David E.J. Linden

YNICL Journal 2023 Journal Article

The association of prediabetes and type 2 diabetes with hippocampal subfields volume: The Maastricht study

• Jennifer Monereo-Sánchez
• Jacobus F.A. Jansen
• Sebastian Köhler
• Martin P.J. van Boxtel
• Walter H. Backes
• Coen D.A. Stehouwer
• Abraham A. Kroon
• Jeroen P. Kooman

AIMS/HYPOTHESIS: We investigated whether prediabetes, type 2 diabetes, and continuous measures of hyperglycemia are associated with tissue volume differences in specific subfields of the hippocampus. METHODS: We used cross-sectional data from 4,724 participants (58.7 ± 8.5 years, 51.5% women) of The Maastricht Study, a population-based prospective cohort. Glucose metabolism status was assessed with an oral glucose tolerance test, and defined as type 2 diabetes (n = 869), prediabetes (n = 671), or normal glucose metabolism (n = 3184). We extracted 12 hippocampal subfield volumes per hemisphere with FreeSurfer v6.0 using T1w and FLAIR 3T MRI images. We used multiple linear regression and linear trend analysis, and adjusted for total intracranial volume, demographic, lifestyle, and cardiovascular risk factors. RESULTS: Type 2 diabetes was significantly associated with smaller volumes in the hippocampal subfield fimbria (standardized beta coefficient ± standard error (β ± SE) = -0.195 ± 0.04, p-value < 0.001), the hippocampus proper, i.e. Cornu Ammonis (CA) 1, CA2/3, CA4, dentate gyrus, subiculum and presubiculum (β ± SE < -0.105 ± 0.04, p-value < 0.006); as well as the hippocampal tail (β ± SE = -0.162 ± 0.04, p-value < 0.001). Prediabetes showed no significant associations. However, linear trend analysis indicated a dose-response relation from normal glucose metabolism, to prediabetes, to type 2 diabetes. Multiple continuous measures of hyperglycemia were associated with smaller volumes of the subfields fimbria (β ± SE < -0.010 ± 0.011, p-value < 0.001), dentate gyrus (β ± SE < -0.013 ± 0.010, p-value < 0.002), CA3 (β ± SE < -0.014 ± 0.011, p-value < 0.001), and tail (β ± SE < -0.006 ± 0.012, p-value < 0.003). CONCLUSIONS/INTERPRETATION: Type 2 diabetes and measures of hyperglycemia are associated with hippocampal subfield atrophy, independently of lifestyle and cardiovascular risk factors. We found evidence for a dose-response relationship from normal glucose metabolism, to prediabetes, to type 2 diabetes. Prediabetes stages could give a window of opportunity for the early prevention of brain disease.

YNIMG Journal 2022 Journal Article

Uncovering hidden resting state dynamics: A new perspective on auditory verbal hallucinations

• Hanna Honcamp
• Michael Schwartze
• David E.J. Linden
• Wael El-Deredy
• Sonja A. Kotz

In the absence of sensory stimulation, the brain transits between distinct functional networks. Network dynamics such as transition patterns and the time the brain stays in each network link to cognition and behavior and are subject to much investigation. Auditory verbal hallucinations (AVH), the temporally fluctuating unprovoked experience of hearing voices, are associated with aberrant resting state network activity. However, we lack a clear understanding of how different networks contribute to aberrant activity over time. An accurate characterization of latent network dynamics and their relation to neurocognitive changes necessitates methods that capture the sub-second temporal fluctuations of the networks' functional connectivity signatures. Here, we critically evaluate the assumptions and sensitivity of several approaches commonly used to assess temporal dynamics of brain connectivity states in M/EEG and fMRI research, highlighting methodological constraints and their clinical relevance to AVH. Identifying altered brain connectivity states linked to AVH can facilitate the detection of predictive disease markers and ultimately be valuable for generating individual risk profiles, differential diagnosis, targeted intervention, and treatment strategies.

YNICL Journal 2021 Journal Article

Amygdala electrical-finger-print (AmygEFP) NeuroFeedback guided by individually-tailored Trauma script for post-traumatic stress disorder: Proof-of-concept

• Tom Fruchtman-Steinbok
• Jackob N. Keynan
• Avihay Cohen
• Iman Jaljuli
• Shiri Mermelstein
• Gadi Drori
• Efrat Routledge
• Michael Krasnoshtein

