Publications by authors named "Nicolas Villain"

29 Publications

  • Page 1 of 1

A single-center series of 482 patients with functional motor disorders.

J Psychosom Res 2021 Jul 2;148:110565. Epub 2021 Jul 2.

Service de Neurologie, Hôpital Avicenne, Hôpitaux Universitaires de Paris - Seine Saint Denis, Sorbonne Paris Nord, AP-HP, Bobigny, France; Dynamics and Pathophysiology of Neuronal Networks Team, Center for Interdisciplinary Research in Biology, Collège de France, CNRS UMR7241/INSERM U1050, Université PSL, 75005 Paris, France.

Functional motor disorders (FMD) are common and disabling. They are known to predominantly affect women and young to middle-aged patients, although they also occur during childhood or in the elderly. Demographic and clinical characteristics of patients with FMD are poorly known, since large series of consecutive patients are scarce.

Methods: In a chart review study, we retrospectively abstracted data from consecutive FMD patients who were referred to the Neurophysiology Department of the Salpêtrière University Hospital between 2008 and 2016 for treatment with repeated transcranial magnetic stimulation.

Results: 482 patients were included. Most patients were women (73.7%). Median age at symptoms onset was 35.5 years and symptoms were mostly characterized by acute (47.3%) or subacute (46%) onset. Only 23% of patients were active workers, while 58.3% were unemployed because of FMD. Half of the patients had functional motor weakness (n = 241) whereas the other half had movement disorders (n = 241), mainly with tremor (21.1%) or dystonia (20.5%). Among all patients, 66.4% had psychiatric comorbidity and 82.6% reported a history of trauma in the 6 months before symptoms onset. No difference was found in age or gender according to clinical phenotypes.

Conclusion: This large series will contribute to better characterize FMDs.
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http://dx.doi.org/10.1016/j.jpsychores.2021.110565DOI Listing
July 2021

Long-term effect of apomorphine infusion in advanced Parkinson's disease: a real-life study.

NPJ Parkinsons Dis 2021 Jun 11;7(1):50. Epub 2021 Jun 11.

Neurology Department, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.

Long-term effects of continuous subcutaneous apomorphine infusion (CSAI) on health-related quality of life (HRQoL) and predictors of CSAI discontinuation are poorly known. Data from consecutive advanced Parkinson's disease patients treated in routine care were retrospectively collected over 24 months after CSAI initiation, with a focus on the 39-item Parkinson's disease questionnaire (PDQ-39). We determined predictors of CSAI discontinuation and HRQoL improvement using multiple regression analysis. Of the 110 subjects evaluated over a 2-year period, 35% discontinued CSAI. Of those who continued treatment, HRQoL remained stable with a sustained reduction in motor fluctuations. The observed effect on dyskinesias was mild and transient. Of note, patients with preexisting impulse control disorders showed an overall good tolerability. PDQ-39 was the only baseline predictor of HRQoL improvement after 2 years of treatment. The presence of dyskinesias, poorer psychological status, shorter disease duration, male sex, and worse OFF state were predictors of discontinuation. Best candidates for CSAI are patients with: (i) poor baseline HRQoL and (ii) marked motor fluctuations.
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http://dx.doi.org/10.1038/s41531-021-00194-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196159PMC
June 2021

The spatiotemporal changes in dopamine, neuromelanin and iron characterizing Parkinson's disease.

Brain 2021 May 12. Epub 2021 May 12.

Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, INSERM, CNRS, 75013 Paris, France.

In Parkinson's disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson's disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system. Patients with Parkinson's disease (disease duration < 4 years) or idiopathic REM sleep behaviour disorder (a prodromal form of Parkinson's disease) and healthy controls underwent longitudinal examination (baseline and 2-year follow-up). Neuromelanin and iron sensitive MRI and dopamine transporter single-photon emission tomography were performed to assess nigrostriatal levels of neuromelanin, iron, and dopamine. For all three functional territories of the nigrostriatal system, in the clinically most and least affected hemispheres separately, the following was performed: cross-sectional and longitudinal inter-group difference analysis of striatal dopamine and iron, and nigral neuromelanin and iron; in Parkinson's disease patients, exponential fitting analysis to assess the duration of the prodromal phase and the temporal ordering of changes in dopamine, neuromelanin or iron relative to controls; voxel-wise correlation analysis to investigate concomitant spatial changes in dopamine-iron, dopamine-neuromelanin and neuromelanin-iron in the substantia nigra pars compacta. The temporal ordering of dopaminergic changes followed the known spatial pattern of progression involving first the sensorimotor, then the associative and limbic striatal and nigral regions. Striatal dopaminergic denervation occurred first followed by abnormal iron metabolism and finally neuromelanin changes in the substantia nigra pars compacta, which followed the same spatial and temporal gradient observed in the striatum but shifted in time. In conclusion, dopaminergic striatal dysfunction and cell loss in the substantia nigra pars compacta are interrelated with increased nigral iron content.
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http://dx.doi.org/10.1093/brain/awab191DOI Listing
May 2021

Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group.

