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Dorothee P. Auer

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YNICL Journal 2022 Journal Article

Language systems from lesion-symptom mapping in aphasia: A meta-analysis of voxel-based lesion mapping studies

  • Yoonhye Na
  • JeYoung Jung
  • Christopher R. Tench
  • Dorothee P. Auer
  • Sung-Bom Pyun

BACKGROUND: Aphasia is one of the most common causes of post-stroke disabilities. As the symptoms and impact of post-stroke aphasia are heterogeneous, it is important to understand how topographical lesion heterogeneity in patients with aphasia is associated with different domains of language impairments. Here, we aim to provide a comprehensive overview of neuroanatomical basis in post-stroke aphasia through coordinate based meta-analysis of voxel-based lesion-symptom mapping studies. METHODS: We performed a meta-analysis of lesion-symptom mapping studies in post-stroke aphasia. We obtained coordinate-based structural neuroimaging data for 2,007 individuals with aphasia from 25 studies that met predefined inclusion criteria. RESULTS: Overall, our results revealed that the distinctive patterns of lesions in aphasia are associated with different language functions and tasks. Damage to the insular-motor areas impaired speech with preserved comprehension and a similar pattern was observed when the lesion covered the insular-motor and inferior parietal lobule. Lesions in the frontal area severely impaired speaking with relatively good comprehension. The repetition-selective deficits only arise from lesions involving the posterior superior temporal gyrus. Damage in the anterior-to-posterior temporal cortex was associated with semantic deficits. CONCLUSION: The association patterns of lesion topography and specific language deficits provide key insights into the specific underlying language pathways. Our meta-analysis results strongly support the dual pathway model of language processing, capturing the link between the different symptom complexes of aphasias and the different underlying location of damage.

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YNICL Journal 2021 Journal Article

Altered hippocampal functional connectivity patterns in patients with cognitive impairments following ischaemic stroke: A resting-state fMRI study

  • JeYoung Jung
  • Rosanna Laverick
  • Kurdow Nader
  • Thomas Brown
  • Haley Morris
  • Martin Wilson
  • Dorothee P. Auer
  • Pia Rotshtein

BACKGROUND: Ischemic stroke with cognitive impairment is a considerable risk factor for developing dementia. Identifying imaging markers of cognitive impairment following ischemic stroke will help to develop prevention strategies against post-stroke dementia. METHODS: We investigated the hippocampal functional connectivity (FC) pattern following ischemic stroke, using resting-state fMRI (rs-fMRI). Thirty-three cognitively impaired patients after ischemic stroke and sixteen age-matched controls with no known history of neurological disorder were recruited for the study. No patient had a direct ischaemic insult to hippocampus on the examination of brain imaging. Seven subfields of hippocampus were used as seeds region for FC analyses. RESULTS: Across all hippocampal subfields, FC with the inferior parietal lobule was reduced in stroke patients as compared with healthy controls. This decreased FC included both supramarginal gyrus and angular gyrus. The FC of hippocampal subfields with cerebellum was increased. Importantly, the degree of the altered FC between hippocampal subfields and inferior parietal lobule was associated with their impaired memory function. CONCLUSION: Our results demonstrated that decreased hippocampal-inferior parietal lobule connectivity was associated with cognitive impairment in patients with ischemic stroke. These findings provide novel insights into the role of hippocampus in cognitive impairment following ischemic stroke.

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YNICL Journal 2020 Journal Article

Distinguishing between paediatric brain tumour types using multi-parametric magnetic resonance imaging and machine learning: A multi-site study

  • James T. Grist
  • Stephanie Withey
  • Lesley MacPherson
  • Adam Oates
  • Stephen Powell
  • Jan Novak
  • Laurence Abernethy
  • Barry Pizer

The imaging and subsequent accurate diagnosis of paediatric brain tumours presents a radiological challenge, with magnetic resonance imaging playing a key role in providing tumour specific imaging information. Diffusion weighted and perfusion imaging are commonly used to aid the non-invasive diagnosis of children's brain tumours, but are usually evaluated by expert qualitative review. Quantitative studies are mainly single centre and single modality. The aim of this work was to combine multi-centre diffusion and perfusion imaging, with machine learning, to develop machine learning based classifiers to discriminate between three common paediatric tumour types. The results show that diffusion and perfusion weighted imaging of both the tumour and whole brain provide significant features which differ between tumour types, and that combining these features gives the optimal machine learning classifier with >80% predictive precision. This work represents a step forward to aid in the non-invasive diagnosis of paediatric brain tumours, using advanced clinical imaging.