BACKGROUND: Amygdala activity dysregulation plays a central role in post-traumatic stress disorder (PTSD). Hence learning to self-regulate one's amygdala activity may facilitate recovery. PTSD is further characterized by abnormal contextual processing related to the traumatic memory. Therefore, provoking the personal traumatic narrative while training amygdala down-regulation could enhance clinical efficacy. We report the results of a randomized controlled trial (NCT02544971) of a novel self-neuromodulation procedure (i.e. NeuroFeedback) for PTSD, aimed at down-regulating limbic activity while receiving feedback from an auditory script of a personal traumatic narrative. To scale-up applicability, neural activity was probed by an fMRI-informed EEG model of amygdala activity, termed Amygdala Electrical Finger-Print (AmygEFP). METHODS: Fifty-nine adults meeting DSM-5 criteria for PTSD were randomized between three groups: Trauma-script feedback interface (Trauma-NF) or Neutral feedback interface (Neutral-NF), and a control group of No-NF (to control for spontaneous recovery). Before and immediately after 15 NF training sessions patients were blindly assessed for PTSD symptoms and underwent one session of amygdala fMRI-NF for transferability testing. Follow-up clinical assessment was performed at 3- and 6-months following NF treatment. RESULTS: Patients in both NF groups learned to volitionally down-regulate AmygEFP signal and demonstrated a greater reduction in PTSD symptoms and improved down-regulation of the amygdala during fMRI-NF, compared to the No-NF group. The Trauma-NF group presented the largest immediate clinical improvement. CONCLUSIONS: This proof-of-concept study indicates the feasibility of the AmygEFP-NF process-driven as a scalable intervention for PTSD and illustrates its clinical potential. Further investigation is warranted to elucidate the contribution of AmygEFP-NF beyond exposure and placebo effects.

YNIMG Journal 2021 Journal Article

Quality control strategies for brain MRI segmentation and parcellation: Practical approaches and recommendations - insights from the Maastricht study

• Jennifer Monereo-Sánchez
• Joost J.A. de Jong
• Gerhard S. Drenthen
• Magdalena Beran
• Walter H. Backes
• Coen D.A. Stehouwer
• Miranda T. Schram
• David E.J. Linden

Quality control of brain segmentation is a fundamental step to ensure data quality. Manual quality control strategies are the current gold standard, although these may be unfeasible for large neuroimaging samples. Several options for automated quality control have been proposed, providing potential time efficient and reproducible alternatives. However, those have never been compared side to side, which prevents consensus in the appropriate quality control strategy to use. This study aimed to elucidate the changes manual editing of brain segmentations produce in morphological estimates, and to analyze and compare the effects of different quality control strategies on the reduction of the measurement error. Structural brain MRI from 259 participants of The Maastricht Study were used. Morphological estimates were automatically extracted using FreeSurfer 6.0. Segmentations with inaccuracies were manually edited, and morphological estimates were compared before and after editing. In parallel, 12 quality control strategies were applied to the full sample. Those included: two manual strategies, in which images were visually inspected and either excluded or manually edited; five automated strategies, where outliers were excluded based on the tools "MRIQC" and "Qoala-T", and the metrics "morphological global measures", "Euler numbers" and "Contrast-to-Noise ratio"; and five semi-automated strategies, where the outliers detected through the mentioned tools and metrics were not excluded, but visually inspected and manually edited. In order to quantify the effects of each quality control strategy, the proportion of unexplained variance relative to the total variance was extracted after the application of each strategy, and the resulting differences compared. Manually editing brain surfaces produced particularly large changes in subcortical brain volumes and moderate changes in cortical surface area, thickness and hippocampal volumes. The performance of the quality control strategies depended on the morphological measure of interest. Overall, manual quality control strategies yielded the largest reduction in relative unexplained variance. The best performing automated alternatives were those based on Euler numbers and MRIQC scores. The exclusion of outliers based on global morphological measures produced an increase of relative unexplained variance. Manual quality control strategies are the most reliable solution for quality control of brain segmentation and parcellation. However, measures must be taken to prevent the subjectivity associated with these strategies. The detection of inaccurate segmentations based on Euler numbers or MRIQC provides a time efficient and reproducible alternative. The exclusion of outliers based on global morphological estimates must be avoided.

YNICL Journal 2020 Journal Article

A systematic review of fMRI neurofeedback reporting and effects in clinical populations

• Anita Tursic
• Judith Eck
• Michael Lührs
• David E.J. Linden
• Rainer Goebel

Real-time fMRI-based neurofeedback is a relatively young field with a potential to impact the currently available treatments of various disorders. In order to evaluate the evidence of clinical benefits and investigate how consistently studies report their methods and results, an exhaustive search of fMRI neurofeedback studies in clinical populations was performed. Reporting was evaluated using a limited number of Consensus on the reporting and experimental design of clinical and cognitive-behavioral neurofeedback studies (CRED-NF checklist) items, which was, together with a statistical power and sensitivity calculation, used to also evaluate the existing evidence of the neurofeedback benefits on clinical measures. The 62 found studies investigated regulation abilities and/or clinical benefits in a wide range of disorders, but with small sample sizes and were therefore unable to detect small effects. Most points from the CRED-NF checklist were adequately reported by the majority of the studies, but some improvements are suggested for the reporting of group comparisons and relations between regulation success and clinical benefits. To establish fMRI neurofeedback as a clinical tool, more emphasis should be placed in the future on using larger sample sizes determined through a priori power calculations and standardization of procedures and reporting.

