Publications by authors named "Eleftherios Kavroulakis"

10 Publications

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T2 Relaxometry Evidence of Microstructural Changes in Diffusely Abnormal White Matter in Relapsing-Remitting Multiple Sclerosis and Clinically Isolated Syndrome: Impact on Visuomotor Performance.

J Magn Reson Imaging 2021 May 6. Epub 2021 May 6.

Institute of Computer Science, Foundation of Research and Technology-Hellas, Heraklion, Greece.

Background: Although diffusely abnormal white matter (DAWM) is commonly seen in multiple sclerosis (MS), it is rarely considered in clinical/imaging studies.

Purpose: To evaluate quantitative markers of microstructural changes in DAWM of patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RR-MS) in relation to MS lesions and degree of neurocognitive impairment, by using a multi-echo spin echo (MESE) Proton Density PD-to-T2 sequence.

Study Type: Prospective, cross-sectional.

Population: Thirty-seven RR-MS patients, 33 CIS patients, and 52 healthy controls.

Field Strength/sequence: 1.5 T/T1-, T2-weighted, fluid-attenuated inversion recovery, and MESE sequences.

Assessment: Long T2, short T2, and myelin water fraction (MWF) values were estimated as indices of intra/extracellular water content and myelin content, respectively, in DAWM, posterior periventricular normal appearing white matter (NAWM), and focal MS lesions, classified according to their signal intensity on T1 sequences. Patients were, also, administered a battery of neuropsychological tests.

Statistical Tests: Comparisons of T2 and MWF values in DAWM, NAWM, and MS lesions were examined, using two-way mixed analyses of variance. Associations of Grooved Pegboard performance with T2 and MWF values in DAWM and NAWM were assessed using Pearson correlation coefficients.

Results: T2 and MWF values of DAWM were intermediate between the respective values of NAWM and T1 hypointense focal lesions, while there was no difference between the respective values of DAWM and T1-isointense lesions. T2 values in DAWM were strongly associated with visuomotor performance in CIS patients.

Data Conclusion: Intra/extracellular water and myelin water content of DAWM are similar to those of T1-isointense lesions and predict visuomotor performance in CIS patients.

Level Of Evidence: 2 TECHNICAL EFFICACY: Stage 2.
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http://dx.doi.org/10.1002/jmri.27661DOI Listing
May 2021

Anxiety and depression severity in neuropsychiatric SLE are associated with perfusion and functional connectivity changes of the frontolimbic neural circuit: a resting-state f(unctional) MRI study.

Lupus Sci Med 2021 04;8(1)

Computational Bio-Medicine Laboratory, Institute of Computer Science, Foundation for Research and Technology - Hellas, Heraklion, Crete, Greece

Objective: To examine the hypothesis that perfusion and functional connectivity disturbances in brain areas implicated in emotional processing are linked to emotion-related symptoms in neuropsychiatric SLE (NPSLE).

Methods: Resting-state fMRI (rs-fMRI) was performed and anxiety and/or depression symptoms were assessed in 32 patients with NPSLE and 18 healthy controls (HC). Whole-brain time-shift analysis (TSA) maps, voxel-wise global connectivity (assessed through intrinsic connectivity contrast (ICC)) and within-network connectivity were estimated and submitted to one-sample t-tests. Subgroup differences (high vs low anxiety and high vs low depression symptoms) were assessed using independent-samples t-tests. In the total group, associations between anxiety (controlling for depression) or depression symptoms (controlling for anxiety) and regional TSA or ICC metrics were also assessed.

Results: Elevated anxiety symptoms in patients with NPSLE were distinctly associated with relatively faster haemodynamic response (haemodynamic lead) in the right amygdala, relatively lower intrinsic connectivity of orbital dlPFC, and relatively lower bidirectional connectivity between dlPFC and vmPFC combined with relatively higher bidirectional connectivity between ACC and amygdala. Elevated depression symptoms in patients with NPSLE were distinctly associated with haemodynamic lead in vmPFC regions in both hemispheres (lateral and medial orbitofrontal cortex) combined with relatively lower intrinsic connectivity in the right medial orbitofrontal cortex. These measures failed to account for self-rated, milder depression symptoms in the HC group.

Conclusion: By using rs-fMRI, altered perfusion dynamics and functional connectivity was found in limbic and prefrontal brain regions in patients with NPSLE with severe anxiety and depression symptoms. Although these changes could not be directly attributed to NPSLE pathology, results offer new insights on the pathophysiological substrate of psychoemotional symptomatology in patients with lupus, which may assist its clinical diagnosis and treatment.
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http://dx.doi.org/10.1136/lupus-2020-000473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094334PMC
April 2021

Evidence of Age-Related Hemodynamic and Functional Connectivity Impairment: A Resting State fMRI Study.