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YNICL Journal 2018 Journal Article

Parkinson's disease related signal change in the nigrosomes 1–5 and the substantia nigra using T2* weighted 7T MRI

  • Stefan Theodor Schwarz
  • Olivier Mougin
  • Yue Xing
  • Anna Blazejewska
  • Nin Bajaj
  • Dorothee P. Auer
  • Penny Gowland

Improved markers for the progression of Parkinson's disease (PD) are required. Previous work has proven that iron dependent MRI scans can detect the largest Nigrosome (N1) within the substantia nigra (SN) pars compacta and changes in PD. Histopathological studies have shown that N1 is particularly affected in early PD whereas the other nigrosomes (N2–N5) and the surrounding iron-rich SN are affected later. In this study we aimed to determine whether MRI can detect the smaller nigrosomes (N2–N5) and whether graded signal alterations can be detected on T2*-weighted MRI at different disease stages consistent with histopathological changes. An observational prospective study was performed within the research imaging centre at the University of Nottingham, UK. Altogether 26 individuals with confirmed PD (median Hoehn&Yahr stage = 1, Unified PD Rating Scale [UPDRS] = 12. 5) and 15 healthy controls participated. High resolution T2*weighted 7T MRI of the brain was performed and visibility of N1-N5 within the SN was qualitatively rated. Normalised T2*weighted signal intensities in manually segmented N1–N5 regions and iron-rich SN were calculated. We performed group comparisons and correlations with severity based on UPDRS. Qualitative measures were a nigrosome visibility score and a confidence score for identification. Quantitative measures were T2*weighted contrast of N1–5 and iron-rich SN relative to white matter. We found that visual assessment of the SN for N1–N5 revealed normal range visibility scores in 14 of 15 controls. N1 was identified with the highest confidence and visibility was in abnormal range in all 26 PD patients. The other nigrosomes were less well visible and less confidently identified. There was a larger PD induced signal reduction in all nigrosomes than in the iron-rich SN (median signal difference N1–5 PD compared to controls: 19. 4% [IQR = 24%], iron-rich SN 11% [IQR = 24%, p = 0. 017]). The largest PD induced signal reduction was in N1: 37. 2% [IQR = 19%] which inversely correlated with UPDRS in PD (R2 = 0. 19). All nigrosomes can be detected using 7T MRI, and PD induced T2*weighted signal reduction was greatest in the nigrosomes (especially N1). The graded T2*weighted signal alterations in the nigrosomes match previously described differential histopathological effects of PD. N1 was identified with the highest confidence and T2*weighted signal in N1 correlated with UPDRS confirming N1 as the most promising SN marker of PD pathology.

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YNICL Journal 2018 Journal Article

Patterns of grey matter loss associated with motor subscores in early Parkinson's disease

  • Xingfeng Li
  • Yue Xing
  • Antonio Martin-Bastida
  • Paola Piccini
  • Dorothee P. Auer

Classical motor symptoms of Parkinson's disease (PD) such as tremor, rigidity, bradykinesia, and axial symptoms are graded in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III. It is yet to be ascertained whether parkinsonian motor symptoms are associated with different anatomical patterns of neurodegeneration as reflected by brain grey matter (GM) alteration. This study aimed to investigate associations between motor subscores and brain GM at voxel level. High resolution structural MRI T1 scans from the Parkinson's Progression Markers Initiative (PPMI) repository were employed to estimate brain GM intensity of PD subjects. Correlations between GM intensity and total MDS-UPDRS III and its four subscores were computed. The total MDS-UPDRS III score was significantly negatively correlated bilaterally with putamen and caudate GM density. Lower anterior striatal GM intensity was significantly associated with higher rigidity subscores, whereas left-sided anterior striatal and precentral cortical GM reduction were correlated with severity of axial symptoms. No significant morphometric associations were demonstrated for tremor subscores. In conclusion, we provide evidence for neuroanatomical patterns underpinning motor symptoms in early PD.