YNIMG Journal 2019 Journal Article

Control freaks: Towards optimal selection of control conditions for fMRI neurofeedback studies

• Bettina Sorger
• Frank Scharnowski
• David E.J. Linden
• Michelle Hampson
• Kymberly D. Young

fMRI Neurofeedback research employs many different control conditions. Currently, there is no consensus as to which control condition is best, and the answer depends on what aspects of the neurofeedback-training design one is trying to control for. These aspects can range from determining whether participants can learn to control brain activity via neurofeedback to determining whether there are clinically significant effects of the neurofeedback intervention. Lack of consensus over criteria for control conditions has hampered the design and interpretation of studies employing neurofeedback protocols. This paper presents an overview of the most commonly employed control conditions currently used in neurofeedback studies and discusses their advantages and disadvantages. Control conditions covered include no control, treatment-as-usual, bidirectional-regulation control, feedback of an alternative brain signal, sham feedback, and mental-rehearsal control. We conclude that the selection of the control condition(s) should be determined by the specific research goal of the study and best procedures that effectively control for relevant confounding factors.

YNIMG Journal 2019 Journal Article

The BOLD response in primary motor cortex and supplementary motor area during kinesthetic motor imagery based graded fMRI neurofeedback

• David M.A. Mehler
• Angharad N. Williams
• Florian Krause
• Michael Lührs
• Richard G. Wise
• Duncan L. Turner
• David E.J. Linden
• Joseph R. Whittaker

There is increasing interest in exploring the use of functional MRI neurofeedback (fMRI-NF) as a therapeutic technique for a range of neurological conditions such as stroke and Parkinson's disease (PD). One main therapeutic potential of fMRI-NF is to enhance volitional control of damaged or dysfunctional neural nodes and networks via a closed-loop feedback model using mental imagery as the catalyst of self-regulation. The choice of target node/network and direction of regulation (increase or decrease activity) are central design considerations in fMRI-NF studies. Whilst it remains unclear whether the primary motor cortex (M1) can be activated during motor imagery, the supplementary motor area (SMA) has been robustly activated during motor imagery. Such differences in the regulation potential between primary and supplementary motor cortex are important because these areas can be differentially affected by a stroke or PD, and the choice of fMRI-NF target and grade of self-regulation of activity likely have substantial influence on the clinical effects and cost effectiveness of NF-based interventions. In this study we therefore investigated firstly whether healthy subjects would be able to achieve self-regulation of the hand-representation areas of M1 and the SMA using fMRI-NF training. There was a significant decrease in M1 neural activity during fMRI-NF, whereas SMA neural activity was increased, albeit not with the predicated graded effect. This study has important implications for fMRI-NF protocols that employ motor imagery to modulate activity in specific target regions of the brain and to determine how they may be tailored for neurorehabilitation.

YNICL Journal 2017 Journal Article

Reduced intrinsic visual cortical connectivity is associated with impaired perceptual closure in schizophrenia

• Vincent van de Ven
• Anna Rotarska Jagiela
• Viola Oertel-Knöchel
• David E.J. Linden

Sensory perceptual processing deficits, such as impaired visual object identification and perceptual closure, have been reported in schizophrenia. These perceptual impairments may be associated with neural deficits in visual association areas, including lateral occipital cortex and inferior temporal areas. However, it remains unknown if such deficits can be found in the intrinsic architecture of the visual system. In the current study, we measured perceptual closure performance and resting-state functional connectivity using functional magnetic resonance imaging (FMRI) in 16 schizophrenia patients and 16 matched healthy controls. We estimated intrinsic functional connectivity using self-organized grouping spatial ICA, which clusters component maps in the subject space according to spatial similarity. Patients performed worse than controls in the perceptual closure task. This impaired closure performance of patients was correlated with increased severity of psychotic symptoms. We also found that intrinsic connectivity of the visual processing system was diminished in patients compared to controls. Lower perceptual closure performance was correlated to lower visual cortical intrinsic connectivity overall. We suggest that schizophrenia is associated with impaired intrinsic connectivity of the visual system, and that it is a potential mechanism leading to impaired visual object perception. These findings contribute to increasing evidence for impairments of higher visual functions in schizophrenia.

YNIMG Journal 2016 Journal Article

Meta-analysis of real-time fMRI neurofeedback studies using individual participant data: How is brain regulation mediated?