Front Neurol 2021 23;12:633500. Epub 2021 Mar 23.

Department of Radiology, School of Medicine, University of Crete, University Hospital of Heraklion, Heraklion, Greece.

To assess age-related changes in intrinsic functional brain connectivity and hemodynamics during adulthood in the context of the retrogenesis hypothesis, which states that the rate of age-related changes is higher in late-myelinating (prefrontal, lateral-posterior temporal) cerebrocortical areas as compared to early myelinating (parietal, occipital) regions. In addition, to examine the dependence of age-related changes upon concurrent subclinical depression symptoms which are common even in healthy aging. Sixty-four healthy adults (28 men) aged 23-79 years (mean 45.0, = 18.8 years) were examined. Resting-state functional MRI (rs-fMRI) time series were used to compute voxel-wise intrinsic connectivity contrast (ICC) maps reflecting the strength of functional connectivity between each voxel and the rest of the brain. We further used Time Shift Analysis (TSA) to estimate voxel-wise hemodynamic lead or lag for each of 22 ROIs from the automated anatomical atlas (AAL). Adjusted for depression symptoms, gender and education level, reduced ICC with age was found primarily in frontal, temporal regions, and putamen, whereas the opposite trend was noted in inferior occipital cortices ( < 0.002). With the same covariates, increased hemodynamic lead with advancing age was found in superior frontal cortex and thalamus, with the opposite trend in inferior occipital cortex ( < 0.002). There was also evidence of reduced coupling between voxel-wise intrinsic connectivity and hemodynamics in the inferior parietal cortex. Age-related intrinsic connectivity reductions and hemodynamic changes were demonstrated in several regions-most of them part of DMN and salience networks-while impaired neurovascular coupling was, also, found in parietal regions. Age-related reductions in intrinsic connectivity were greater in anterior as compared to posterior cortices, in line with implications derived from the retrogenesis hypothesis. These effects were affected by self-reported depression symptoms, which also increased with age.
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http://dx.doi.org/10.3389/fneur.2021.633500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021915PMC
March 2021

Quantitative Identification of Functional Connectivity Disturbances in Neuropsychiatric Lupus Based on Resting-State fMRI: A Robust Machine Learning Approach.

Brain Sci 2020 Oct 25;10(11). Epub 2020 Oct 25.

Computational Bio-Medicine Laboratory, Institute of Computer Science, Foundation for Research and Technology-Hellas, 70013 Heraklion, Greece.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is an autoimmune entity comprised of heterogenous syndromes affecting both the peripheral and central nervous system. Research on the pathophysiological substrate of NPSLE manifestations, including functional neuroimaging studies, is extremely limited. The present study examined person-specific patterns of whole-brain functional connectivity in NPSLE patients ( = 44) and age-matched healthy control participants ( = 39). Static functional connectivity graphs were calculated comprised of connection strengths between 90 brain regions. These connections were subsequently filtered through rigorous surrogate analysis, a technique borrowed from physics, novel to neuroimaging. Next, global as well as nodal network metrics were estimated for each individual functional brain network and were input to a robust machine learning algorithm consisting of a random forest feature selection and nested cross-validation strategy. The proposed pipeline is data-driven in its entirety, and several tests were performed in order to ensure model robustness. The best-fitting model utilizing nodal graph metrics for 11 brain regions was associated with 73.5% accuracy (74.5% sensitivity and 73% specificity) in discriminating NPSLE from healthy individuals with adequate statistical power. Closer inspection of graph metric values suggested an increased role within the functional brain network in NSPLE (indicated by higher nodal degree, local efficiency, betweenness centrality, or eigenvalue efficiency) as compared to healthy controls for seven brain regions and a reduced role for four areas. These findings corroborate earlier work regarding hemodynamic disturbances in these brain regions in NPSLE. The validity of the results is further supported by significant associations of certain selected graph metrics with accumulated organ damage incurred by lupus, with visuomotor performance and mental flexibility scores obtained independently from NPSLE patients.
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http://dx.doi.org/10.3390/brainsci10110777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692139PMC
October 2020

Cerebral perfusion disturbances in chronic mild traumatic brain injury correlate with psychoemotional outcomes.

Brain Imaging Behav 2020 Jul 30. Epub 2020 Jul 30.

Institute of Computer Science, Foundation of Research and Technology-Hellas, Voutes, Heraklion, Greece.