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YNIMG Journal 2017 Journal Article

Activation induced changes in GABA: Functional MRS at 7 T with MEGA-sLASER

  • Chen Chen
  • Hilmar P. Sigurdsson
  • Sophia E. Pépés
  • Dorothee P. Auer
  • Peter G. Morris
  • Paul S. Morgan
  • Penny A. Gowland
  • Stephen R. Jackson

Functional magnetic resonance spectroscopy (fMRS) has been used to assess the dynamic metabolic responses of the brain to a physiological stimulus non-invasively. However, only limited information on the dynamic functional response of γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain, is available. We aimed to measure the activation-induced changes in GABA unambiguously using a spectral editing method, instead of the conventional direct detection techniques used in previous fMRS studies. The Mescher-Garwood-semi-localised by adiabatic selective refocusing (MEGA-sLASER) sequence was developed at 7T to obtain the time course of GABA concentration without macromolecular contamination. A significant decrease (−12±5%) in the GABA to total creatine ratio (GABA/tCr) was observed in the motor cortex during a period of 10min of hand-clenching, compared to an initial baseline level (GABA/tCr =0. 11±0. 02) at rest. An increase in the Glx (glutamate and glutamine) to tCr ratio was also found, which is in agreement with previous findings. In contrast, no significant changes in NAA/tCr and tCr were detected. With consistent and highly efficient editing performance for GABA detection and the advantage of visually identifying GABA resonances in the spectra, MEGA-sLASER is demonstrated to be an effective method for studying of dynamic changes in GABA at 7T.

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YNIMG Journal 2017 Journal Article

Targeted transcranial theta-burst stimulation alters fronto-insular network and prefrontal GABA

  • Sarina J. Iwabuchi
  • Felix Raschke
  • Dorothee P. Auer
  • Peter F. Liddle
  • Sudheer T. Lankappa
  • Lena Palaniyappan

Repetitive transcranial magnetic stimulation (rTMS) has been used worldwide to treat depression. However, the exact physiological effects are not well understood. Pathophysiology of depression involves crucial limbic structures (e. g. insula), and it is still not clear if these structures can be modulated through neurostimulation of surface regions (e. g. dorsolateral prefrontal cortex, DLPFC), and whether rTMS-induced excitatory/inhibitory transmission alterations relate to fronto-limbic connectivity changes. Therefore, we sought proof-of-concept for neuromodulation of insula via prefrontal intermittent theta-burst stimulation (iTBS), and how these effects relate to GABAergic and glutamatergic systems. In 27 healthy controls, we employed a single-blind crossover randomised-controlled trial comparing placebo and real iTBS using resting-state functional MRI and magnetic resonance spectroscopy. Granger causal analysis was seeded from right anterior insula (rAI) to locate individualized left DLPFC rTMS targets. Effective connectivity coefficients within rAI and DLPFC were calculated, and levels of GABA/Glx, GABA/Cr and Glx/Cr in DLPFC and anterior cingulate voxels were also measured. ITBS significantly dampened fronto-insular connectivity and reduced GABA/Glx in both voxels. GABA/Glx had a significant mediating effect on iTBS-induced changes in DLPFC-to-rAI connectivity. We demonstrate modulation of the rAI using targeted iTBS through alterations of excitatory/inhibitory interactions, which may underlie therapeutic effects of rTMS, offering promise for rTMS treatment optimization.