• Kirsten Emmert
• Rotem Kopel
• James Sulzer
• Annette B. Brühl
• Brian D. Berman
• David E.J. Linden
• Silvina G. Horovitz
• Markus Breimhorst

An increasing number of studies using real-time fMRI neurofeedback have demonstrated that successful regulation of neural activity is possible in various brain regions. Since these studies focused on the regulated region(s), little is known about the target-independent mechanisms associated with neurofeedback-guided control of brain activation, i. e. the regulating network. While the specificity of the activation during self-regulation is an important factor, no study has effectively determined the network involved in self-regulation in general. In an effort to detect regions that are responsible for the act of brain regulation, we performed a post-hoc analysis of data involving different target regions based on studies from different research groups. We included twelve suitable studies that examined nine different target regions amounting to a total of 175 subjects and 899 neurofeedback runs. Data analysis included a standard first- (single subject, extracting main paradigm) and second-level (single subject, all runs) general linear model (GLM) analysis of all participants taking into account the individual timing. Subsequently, at the third level, a random effects model GLM included all subjects of all studies, resulting in an overall mixed effects model. Since four of the twelve studies had a reduced field of view (FoV), we repeated the same analysis in a subsample of eight studies that had a well-overlapping FoV to obtain a more global picture of self-regulation. The GLM analysis revealed that the anterior insula as well as the basal ganglia, notably the striatum, were consistently active during the regulation of brain activation across the studies. The anterior insula has been implicated in interoceptive awareness of the body and cognitive control. Basal ganglia are involved in procedural learning, visuomotor integration and other higher cognitive processes including motivation. The larger FoV analysis yielded additional activations in the anterior cingulate cortex, the dorsolateral and ventrolateral prefrontal cortex, the temporo-parietal area and the visual association areas including the temporo-occipital junction. In conclusion, we demonstrate that several key regions, such as the anterior insula and the basal ganglia, are consistently activated during self-regulation in real-time fMRI neurofeedback independent of the targeted region-of-interest. Our results imply that if the real-time fMRI neurofeedback studies target regions of this regulation network, such as the anterior insula, care should be given whether activation changes are related to successful regulation, or related to the regulation process per se. Furthermore, future research is needed to determine how activation within this regulation network is related to neurofeedback success.

YNIMG Journal 2016 Journal Article

Using real-time fMRI to influence effective connectivity in the developing emotion regulation network

• Kathrin Cohen Kadosh
• Qiang Luo
• Calem de Burca
• Moses O. Sokunbi
• Jianfeng Feng
• David E.J. Linden
• Jennifer Y.F. Lau

For most people, adolescence is synonymous with emotional turmoil and it has been shown that early difficulties with emotion regulation can lead to persistent problems for some people. This suggests that intervention during development might reduce long-term negative consequences for those individuals. Recent research has highlighted the suitability of real-time fMRI-based neurofeedback (NF) in training emotion regulation (ER) networks in adults. However, its usefulness in directly influencing plasticity in the maturing ER networks remains unclear. Here, we used NF to teach a group of 17 7–16 year-olds to up-regulate the bilateral insula, a key ER region. We found that all participants learned to increase activation during the up-regulation trials in comparison to the down-regulation trials. Importantly, a subsequent Granger causality analysis of Granger information flow within the wider ER network found that during up-regulation trials, bottom-up driven Granger information flow increased from the amygdala to the bilateral insula and from the left insula to the mid-cingulate cortex, supplementary motor area and the inferior parietal lobe. This was reversed during the down-regulation trials, where we observed an increase in top-down driven Granger information flow to the bilateral insula from mid-cingulate cortex, pre-central gyrus and inferior parietal lobule. This suggests that: 1) NF training had a differential effect on up-regulation vs down-regulation network connections, and that 2) our training was not only superficially concentrated on surface effects but also relevant with regards to the underlying neurocognitive bases. Together these findings highlight the feasibility of using NF in children and adolescents and its possible use for shaping key social cognitive networks during development.

YNIMG Journal 2015 Journal Article

Elevated P3b latency variability in carriers of ZNF804A risk allele for psychosis

• Christopher W.N. Saville
• Thomas M. Lancaster
• Timothy J. Davies
• Maida Toumaian
• Eleni Pappa
• Simon Fish
• Bernd Feige
• Stephan Bender

Increased intra-subject variability (ISV) in reaction times (RTs) is a candidate endophenotype for several psychiatric and neurological conditions, including schizophrenia. ISV reflects the degree of variability in RTs and is thought to be an index of the stability of cognition. It is generally assumed to have the same underlying physiological basis across conditions, but recent evidence raises the possibility that the neural underpinnings of ISV vary with aetiology. Combining genetics with single-trial event-related potentials is an ideal method for investigating the neural basis of ISV in groups where ISV may vary for relatively homogenous reasons. Here we examine the association between P3b latency variability and a polymorphism on the ZNF804A gene associated with psychosis. Ninety-one healthy volunteers genotyped for rs1344706, a polymorphism on ZNF804A, had electroencephalographic data recorded while carrying out three n-back tasks. Data were analysed with a single-trial approach and latency variability of the P3b was compared between the AA homozygous risk group (N=30) and C allele carriers (N=61). P3b latencies were more variable for AA carriers than C carriers. Behavioural ISV, however, was not associated with genotype. The increase in neurophysiological variability, unaccompanied by increased behavioural variability, suggests that this risk gene is associated with an attenuated form of an endophenotype associated with the psychosis phenotype. The increase in both stimulus and response-locked variability also contrasts with previous work into attention-deficit hyperactivity disorder, where only response-locked P3b variability was elevated, suggesting that increased ISV may not signify the same underlying processes in all conditions with which it is associated.

