen Chang
• Martin Tik
• Paul Taylor
• Jonas Björklund
• Lucia Bulubas
• Frank Padberg
• Daniel Keeser

BACKGROUND: High-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) serves as an effective treatment for major depression and other psychiatric disorders. Despite its growing clinical application, the neural mechanisms by which prefrontal rTMS exerts its therapeutic effects remain incompletely understood. To address this gap, we investigated the immediate blood-oxygen-level-dependent (BOLD) activity during 600 stimuli of left DLPFC 10 Hz rTMS in healthy individuals using interleaved TMS-fMRI. METHODS: In a crossover design, 17 healthy subjects received 10 Hz rTMS (60 trains with 9-second intertrain intervals) over the left DLPFC at 40 % and 80 % of their resting motor threshold (rMT) inside the MR scanner. RESULTS: 10 Hz rTMS over the left DLPFC elicited BOLD responses in prefrontal regions, cingulate cortex, insula, striatum, thalamus, as well as auditory and somatosensory areas. Notably, our findings revealed that 10 Hz rTMS effects were lateralized towards the contralateral (right) DLPFC. Dose-response effects between 40 % vs. 80 % rMT were exclusively observed in the hippocampus. CONCLUSIONS: The 10 Hz rTMS protocol used in this study induced distinct target engagement and propagation patterns in the prefrontal cortex. These patterns differ from our previous interleaved TMS-fMRI findings using 600 stimuli of left DLPFC intermittent theta burst stimulation (iTBS) at the same intensities. Thus, interleaved TMS-fMRI emerges as a valuable method for comparing clinical prefrontal rTMS protocols regarding their immediate effect on brain circuits in order to differentiate their action mechanisms and to potentially inform clinical applications.

YNICL Journal 2025 Journal Article

Corrigendum to “Impact of adult-onset multiple sclerosis on MRI-based intracranial volume: A study in clinically discordant monozygotic twins“ [NeuroImage Clin. 42 (2024) 103597]

• Matin Mortazavi
• Lisa Ann Gerdes
• Öznur Hizarci
• Tania Kümpfel
• Katja Anslinger
• Frank Padberg
• Sophia Stöcklein
• Daniel Keeser

YNIMG Journal 2025 Journal Article

How to measure functional connectivity using resting-state fMRI? A comprehensive empirical exploration of different connectivity metrics

• Lukas Roell
• Stephan Wunderlich
• David Roell
• Florian Raabe
• Elias Wagner
• Zhuanghua Shi
• Andrea Schmitt
• Peter Falkai

BACKGROUND: Functional connectivity in the context of functional magnetic resonance imaging is typically quantified by Pearson´s or partial correlation between regional time series of the blood oxygenation level dependent signal. However, a recent interdisciplinary methodological work proposes >230 different metrics to measure similarity between different types of time series. OBJECTIVE: Hence, we systematically evaluated how the results of typical research approaches in functional neuroimaging vary depending on the functional connectivity metric of choice. We further explored which metrics most accurately detect presumed reductions in connectivity related to age and malignant brain tumors, aiming to initiate a debate on the best approaches for assessing brain connectivity in functional neuroimaging research. METHODS: We addressed both research questions using four independent neuroimaging datasets, comprising multimodal data from a total of 1187 individuals. We analyzed resting-state functional sequences to calculate functional connectivity using 20 representative metrics from four distinct mathematical domains. We further used T1- and T2-weighted images to compute regional brain volumes, diffusion-weighted imaging data to build structural connectomes, and pseudo-continuous arterial spin labeling to measure regional brain perfusion. RESULTS: First, our findings demonstrate that the results of typical functional neuroimaging approaches differ fundamentally depending on the functional connectivity metric of choice. Second, we show that correlational and distance metrics are most appropriate to cover reductions in connectivity linked to aging. In this context, partial correlation performs worse than other correlational metrics. Third, our findings suggest that the FC metric of choice depends on the utilized scanning parameters, the regions of interest, and the individual investigated. Lastly, beyond the major objective of this study, we provide evidence in favor of brain perfusion measured via pseudo-continuous arterial spin labeling as a robust neural entity mirroring age-related neural and cognitive decline. CONCLUSION: Our empirical evaluation supports a recent theoretical functional connectivity framework. Future functional imaging studies need to comprehensively define the study-specific theoretical property of interest, the methodological property to assess the theoretical property, and the confounding property that may bias the conclusions.