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YNICL Journal 2016 Journal Article

Associations of limbic-affective brain activity and severity of ongoing chronic arthritis pain are explained by trait anxiety

  • William J. Cottam
  • Laura Condon
  • Hamza Alshuft
  • Diane Reckziegel
  • Dorothee P. Auer

Functional magnetic resonance imaging studies (fMRI) have transformed our understanding of central processing of evoked pain but the typically used block and event-related designs are not best suited to the study of ongoing pain. Here we used arterial spin labelling (ASL) for cerebral blood flow mapping to characterise the neural correlates of perceived intensity of osteoarthritis (OA) pain and its interrelation with negative affect. Twenty-six patients with painful knee OA and twenty-seven healthy controls underwent pain phenotyping and ASL MRI at 3T. Intensity of OA pain correlated positively with blood flow in the anterior mid-cingulate cortex (aMCC), subgenual cingulate cortex (sgACC), bilateral hippocampi, bilateral amygdala, left central operculum, mid-insula, putamen and the brainstem. Additional control for trait anxiety scores reduced the pain-CBF association to the aMCC, whilst pain catastrophizing scores only explained some of the limbic correlations. In conclusion, we found that neural correlates of reported intensity of ongoing chronic pain intensity mapped to limbic-affective circuits, and that the association pattern apart from aMCC was explained by trait anxiety thus highlighting the importance of aversiveness in the experience of clinical pain.

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YNICL Journal 2013 Journal Article

Diffusion tensor imaging of nigral degeneration in Parkinson's disease: A region-of-interest and voxel-based study at 3 T and systematic review with meta-analysis

  • Stefan T. Schwarz
  • Maryam Abaei
  • Vamsi Gontu
  • Paul S. Morgan
  • Nin Bajaj
  • Dorothee P. Auer

There is increasing interest in developing a reliable, affordable and accessible disease biomarker of Parkinson's disease (PD) to facilitate disease modifying PD-trials. Imaging biomarkers using magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) can describe parameters such as fractional anisotropy (FA), mean diffusivity (MD) or apparent diffusion coefficient (ADC). These parameters, when measured in the substantia nigra (SN), have not only shown promising but also varying and controversial results. To clarify the potential diagnostic value of nigral DTI in PD and its dependency on selection of region-of-interest, we undertook a high resolution DTI study at 3 T. 59 subjects (32 PD patients, 27 age and sex matched healthy controls) were analysed using manual outlining of SN and substructures, and voxel-based analysis (VBA). We also performed a systematic literature review and meta-analysis to estimate the effect size (DES) of disease related nigral DTI changes. We found a regional increase in nigral mean diffusivity in PD (mean ± SD, PD 0.80 ± 0.10 vs. controls 0.73 ± 0.06 · 10(- 3) mm(2)/s, p = 0.002), but no difference using a voxel based approach. No significant disease effect was seen using meta-analysis of nigral MD changes (10 studies, DES = + 0.26, p = 0.17, I(2) = 30%). None of the nigral regional or voxel based analyses of this study showed altered fractional anisotropy. Meta-analysis of 11 studies on nigral FA changes revealed a significant PD induced FA decrease. There was, however, a very large variation in results (I(2) = 86%) comparing all studies. After exclusion of five studies with unusual high values of nigral FA in the control group, an acceptable heterogeneity was reached, but there was non-significant disease effect (DES = - 0.5, p = 0.22, I(2) = 28%). The small PD related nigral MD changes in conjunction with the negative findings on VBA and meta-analysis limit the usefulness of nigral MD measures as biomarker of Parkinson's disease. The negative results of nigral FA measurements at regional, sub-regional and voxel level in conjunction with the results of the meta-analysis of nigral FA changes question the stability and validity of this measure as a PD biomarker.

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YNIMG Journal 2010 Journal Article

Pathway-based approaches to imaging genetics association studies: Wnt signaling, GSK3beta substrates and major depression

  • Becky Inkster
  • Thomas E. Nichols
  • Philipp G. Saemann
  • Dorothee P. Auer
  • Florian Holsboer
  • Pierandrea Muglia
  • Paul M. Matthews