YNICL Journal 2015 Journal Article

Schizophrenia risk variants modulate white matter volume across the psychosis spectrum: Evidence from two independent cohorts

• Viola Oertel-Knöchel
• Thomas M. Lancaster
• Christian Knöchel
• Michael Stäblein
• Helena Storchak
• Britta Reinke
• Alina Jurcoane
• Jonathan Kniep

Polygenic risk scores, based on risk variants identified in genome-wide-association-studies (GWAS), explain a considerable portion of the heritability for schizophrenia (SZ) and bipolar disorder (BD). However, little is known about the combined effects of these variants, although polygenic neuroimaging has developed into a powerful tool of translational neuroscience. In this study, we used genome wide significant SZ risk variants to test the predictive capacity of the polygenic model and explored potential associations with white matter volume, a key candidate in imaging phenotype for psychotic disorders. By calculating the combined additive schizophrenia risk of seven SNPs (significant hits from a recent schizophrenia GWAS study), we show that increased additive genetic risk for SZ was associated with reduced white matter volume in a group of participants (n = 94) consisting of healthy individuals, SZ first-degree relatives, SZ patients and BD patients. This effect was also seen in a second independent sample of healthy individuals (n = 89). We suggest that a moderate portion of variance (~4%) of white matter volume can be explained by the seven hits from the recent schizophrenia GWAS. These results provide evidence for associations between cumulative genetic risk for schizophrenia and intermediate neuroimaging phenotypes in models of psychosis. Our work contributes to a growing body of literature suggesting that polygenic risk may help to explain white matter alterations associated with familial risk for psychosis.

YNICL Journal 2014 Journal Article

Multimodal assessments of the hippocampal formation in schizophrenia and bipolar disorder: Evidences from neurobehavioral measures and functional and structural MRI

• Christian Knöchel
• Michael Stäblein
• Helena Storchak
• Britta Reinke
• Alina Jurcoane
• David Prvulovic
• David E.J. Linden
• Vincent van de Ven

A potential clinical and etiological overlap between schizophrenia (SZ) and bipolar disorder (BD) has long been a subject of discussion. Imaging studies imply functional and structural alterations of the hippocampus in both diseases. Thus, imaging this core memory region could provide insight into the pathophysiology of these disorders and the associated cognitive deficits. To examine possible shared alterations in the hippocampus, we conducted a multi-modal assessment, including functional and structural imaging as well as neurobehavioral measures of memory performance in BD and SZ patients compared with healthy controls. We assessed episodic memory performance, using tests of verbal and visual learning (HVLT, BVMT) in three groups of participants: BD patients (n = 21), SZ patients (n = 21) and matched (age, gender, education) healthy control subjects (n = 21). In addition, we examined hippocampal resting state functional connectivity, hippocampal volume using voxel-based morphometry (VBM) and fibre integrity of hippocampal connections using diffusion tensor imaging (DTI). We found memory deficits, changes in functional connectivity within the hippocampal network as well as volumetric reductions and altered white matter fibre integrity across patient groups in comparison with controls. However, SZ patients when directly compared with BD patients were more severely affected in several of the assessed parameters (verbal learning, left hippocampal volumes, mean diffusivity of bilateral cingulum and right uncinated fasciculus). The results of our study suggest a graded expression of verbal learning deficits accompanied by structural alterations within the hippocampus in BD patients and SZ patients, with SZ patients being more strongly affected. Our findings imply that these two disorders may share some common pathophysiological mechanisms. The results could thus help to further advance and integrate current pathophysiological models of SZ and BD.

YNIMG Journal 2014 Journal Article

Replication of brain function effects of a genome-wide supported psychiatric risk variant in the CACNA1C gene and new multi-locus effects

• Susanne Erk
• Andreas Meyer-Lindenberg
• David E.J. Linden
• Thomas Lancaster
• Sebastian Mohnke
• Oliver Grimm
• Franziska Degenhardt
• Peter Holmans

Variation in the CACNA1C gene has consistently been associated with psychosis in genome wide association studies. We have previously shown in a sample of n=110 healthy subjects that carriers of the CACNA1C rs1006737 risk variant exhibit hippocampal and perigenual anterior cingulate dysfunction (pgACC) during episodic memory recall. Here, we aimed to replicate our results, by testing for the effects of the rs1006737 risk variant in a new large cohort of healthy controls. We furthermore sought to refine these results by identifying the impact of a CACNA1C specific, gene-wide risk score in the absence of clinical pathology. An independent sample of 179 healthy subjects genotyped for rs1006737 underwent functional magnetic resonance imaging (fMRI) while performing an associative episodic memory task and underwent psychological testing similar to the discovery sample. The effect of gene-wide risk scores was analyzed in the combined sample of 289 subjects. We replicated our discovery findings of hippocampal and pgACC dysfunction in carriers of the rs1006737 risk variant. Additionally, we observed diminished activation of the dorsolateral prefrontal cortex, in the replication sample. Our replicated results as well as this new effect were also observable in the combined sample. Moreover, the same system-level phenotypes were significantly associated with the individual gene-based genetic risk score. Our findings suggest that altered hippocampal and frontolimbic function is associated with variants in the CACNA1C gene. Since CACNA1C variants have been associated repeatedly with psychosis at a genome-wide level, and preclinical data provide convergent evidence for the relevance of the CACNA1C gene for hippocampal and frontolimbic plasticity and adaptive regulation of stress, our data suggest a potential pathophysiological mechanism conferred by CACNA1C variants that may mediate risk for symptom dimensions shared among bipolar disorder, major depression, and schizophrenia.