YNICL Journal 2025 Journal Article

Neural processing of social reciprocity in autism

• Afton M. Bierlich
• Irene Sophia Plank
• Nanja T. Scheel
• Daniel Keeser
• Christine M. Falter-Wagner

Social reciprocity and interpersonal synchrony implicitly mediate social interactions to facilitate natural exchanges. These processes are altered in autism, but it is unclear how such alterations manifest at the neural level during social interaction processing. Using task-based fMRI, we investigated the neural correlates of interpersonal synchrony during basic reciprocal interactions in a preregistered study. Participants communicated with a virtual partner by sending visual signals. Analyses showed comparable activation patterns and experienced synchrony ratings between autistic and non-autistic participants, as well as between interactions with virtual partners who had high or low synchronous responses. An exploratory whole brain analysis for the effect of task revealed significant activation of the inferior frontal gyrus, insular cortex, and anterior inferior parietal lobe; areas associated with cognitive control, rhythmic temporal coordination, and action observation. This activation was independent of the virtual partner's response synchrony and was similar for autistic and non-autistic participants. These results provide an initial look into the neural basis of processing social reciprocity in autism, particularly when individuals are part of an interaction, and hint that the neural processing of social reciprocity may be spared in autism when their partners' behavior is predictable.

YNICL Journal 2024 Journal Article

Impact of adult-onset multiple sclerosis on MRI-based intracranial volume: A study in clinically discordant monozygotic twins

• Matin Mortazavi
• Lisa Ann Gerdes
• Öznur Hizarci
• Tania Kümpfel
• Katja Anslinger
• Frank Padberg
• Sophia Stöcklein
• Daniel Keeser

OBJECTIVE: Intracranial volume (ICV) represents the maximal brain volume for an individual, attained prior to late adolescence and remaining constant throughout life after. Thus, ICV serves as a surrogate marker for brain growth integrity. To assess the potential impact of adult-onset multiple sclerosis (MS) and its preceding prodromal subclinical changes on ICV in a large cohort of monozygotic twins clinically discordant for MS. METHODS: FSL software was used to derive ICV estimates from 3D-T1-weighted-3 T-MRI images by using an atlas scaling factor method. ICV were compared between clinically affected and healthy co-twins. All twins were compared to a large healthy reference cohort using standardized ICV z-scores. Mixed models assessed the impact of age at MS diagnosis on ICV. RESULTS: ). Younger age at MS diagnosis was strongly associated with lower ICVs (t = 3.76, P = 0.0003). Stratification of twin-pairs by age at MS diagnosis of the affected co-twin (≤30 versus > 30 years) yielded lower ICVs in those twin pairs with younger age at diagnosis (P = 0.01). Comparison within individual twin-pairs identified lower ICVs in the MS-affected co-twins with younger age at diagnosis compared to their corresponding healthy co-twins (P = 0.003). CONCLUSION: We offer for the first-time evidence for strong associations between adult-onset MS and lower ICV, which is more pronounced with younger age at diagnosis. This suggests pre-clinical alterations in early neurodevelopment associated with susceptibility to MS both in individuals with and without clinical manifestation of the disease.

YNIMG Journal 2024 Journal Article

Neural response during prefrontal theta burst stimulation: Interleaved TMS-fMRI of full iTBS protocols

• Kai-Yen Chang
• Martin Tik
• Yuki Mizutani-Tiebel
• Anna-Lisa Schuler
• Paul Taylor
• Mattia Campana
• Ulrike Vogelmann
• Barbara Huber

BACKGROUND: Left prefrontal intermittent theta-burst stimulation (iTBS) has emerged as a safe and effective transcranial magnetic stimulation (TMS) treatment protocol in depression. Though network effects after iTBS have been widely studied, the deeper mechanistic understanding of target engagement is still at its beginning. Here, we investigate the feasibility of a novel integrated TMS-fMRI setup and accelerated echo planar imaging protocol to directly observe the immediate effects of full iTBS treatment sessions. OBJECTIVE/HYPOTHESIS: In our effort to explore interleaved iTBS-fMRI feasibility, we hypothesize that TMS will induce acute BOLD signal changes in both the stimulated area and interconnected neural regions. METHODS: Concurrent TMS-fMRI with full sessions of neuronavigated iTBS (i.e. 600 pulses) of the left dorsolateral prefrontal cortex (DLPFC) was investigated in 18 healthy participants. In addition, we conducted four TMS-fMRI sessions in a single patient on long-term maintenance iTBS for bipolar depression to test the transfer to clinical cases. RESULTS: Concurrent TMS-fMRI was feasible for iTBS sequences with 600 pulses. During interleaved iTBS-fMRI, an increase of the BOLD signal was observed in a network including bilateral DLPFC regions. In the clinical case, a reduced BOLD response was found in the left DLPFC and the subgenual anterior cingulate cortex, with high variability across individual sessions. CONCLUSIONS: Full iTBS sessions as applied for the treatment of depressive disorders can be established in the interleaved iTBS-fMRI paradigm. In the future, this experimental approach could be valuable in clinical samples, for demonstrating target engagement by iTBS protocols and investigating their mechanisms of therapeutic action.