Several lines of evidence implicate glycogen synthase kinase 3 beta (GSK3β) in mood disorders. We recently reported associations between GSK3β polymorphisms and brain structural changes in patients with recurrent major depressive disorder (MDD). Here we provide supporting observations by showing that polymorphisms in additional genes encoding proteins directly related to GSK3β biological functions are associated with similar regional grey matter (GM) volume changes in MDD patients. We tested specifically for associations with genetic variation in canonical Wnt signaling pathway genes and in genes that encode substrate proteins of GSK3β. We applied a general linear model with non-stationary cluster-based inference to examine associations between polymorphisms and regional voxel-based morphometry GM volume differences in recurrent MDD patients (n =134) and in age-, gender-, and ethnicity-matched healthy controls (n =144) to test for genotype-by-MDD interactions. We observed associations for polymorphisms in 8/13 canonical Wnt pathway genes and 5/10 GSK3β substrate genes, predominantly in the temporolateral and medial prefrontal cortices. Similar associations were not found for 100 unrelated polymorphisms tested. This work suggests that identifying SNPs related to genes that encode functionally-interacting proteins that modulate common anatomical regions offers a useful approach to increasing confidence in outcomes from imaging genetics association studies. This is of particular interest when replication datasets are not available. Our observations lend support to the hypothesis that polymorphisms in GSK3β play a role in MDD susceptibility or expression, in part, by acting via the canonical Wnt signaling pathway and related substrates.

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YNIMG Journal 2010 Journal Article

Slow EEG pattern predicts reduced intrinsic functional connectivity in the default mode network: An inter-subject analysis

  • Jaroslav Hlinka
  • Charilaos Alexakis
  • Ana Diukova
  • Peter F. Liddle
  • Dorothee P. Auer

The last two decades have witnessed great progress in mapping neural networks associated with task-induced brain activation. More recently, identification of resting state networks (RSN) paved the way to investigate spontaneous task-unrelated brain activity. The cardinal features characterising RSN are low-frequency fluctuations of blood oxygenation level dependent (BOLD) signals synchronised between spatially distinct, but functionally connected brain areas. Simultaneous EEG/fMRI has been previously deployed to study the neurophysiological signature of RSN by comparing EEG power with BOLD amplitudes. We hypothesised that band-limited EEG power may be directly related to network-specific functional connectivity (FC) of BOLD signal time courses. Hence, we studied the association between individual EEG signature and FC in a core RSN, the so-called default mode network (DMN). Combined EEG/fMRI data of 20 healthy volunteers collected during a 15-minute rest period were analysed. Using an inter-subject analysis design, we demonstrated a network and frequency specific relation between RSN FC and EEG. In a multiple regression model, EEG band-powers explained 70% of DMN FC variance, with significant partial correlations of DMN FC to delta (r=−0. 73) and beta (r=0. 53) power. The identified EEG pattern has been previously associated with increased alertness. Conversely, an established EEG-derived sedation index (spectral edge frequency SEF95) closely correlated with DMN FC. The study presents an approach that opens a new perspective to EEG/fMRI correlation. Direct evidence was provided for a distinct neurophysiological correlate of DMN FC. This finding further validates the biological relevance of network-specific intrinsic FC and provides an initial neurophysiological basis for interpreting studies of DMN FC alterations.

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YNIMG Journal 2004 Journal Article

High trait anxiety and hyporeactivity to stress of the dorsomedial prefrontal cortex: a combined phMRI and Fos study in rats

  • Raffael Kalisch
  • Nicolas Salomé
  • Stefan Platzer
  • Alexandra Wigger
  • Michael Czisch
  • Wolfgang Sommer
  • Nicolas Singewald
  • Markus Heilig

The neural basis of trait anxiety is poorly understood. In genetically selected hyperanxious (high anxiety-related behavior; HAB) rats, diazepam induces a stronger anxiolytic response than in hypoanxious (low anxiety-related behavior; LAB) rats. A screen for neuronal response differences to diazepam between HAB and LAB rats using pharmacologic fMRI (phMRI) at 7 T revealed a blunted diazepam-induced neuronal deactivation in the dorsomedial prefrontal cortex (dmPFC) of HABs. This was not due to reduced benzodiazepine (BDZ) receptor densities in this region. Instead, dmPFC tissue oxygenation at baseline was found to be significantly lower in HABs. This suggests a tonic relative hypoactivity under the highly stressful phMRI conditions, offering an explanation for the reduced responsivity to the neural depressant effect of diazepam in the sense of a floor effect. Subsequently, Fos immunoreactivity (Fos-IR) showed that ethologically relevant stressors also cause less dmPFC activation in HABs. In the context of an anxiety-inhibiting role of the dmPFC, we propose that failure to sufficiently activate this region in stressful situations may contribute to high trait anxiety.