YNIMG Journal 2012 Journal Article

Interhemispheric hypoconnectivity in schizophrenia: Fiber integrity and volume differences of the corpus callosum in patients and unaffected relatives

• Christian Knöchel
• Viola Oertel-Knöchel
• Ralf Schönmeyer
• Anna Rotarska-Jagiela
• Vincent van de Ven
• David Prvulovic
• Corinna Haenschel
• Peter Uhlhaas

Changes in hemispheric asymmetry and inter-hemispheric connectivity have been reported in schizophrenia. However, the genetic contribution to these alterations is still unclear. In the current study, we applied an automatic segmentation method to structural MRI and diffusion tensor imaging (DTI) data and examined volume and fiber integrity of the corpus callosum (CC), the main interhemispheric fiber tract, in 16 chronic schizophrenia (SZ) patients, matched first degree relatives and controls. SZ patients and relatives had smaller CC volumes than controls, particularly in the posterior genu, isthmus and splenium. Fractional anisotropy (FA), an indicator of fiber integrity, was reduced in patients and relatives in the whole CC, the inferior genu, the superior genu and the isthmus. Correspondingly, the mean diffusivity (MD) values of the whole CC and the isthmus were higher in patients and their unaffected relatives, indicating decreased compactness and increased intercellular space. Relatives had intermediate values in the volumetric and fiber integrity measurements between patients and controls. Lower CC volume and fiber integrity in SZ patients were associated with more severe auditory hallucinations. These results support the connectivity hypothesis of SZ (Friston, 1998) and particularly highlight the altered interhemispheric connectivity, which appears to be a genetic feature of SZ risk.

YNIMG Journal 2009 Journal Article

Orientation-specific adaptation to mentally generated lines in human visual cortex

• Harald M. Mohr
• Nicolas S. Linder
• David E.J. Linden
• Jochen Kaiser
• Ruxandra Sireteanu

Previous studies have shown that prolonged inspection of a tilted visual pattern leads to changes in perception (“tilt after-effect”, TAE), as well as to a reduction of the neural activation evoked by this pattern (“neural adaptation”). In this fMRI study, we investigated whether such perceptual and neural adaptation can be induced solely by mental imagination. The subjects were asked to mentally generate tilted lines, after which they were presented test lines oriented in the same or the direction orthogonal to the mentally tilted lines. Subjects showed a TAE even after mental imagery (“mental TAE”). Furthermore, a significant orientation-specific adaptation occurred in extrastriate visual areas (V3–V4), showing a decreasing gradient of adaptation from areas V4 to V1. Both this neural adaptation and the individual size of the mental TAE correlated with performance in a behavioural task probing mental imagery. Thus, orientation-selective neurons in visual areas seem to be recruited by mental imagery, and the amount of recruitment correlates with the degree of success of mental imagery operations. The influence of mental imagery on perception and on the neural activity in extrastriate visual areas provides evidence for analogue coding of mental images.

YNIMG Journal 2008 Journal Article

The corpus callosum in schizophrenia-volume and connectivity changes affect specific regions

• Anna Rotarska-Jagiela
• Ralf Schönmeyer
• Viola Oertel
• Corinna Haenschel
• Kai Vogeley
• David E.J. Linden

The corpus callosum (CC) is of great interest for pathophysiological models of schizophrenia. Volume and structural integrity of the CC have been examined by volumetric and diffusion tensor imaging (DTI) studies, but results were not consistent across methods or studies. A possible explanation may be varying methodologies and accuracy of measurements based on a single slice or small regions of interest. In addition, none of the studies examined volume and diffusion values in the same group of patients, and thus the relationship between these anatomical measures is not clear. We used an automatic algorithm to segment seven midline slices of the CC from DTI images. We compared volume and the DTI measures fractional anisotropy (FA) and mean diffusivity (MD) in the CC and its subdivisions in the schizophrenia patients and matched controls. Patients had decreased volume, decreased FA and increased MD of the whole CC. The important novel finding is, however, that not all regions were equally affected by anatomical changes. The results emphasize the importance of using different methods in evaluation of white matter (WM) in schizophrenia to avoid false negative findings. In addition, the measures were highly correlated with each other, implying a common pathological process influencing FA, MD and volume of the CC. Although we cannot rule out other mechanisms affecting volume, FA and MD, converging evidence from cytoarchitectonic and genetic studies suggests that WM changes observed in schizophrenia may involve disintegration of healthy, functional axons and strengthening of aberrant connections resulting in increased severity of clinical symptoms.