YNICL Journal 2023 Journal Article

Neurofunctional differences and similarities between persistent postural-perceptual dizziness and anxiety disorder

• Maximilian Maywald
• Oliver Pogarell
• Susanne Levai
• Marco Paolini
• Nadja Tschentscher
• Boris Stephan Rauchmann
• Daniela Krause
• Sophia Stöcklein

INTRODUCTION: Persistent postural-perceptual dizziness (PPPD) (ICD-11) and anxiety disorders (ANX) share behavioural symptoms like anxiety, avoidance, social withdrawal, hyperarousal, or palpitation as well as neurological symptoms like vertigo, stance and gait disorders. Furthermore, previous studies have shown a bidirectional link between vestibulo-spatial and anxiety neural networks. So far, there have been no neuroimaging-studies comparing these groups. OBJECTIVES: The aim of this explorative study was to investigate differences and similarities of neural correlates between these two patient groups and to compare their findings with a healthy control group. METHODS: 63 participants, divided in two patient groups (ANX = 20 and PPPD = 14) and two sex and age matched healthy control groups (HC-A = 16, HC-P = 13) were included. Anxiety and dizziness related pictures were shown during fMRI-measurements in a block-design in order to induce emotional responses. All subjects filled in questionnaires regarding vertigo (VSS, VHQ), anxiety (STAI), depression (BDI-II), alexithymia (TAS), and illness-perception (IPQ). After modelling the BOLD response with a standard canonical HRF, voxel-wise t-tests between conditions (emotional-negative vs neutral stimuli) were used to generate statistical contrast maps and identify relevant brain areas (pFDR 30 voxels). ROI-analyses were performed for amygdala, cingulate gyrus, hippocampus, inferior frontal gyrus, insula, supramarginal gyrus and thalamus (p ≤ 0.05). RESULTS: Patient groups differed from both HC groups regarding anxiety, dizziness, depression and alexithymia scores; ratings of the PPPD group and the ANX group did differ significantly only in the VSS subscale 'vertigo and related symptoms' (VSS-VER). The PPPD group showed increased neural responses in the vestibulo-spatial network, especially in the supramarginal gyrus (SMG), and superior temporal gyrus (STG), compared to ANX and HC-P group. The PPPD group showed increased neural responses compared to the HC-P group in the anxiety network including amygdala, insula, lentiform gyrus, hippocampus, inferior frontal gyrus (IFG) and brainstem. Neuronal responses were enhanced in visual structures, e.g. fusiform gyrus, middle occipital gyrus, and in the medial orbitofrontal cortex (mOFC) in healthy controls compared to patients with ANX and PPPD, and in the ANX group compared to the PPPD group. CONCLUSIONS: These findings indicate that neuronal responses to emotional information in the PPPD and the ANX group are comparable in anxiety networks but not in vestibulo-spatial networks. Patients with PPPD revealed a stronger neuronal response especially in SMG and STG compared to the ANX and the HC group. These results might suggest higher sensitivity and poorer adaptation processes in the PPPD group to anxiety and dizziness related pictures. Stronger activation in visual processing areas in HC subjects might be due to less emotional and more visual processing strategies.

YNICL Journal 2022 Journal Article

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

• Yuki Mizutani-Tiebel
• Shun Takahashi
• Temmuz Karali
• Eva Mezger
• Lucia Bulubas
• Irina Papazova
• Esther Dechantsreiter
• Sophia Stoecklein

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.