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YNIMG Journal 2003 Journal Article

Is the brain cortex a fractal?

  • Valerij G. Kiselev
  • Klaus R. Hahn
  • Dorothee P. Auer

The notion of fractal has been largely used to describe geometrical properties of complex objects in biology and medicine. In the present study the question is addressed whether the human cerebral cortex is self-similar in a statistical sense, which is commonly referred to as being a fractal. A new calculational method is presented, which is volumetric and based on the fast Fourier transform (FFT) of segmented three-dimensional high-resolution magnetic resonance images. The analysis covers a wide range of spatial scales from the size of the whole cortex to the ultimate pixel size. Results obtained in six subjects confirm the fractal nature of the human cerebral cortex down to a spatial scale of 3 mm. The obtained fractal dimension is D = 2. 80 ± 0. 05, which is in reasonable agreement with previously reported results. Deployment of FFT enables a simple interpretation of the results and yields a high performance, which is necessary to analyze the entire cortex. Thus the FFT-based analysis of segmented MR images offers a comprehensive approach to study neurodevelopmental and neurodegenerative changes in the fractal geometry of the cerebral cortex.

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YNIMG Journal 2002 Journal Article

Altered Processing of Acoustic Stimuli during Sleep: Reduced Auditory Activation and Visual Deactivation Detected by a Combined fMRI/EEG Study

  • Michael Czisch
  • Thomas C. Wetter
  • Christian Kaufmann
  • Thomas Pollmächer
  • Florian Holsboer
  • Dorothee P. Auer

Although there is evidence that acoustic stimuli are processed differently during sleep and wakefulness, little is known about the underlying neuronal mechanisms. In the present study, the processing of an acoustic stimulus was investigated during different non rapid eye movement (NREM) sleep stages using a combined EEG/fMRI approach in healthy human volunteers: A text stimulus was presented to sleep-deprived subjects prior to and after the onset of sleep, and single-slice silent fMRI were acquired. We found significantly different blood oxygenation level-dependent (BOLD) contrast responses during sleep compared to wakefulness. During NREM sleep stages 1 and 2 and during slow wave sleep (SWS) we observed reduced activation in the auditory cortex and a pronounced negative signal in the visual cortex and precuneus. Acoustic stimulation during sleep was accompanied by an increase in EEG frequency components in the low delta frequency range. Provided that neurovascular coupling is not altered during sleep, the negative transmodal BOLD response which is most pronounced during NREM sleep stages 1 and 2 reflects a deactivation predominantly in the visual cortex suggesting that this decrease in neuronal activity protects the brain from the arousing effects of external stimulation during sleep not only in the primary targeted sensory cortex but also in other brain regions.

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YNIMG Journal 2001 Journal Article

Blood Pressure Changes Induced by Arterial Blood Withdrawal Influence Bold Signal in Anesthesized Rats at 7 Tesla: Implications for Pharmacologic MRI

  • Raffael Kalisch
  • Gregor-Konstantin Elbel
  • Christoff Gössl
  • Michael Czisch
  • Dorothee P. Auer

Functional magnetic resonance imaging (fMRI) using the blood oxygenation level-dependent (BOLD) contrast is now increasingly applied for measuring drug effects on brain activity. A possible confound in pharmacologic fMRI (phMRI) is that the BOLD signal may be sensitive to systemic cardiovascular or respiratory parameters, which can themselves be modulated by a drug. To assess whether abrupt changes in arterial blood pressure (BP) as may be observed in phMRI experiments influence the BOLD signal, a hemorrhage model was studied in anesthesized rats at 7 T using spin-echo EPI. BP and BOLD signal time courses were found to be significantly correlated (P < 0. 01). This effect was detected under the three different anesthetic regimens employed (isoflurane, halothane, and propofol). The regional pattern of BP-BOLD correlations was heterogeneous and may reflect vascular density. In physiological terms, a BOLD decrease during a decrease in BP may result from an increase in mostly venous cerebral blood volume (CBV) as an autoregulatory response to maintain cerebral blood flow (CBF) during decreased perfusion pressure. The observed influence of BP on BOLD may complicate qualitative and quantitative description of drug effects.

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v2026.09.13