YNIMG Journal 2008 Journal Article

The neural substrates of person comparison—An fMRI study

• Michael Lindner
• Tanja Hundhammer
• Angela Ciaramidaro
• David E.J. Linden
• Thomas Mussweiler

Person comparison is pervasive in social judgment and human decision making and yet its neural substrate is poorly explored. We measured brain activity when participants compared psychological (intelligence) and physical (height) characteristics of famous people and found activation of medial frontal, orbitofrontal and limbic areas and the temporoparietal junction. This network was largely driven by the psychological comparison, with activity being higher for intelligence than height comparison in several areas in medial prefrontal cortex, suggesting that their activation scales with the demand on person comparison. The person comparison network overlaps strikingly with that commonly described for classic theory of mind tasks. We interpret this overlap as indexing the use of perspective taking common to person comparison and theory of mind.

YNIMG Journal 2007 Journal Article

Common neural substrates for visual working memory and attention

• Jutta S. Mayer
• Robert A. Bittner
• Danko Nikolić
• Christoph Bledowski
• Rainer Goebel
• David E.J. Linden

Humans are severely limited in their ability to memorize visual information over short periods of time. Selective attention has been implicated as a limiting factor. Here we used functional magnetic resonance imaging to test the hypothesis that this limitation is due to common neural resources shared by visual working memory (WM) and selective attention. We combined visual search and delayed discrimination of complex objects and independently modulated the demands on selective attention and WM encoding. Participants were presented with a search array and performed easy or difficult visual search in order to encode one or three complex objects into visual WM. Overlapping activation for attention-demanding visual search and WM encoding was observed in distributed posterior and frontal regions. In the right prefrontal cortex and bilateral insula blood oxygen-level-dependent activation additively increased with increased WM load and attentional demand. Conversely, several visual, parietal and premotor areas showed overlapping activation for the two task components and were severely reduced in their WM load response under the condition with high attentional demand. Regions in the left prefrontal cortex were selectively responsive to WM load. Areas selectively responsive to high attentional demand were found within the right prefrontal and bilateral occipital cortex. These results indicate that encoding into visual WM and visual selective attention require to a high degree access to common neural resources. We propose that competition for resources shared by visual attention and WM encoding can limit processing capabilities in distributed posterior brain regions.

YNIMG Journal 2006 Journal Article

The temporal characteristics of motion processing in hMT/V5+: Combining fMRI and neuronavigated TMS

• Alexander T. Sack
• Axel Kohler
• David E.J. Linden
• Rainer Goebel
• Lars Muckli

Functional imaging has demonstrated the specific involvement of the human middle–temporal complex (hMT/V5+) during processing of moving stimuli. Some studies applied transcranial magnetic stimulation (TMS) to investigate the causal relevance of hMT/V5+ for motion perception. Although the studies used similar visual stimuli and TMS parameters, the critical time point of functionally relevant hMT/V5+ activity differed by 100 ms and more. The present study aimed to elucidate further the temporal characteristics of motion processing in hMT/V5+ by investigating all critical time windows currently debated in the literature. In contrast to previous studies, we used TMS neuronavigation based on individual fMRI results of five participants to target hMT/V5+, applying single-pulse TMS at 24 different time windows (−50 till +200 ms relative to stimulus onset). We revealed that TMS significantly impaired motion perception when applied over hMT/V5+ at 40 to 30 ms before as well as 130 to 150 ms after onset of the moving stimuli. While the late effective time window conforms to results from previous experiments, we did not find evidence for an early time window around 0 ms that has been reported in other studies. Our neuronavigation approach enabled us to quantify the interindividual variance in the exact location of hMT/V5+ and the respective TMS target position on the skull of the participants. Considering that shifting the TMS coil position only by a few millimeters can already lead to a complete loss of TMS effects, our study clearly demonstrates the utility of neuronavigated TMS when investigating specific neuronal effects as in the case of motion processing.