The study explored associations between hemodynamic changes and psychoemotional status in 32 patients with chronic mild traumatic brain injury (mTBI) and 31 age-matched healthy volunteers. Cerebral blood flow (CBF) and cerebral blood volume (CBV) values were obtained using Dynamic Susceptibility Contrast Magnetic Resonance Imaging in brain regions suspected to play a role in anxiety and depression. Patients were administered self-report measures of anxiety and depression symptoms and underwent neuropsychological assessment. As a group mTBI patients scored significantly below age- and education-adjusted population norms on multiple cognitive domains and reported high rates of anxiety and depression symptomatology. Significantly reduced CBF values were detected in the mTBI group compared to controls in dorsolateral prefrontal areas, putamen, and hippocampus, bilaterally. Within the mTBI group, depressive symptomatology was significantly associated with lower perfusion in the left anterior cingulate gyrus and higher perfusion in the putamen, bilaterally. The latter association was independent from verbal working memory capacity. Moreover, anxiety symptomatology was associated with lower perfusion in the hippocampus (after controlling for verbal episodic memory difficulties). Associations between regional perfusion and psychoemotional scores were specific to depression or anxiety, respectively, and independent of the presence of visible lesions on conventional MRI. Results are discussed in relation to the role of specific limbic and paralimbic regions in the pathogenesis of symptoms of depression and anxiety.
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http://dx.doi.org/10.1007/s11682-020-00343-1DOI Listing
July 2020

Age-related deep white matter changes in myelin and water content: A T relaxometry study.

J Magn Reson Imaging 2019 11 12;50(5):1393-1404. Epub 2019 Mar 12.

Institute of Computer Science, Foundation of Research and Technology, Heraklion, Greece.

Background: According to the retrogenesis hypothesis, the rate of age-related changes in white matter (WM) myelin content varies between early myelinating (parietal, occipital) and late myelinating (prefrontal, lateral-posterior temporal) areas. The multiecho spin echo (MESE), PD-to-T -weighted sequence provides an index of myelin content (myelin water fraction [MWF]) derived from measurements of myelin water (via the short T component [10-50 msec]) and intra- and extracellular water (via the long T component [>50-200 msec]).

Purpose: To assess the shape and regional variations in the rate of age-related myelin and water content changes in deep WM regions using the MESE sequence.

Study Type: Prospective, cross-sectional.

Population: In all, 90 healthy adults aged 22-81 years.

Field Strength/sequence: 1.5T/ T w, T w, fluid attenuated inversion recovery (FLAIR), MESE sequences.

Assessment: Short T , long T , and MWF values were measured in prefrontal, parietal, lateral-posterior temporal, and occipital normal-appearing WM (NAWM) areas.

Statistical Tests: Linear and quadratic effects of age on long T and MWF were assessed through regression analyses. Regional variations in the effect of age on long T and MWF values at both the individual and group level were examined, using regression and analysis of covariance (ANCOVA) analyses, respectively, controlling for total WM volume.

Results: The rate of age-related changes in long T and MWF was higher for older persons and a significant increase or decline, respectively, was first noted at 60-69 years (P < 0.0033). MWF values peaked earlier (at 30 years of age) and displayed a steeper age-related reduction in prefrontal and lateral-posterior temporal NAWM as compared with the occipital lobes (P < 0.05). The opposite pattern of age-related effect was found for long T values.

Data Conclusion: Significant age-related reductions in myelin content were closely followed by corresponding increases in intra- and extracellular water content. These changes were more pronounced among elderly people and followed an anterior-posterior pattern.

Level Of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1393-1404.
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http://dx.doi.org/10.1002/jmri.26707DOI Listing
November 2019

Neuropsychiatric lupus or not? Cerebral hypoperfusion by perfusion-weighted MRI in normal-appearing white matter in primary neuropsychiatric lupus erythematosus.

Ann Rheum Dis 2018 03 19;77(3):441-448. Epub 2017 Dec 19.

Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodestrian University of Athens, Athens, Greece.

Objectives: Cerebral perfusion abnormalities have been reported in systemic lupus erythematosus (SLE) but their value in distinguishing lupus from non-lupus-related neuropsychiatric events remains elusive. We examined whether dynamic susceptibility contrast-enhanced perfusion MRI (DSC-MRI), a minimally invasive and widely available method of cerebral perfusion assessment, may assist neuropsychiatric SLE (NPSLE) diagnosis.

Methods: In total, 76patients with SLE (37 primary NPSLE, 16 secondary NPSLE, 23 non-NPSLE) and 31 healthy controls underwent conventional MRI (cMRI) and DSC-MRI. Attribution of NPSLE to lupus or not was based on multidisciplinary assessment including cMRI results and response to treatment. Cerebral blood volume and flow were estimated in 18 normal-appearing white and deep grey matter areas.