YNICL Journal 2021 Journal Article

Multiple sclerosis and subclinical neuropathology in healthy individuals with familial risk: A scoping review of MRI studies

• Matin Mortazavi
• Öznur Hizarci
• Lisa Ann Gerdes
• Joachim Havla
• Tania Kümpfel
• Reinhard Hohlfeld
• Sophia Stöcklein
• Daniel Keeser

Multiple genetic and non-heritable factors have been linked to the risk of multiple sclerosis (MS). These factors seem to contribute to disease pathogenesis before the onset of clinical symptoms, as suggested by incidental MRI evidence of subclinical MS neuropathology in individuals without clinical symptoms. Individuals with high familial risk for MS, such as first-degree relatives of patients with MS, can be studied by MRI to characterize the neuropathology during a subclinical period of MS. 16 studies published in English, which performed brain MRI on healthy individuals with high familial risk of MS were included in this scoping review. Studies suggest either no conclusive (5), or inconclusive yet considerable (4), or conclusive evidence (7) for the incidence of subclinical neuropathology, including focal and diffuse tissue damage. Across all studies, white matter lesions fulfilling MS criteria were observed in 86 of 613 individuals (14%). Future research is needed to evaluate the longitudinal dynamics and clinical relevance of preclinical imaging abnormalities in MS.

YNIMG Journal 2017 Journal Article

Test-retest reliability of prefrontal transcranial Direct Current Stimulation (tDCS) effects on functional MRI connectivity in healthy subjects

• Jana Wörsching
• Frank Padberg
• Konstantin Helbich
• Alkomiet Hasan
• Lena Koch
• Stephan Goerigk
• Sophia Stoecklein
• Birgit Ertl-Wagner

Transcranial Direct Current Stimulation (tDCS) of the prefrontal cortex (PFC) can be used for probing functional brain connectivity and meets general interest as novel therapeutic intervention in psychiatric and neurological disorders. Along with a more extensive use, it is important to understand the interplay between neural systems and stimulation protocols requiring basic methodological work. Here, we examined the test-retest (TRT) characteristics of tDCS-induced modulations in resting-state functional-connectivity MRI (RS fcMRI). Twenty healthy subjects received 20minutes of either active or sham tDCS of the dorsolateral PFC (2mA, anode over F3 and cathode over F4, international 10–20 system), preceded and ensued by a RS fcMRI (10minutes each). All subject underwent three tDCS sessions with one-week intervals in between. Effects of tDCS on RS fcMRI were determined at an individual as well as at a group level using both ROI-based and independent-component analyses (ICA). To evaluate the TRT reliability of individual active-tDCS and sham effects on RS fcMRI, voxel-wise intra-class correlation coefficients (ICC) of post-tDCS maps between testing sessions were calculated. For both approaches, results revealed low reliability of RS fcMRI after active tDCS (ICC(2, 1) = −0. 09 – 0. 16). Reliability of RS fcMRI (baselines only) was low to moderate for ROI-derived (ICC(2, 1) = 0. 13 – 0. 50) and low for ICA-derived connectivity (ICC(2, 1) = 0. 19 – 0. 34). Thus, for ROI-based analyses, the distribution of voxel-wise ICC was shifted to lower TRT reliability after active, but not after sham tDCS, for which the distribution was similar to baseline. The intra-individual variation observed here resembles variability of tDCS effects in motor regions and may be one reason why in this study robust tDCS effects at a group level were missing. The data can be used for appropriately designing large scale studies investigating methodological issues such as sources of variability and localisation of tDCS effects.

YNIMG Journal 2013 Journal Article

Classifying fMRI-derived resting-state connectivity patterns according to their daily rhythmicity

• Janusch Blautzik
• Céline Vetter
• Isabella Peres
• Evgeny Gutyrchik
• Daniel Keeser
• Albert Berman
• Valerie Kirsch
• Sophia Mueller

The vast majority of biological functions express rhythmic fluctuations across the 24-hour day. We investigated the degree of daily modulation across fMRI (functional Magnetic Resonance Imaging) derived resting-state data in 15 subjects by evaluating the time courses of 20 connectivity patterns over 8h (4 sessions). For each subject, we determined the chronotype, which describes the relationship between the individual circadian rhythm and the local time. We could therefore analyze the daily time course of the connectivity patterns controlling for internal time. Furthermore, as the participants' scan times were staggered as a function of their chronotype, we prevented sleep deprivation and kept time awake constant across subjects. Individual functional connectivity within each connectivity pattern was defined at each session as connectivity strength measured by a mean z-value and, in addition, as the spatial extent expressed by the number of activated voxels. Highly rhythmic connectivity patterns included two sub-systems of the Default-Mode Network (DMN) and a network extending over sensori-motor regions. The network characterized as the most stable across the day is mainly associated with processing of executive control. We conclude that the degree of daily modulation largely varies across fMRI derived resting-state connectivity patterns, ranging from highly rhythmic to stable. This finding should be considered when interpreting results from fMRI studies.