YNIMG Journal 2005 Journal Article

The spatiotemporal pattern of auditory cortical responses during verbal hallucinations

• Vincent G. van de Ven
• Elia Formisano
• Christian H. Röder
• David Prvulovic
• Robert A. Bittner
• Matthias G. Dietz
• Daniela Hubl
• Thomas Dierks

Functional magnetic resonance imaging (fMRI) studies can provide insight into the neural correlates of hallucinations. Commonly, such studies require self-reports about the timing of the hallucination events. While many studies have found activity in higher-order sensory cortical areas, only a few have demonstrated activity of the primary auditory cortex during auditory verbal hallucinations. In this case, using self-reports as a model of brain activity may not be sensitive enough to capture all neurophysiological signals related to hallucinations. We used spatial independent component analysis (sICA) to extract the activity patterns associated with auditory verbal hallucinations in six schizophrenia patients. SICA decomposes the functional data set into a set of spatial maps without the use of any input function. The resulting activity patterns from auditory and sensorimotor components were further analyzed in a single-subject fashion using a visualization tool that allows for easy inspection of the variability of regional brain responses. We found bilateral auditory cortex activity, including Heschl's gyrus, during hallucinations of one patient, and unilateral auditory cortex activity in two more patients. The associated time courses showed a large variability in the shape, amplitude, and time of onset relative to the self-reports. However, the average of the time courses during hallucinations showed a clear association with this clinical phenomenon. We suggest that detection of this activity may be facilitated by examining hallucination epochs of sufficient length, in combination with a data-driven approach.

YNIMG Journal 2003 Journal Article

Cortical capacity constraints for visual working memory: dissociation of fMRI load effects in a fronto-parietal network

• David E.J. Linden
• Robert A. Bittner
• Lars Muckli
• James A. Waltz
• Nikolaus Kriegeskorte
• Rainer Goebel
• Wolf Singer
• Matthias H.J. Munk

Working memory (WM) capacity limitations and their neurophysiological correlates are of special relevance for the understanding of higher cognitive functions. Evidence from behavioral studies suggests that restricted attentional resources contribute to these capacity limitations. In an event-related functional magnetic resonance imaging (fMRI) study, we probed the capacity of the human visual WM system for up to four complex nonnatural objects using a delayed discrimination task. A number of prefrontal and parietal areas bilaterally showed increased blood oxygen level-dependent activity, relative to baseline, throughout the task when more than one object had to be held in memory. Monotonic increases in response to memory load were observed bilaterally in the dorsolateral prefrontal cortex (DLPFC) and the presupplementary motor area (pre-SMA). Conversely, activity in the frontal eye fields (FEFs) and in areas along the intraparietal sulcus (IPS) peaked when subjects had to maintain only two or three objects and decreased in the highest load condition. This dissociation of memory load effects on cortical activity suggests that the cognitive operations subserved by the IPS and FEF, which are most likely related to attention, fail to support visual WM when the capacity limit is approached. The correlation of brain activity with performance implies that only the operations performed by the DLPFC and pre-SMA, which support an integrated representation of visual information, helped subjects to maintain a reasonable level of performance in the highest load condition. These results indicate that at least two distinct cortical subsystems are recruited for visual WM, and that their interplay changes when the capacity limit is reached.

YNIMG Journal 2001 Journal Article

FMRI and EEG in humans performing a delayed discrimination task: The effect of short-term memory load

• David E.J. Linden
• James A. Waltz
• Lars Muckli
• David Prvulovic
• Rainer Goebel
• Friedhelm E. Zanella
• Wolf Singer
• Matthias H.J. Munk

YNIMG Journal 2001 Journal Article

Functional Fields in Human Auditory Cortex Revealed by Time-Resolved fMRI without Interference of EPI Noise

• Francesco Di Salle
• Elia Formisano
• Erich Seifritz
• David E.J. Linden
• Klaus Scheffler
• Claudio Saulino
• Gioacchino Tedeschi
• Friedhelm E. Zanella

The gradient switching during fast echoplanar functional magnetic resonance imaging (EPI-fMRI) produces loud noises that may interact with the functional activation of the central auditory system induced by experimental acoustic stimuli. This interaction is unpredictable and is likely to confound the interpretation of functional maps of the auditory cortex. In the present study we used an experimental design which does not require the presentation of stimuli during EPI acquisitions and allows for mapping of the auditory cortex without the interference of scanner noise. The design relies on the physiological delays between the onset, or the end, of stimulation and the corresponding hemodynamic response. Owing to these delays and through a time-resolved acquisition protocol it is possible to analyze the decay of the stimulus-specific signal changes after the cessation of the stimulus itself and before the onset of the EPI-acoustic noise related activation (decay-sampling technique). This experimental design, which might permit a more detailed insight in the auditory cortex, has been applied to the study of the cortical responses to pulsed 1000 Hz sine tones. Distinct activation clusters were detected in the Heschl's gyri and the planum temporale, with an increased extension compared to a conventional block-design paradigm. Furthermore, the comparison of the hemodynamic response of the most anterior and the posterior clusters of activation highlighted differential response patterns to the sound stimulation and to the EPI-noise. These differences, attributable to reciprocal saturation effects unevenly distributed over the superior temporal cortex, provided evidence for functionally distinct auditory fields.

YNIMG Journal 2001 Journal Article

Visuospatial processing and training effects in Alzheimer's disease (AD) and healthy subjects assessed with fMRI

• David Prvulovic
• Daniela Hubl
• Alexander T. Sack
• Lutz Froelich
• Martin Jandl
• Heinrich Lanfermann
• Friedhelm E. Zanella
• Konrad Maurer