Results: The most common manifestations were mood disorder, cognitive disorder and headache. Patients with primary NPSLE had lower cerebral blood flow and volume in several normal-appearing white matter areas compared with controls (P<0.0001) and lower cerebral blood flow in the semioval centre bilaterally, compared with non-NPSLE and patients with secondary NPSLE (P<0.001). A cut-off for cerebral blood flow of 0.77 in the left semioval centre discriminated primary NPSLE from non-NPSLE/secondary NPSLE with 80% sensitivity and 67%-69% specificity. Blood flow values in the left semioval centre showed substantially higher sensitivity than cMRI (81% vs 19%-24%) for diagnosing primary NPSLE with the combination of the two modalities yielding 94%-100% specificity in discriminating primary from secondary NPSLE.

Conclusion: Primary NPSLE is characterised by significant hypoperfusion in cerebral white matter that appears normal on cMRI. The combination of DSC-MRI-measured blood flow in the brain semioval centre with conventional MRI may improve NPSLE diagnosis.
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http://dx.doi.org/10.1136/annrheumdis-2017-212285DOI Listing
March 2018

Myelin content changes in probable Alzheimer's disease and mild cognitive impairment: Associations with age and severity of neuropsychiatric impairment.

J Magn Reson Imaging 2018 05 31;47(5):1359-1372. Epub 2017 Aug 31.

Department of Radiology, School of Medicine, University of Crete, Heraklion, Crete, Greece.

Background: Existing indices of white matter integrity such as fractional anisotropy and magnetization transfer ratio may not provide optimal specificity to myelin content. In contrast, myelin water fraction (MWF) derived from the multiecho T relaxation time technique may serve as a more direct measure of myelin content.

Purpose/hypothesis: The goal of the present study was to identify markers of regional demyelination in patients with probable Alzheimer's disease (AD) and mild cognitive impairment (MCI) in relation to age and severity of neuropsychiatric impairment.

Population: The sample included patients diagnosed with probable AD (n = 25) or MCI (n = 43), and cognitively intact elderly controls (n = 33).

Field Strength/sequence Assessment: Long T , short T , and MWF values were measured with a 1.5T scanner in periventricular and deep normal-appearing white matter (NAWM), serving as indices of intra/extracellular water content and myelin content. A comprehensive neuropsychological and neuropsychiatric assessment was administered to all participants.

Statistical Tests, Results: AD patients displayed higher age-adjusted long and short T values and reduced MWF values in left temporal/parietal and bilateral periventricular NAWM than controls and MCI patients (P < 0.004; one-way analysis of covariance [ANCOVA] tests). Short T /MWF values in temporal, frontal, and periventricular NAWM of controls and/or MCI patients were significantly associated with episodic and semantic memory performance and depressive symptomatology (P < 0.004; partial correlation indices). The impact of age on memory performance was significantly (P < 0.01; mediated linear regression analyses) mediated by age-related changes in short T and MWF values in these regions.

Data Conclusion: Age-related demyelination is associated with memory impairment (especially in prodromal dementia states) and symptoms of depression in an anatomically specific manner.

Level Of Evidence: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1359-1372.
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http://dx.doi.org/10.1002/jmri.25849DOI Listing
May 2018

Neural foundations of overt and covert actions.

Neuroimage 2017 05 18;152:482-496. Epub 2017 Mar 18.

Institute of Applied and Computational Mathematics, Foundation for Research and Technology Hellas, Iraklion, Crete, Greece; Faculty of Medicine, School of Health Sciences, University of Crete, Iraklion, Crete, Greece. Electronic address:

We used fMRI to assess the human brain areas activated for execution, observation and 1st person motor imagery of a visually guided tracing task with the index finger. Voxel-level conjunction analysis revealed several cortical areas activated in common across all three motor conditions, namely, the upper limb representation of the primary motor and somatosensory cortices, the dorsal and ventral premotor, the superior and inferior parietal cortices as well as the posterior part of the superior and middle temporal gyrus including the temporo-parietal junction (TPj) and the extrastriate body area (EBA). Functional connectivity analyses corroborated the notion that a common sensory-motor fronto-parieto-temporal cortical network is engaged for execution, observation, and imagination of the very same action. Taken together these findings are consistent with the more parsimonious account of motor cognition provided by the mental simulation theory rather than the recently revised mirror neuron view Action imagination and observation were each associated with several additional functional connections, which may serve the distinction between overt action and its covert counterparts, and the attribution of action to the correct agent. For example, the central position of the right middle and inferior frontal gyrus in functional connectivity during motor imagery may reflect the suppression of movements during mere imagination of action, and may contribute to the distinction between 'imagined' and 'real' action. Also, the central role of the right EBA in observation, assessed by functional connectivity analysis, may be related to the attribution of action to the 'external agent' as opposed to the 'self'.
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http://dx.doi.org/10.1016/j.neuroimage.2017.03.036DOI Listing
May 2017