Lancet Neurol 2021 06 29;20(6):484-496. Epub 2021 Apr 29.

Department of Neurosciences, University of California San Diego, La Jolla, CA, USA; Shiley-Marcos Alzheimer's Disease Research Center, University of California San Diego, La Jolla, CA, USA; Alzheimer Disease Cooperative Study, University of California San Diego, La Jolla, CA, USA.

In 2018, the US National Institute on Aging and the Alzheimer's Association proposed a purely biological definition of Alzheimer's disease that relies on biomarkers. Although the intended use of this framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. Furthermore, a positive Alzheimer's disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer's disease pathology is present as a comorbidity. In this Personal View, the International Working Group presents what we consider to be the current limitations of biomarkers in the diagnosis of Alzheimer's disease and, on the basis of this evidence, we propose recommendations for how biomarkers should and should not be used for diagnosing Alzheimer's disease in a clinical setting. We recommend that Alzheimer's disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer's disease phenotypes, whereas biomarker-positive cognitively unimpaired individuals should be considered only at-risk for progression to Alzheimer's disease.
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http://dx.doi.org/10.1016/S1474-4422(21)00066-1DOI Listing
June 2021

NeuroQ: A neurophobia screening tool assesses how roleplay challenges neurophobia.

J Neurol Sci 2021 Feb 20;421:117320. Epub 2021 Jan 20.

AP-HP, Hôpital Pitié-Salpêtrière, Département de Neurologie, Paris, France; Sorbonne Université, France; INSERM U1127, CNRS 7225, Institut du Cerveau, Paris, France.

Background: Neurophobia is a chronic disease of medical students and junior doctors. Early detection is needed to facilitate prevention and management as this fear can negatively impact patient care.

Methods: We conducted a two-part mono-centric study at the faculty of Medicine, Sorbonne University, in Paris. Part one: a cross-sectional study to validate a newly constructed neurophobia scale, NeuroQ. Part two: a prospective longitudinal study to assess the impact of The Move on student neurophobia using NeuroQ. A population-based sample of second-year medical students of the 2019 and 2020 class of the Faculty of Medicine of Sorbonne University were invited to participate.

Results: NeuroQ incorporates the main themes of the neurophobia definition and demonstrates uni-dimensionality. Three hundred and ninety-five medical students participated in the study (mean age was 20.0 years, SD: 2.1 years) assessing the effect of The Move teaching on neurophobia. Two hundred and eighty-eight (72.9%) students were female. After the Move teaching the mean NeuroQ score was significantly lower compared to the baseline NeuroQ score (mean [SD] variation, -1.1 [2.6], p < 0.001). There was a 22.3% relative reduction in the number of neurophobic students after The Move teaching.

Conclusion: Our results highlight the utility of NeuroQ in assessing (i) baseline neurophobia and (ii) the impact of pre-clinical educational interventions on neurophobia. Furthermore, we have shown the importance of pre-clinical educational interventions, such as The Move, in tackling neurophobia.
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http://dx.doi.org/10.1016/j.jns.2021.117320DOI Listing
February 2021

Alzheimer's Disease Including Focal Presentations.

Semin Neurol 2019 Apr 29;39(2):213-226. Epub 2019 Mar 29.

Department of Neurology, Institute of Memory and Alzheimer's Disease, Assistance Publique - Hopitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.

Alzheimer's disease (AD) is the commonest neurodegenerative disease and the most frequent cause of dementia. It affects 30 million people worldwide. Current research criteria focus on biomarkers' status for amyloid and tau using positron emission tomography and cerebrospinal fluid analysis, independent of clinical status. Current epidemiological data, which mostly rely on biomarker-undetermined AD cases, have highlighted ApoE4 and age as the main risk factors. Rare autosomal dominant mutations also account for a small fraction of early-onset AD. The main clinical phenotype at presentation is the amnestic phenotype targeting episodic memory. This is followed by rarer phenotypes such as posterior cortical atrophy, logopenic variant of primary progressive aphasia, frontal variant AD, corticobasal syndrome, and other even rarer presentations mimicking language variants of frontotemporal dementia. Main differential diagnoses include hippocampal sclerosis with TDP-43, primary age-related tauopathy, argyrophilic grain disease, frontotemporal lobar degeneration, Lewy body disease, chronic traumatic encephalopathy as well as nondegenerative disorders such as cerebrovascular disease, chronic alcohol consumption, limbic encephalitis, medial temporal lobe epilepsy, and others. Co-occurrence of AD pathology with other neurodegenerative and vascular diseases is common and increases with age. This presents a challenge in current clinical practice due to a lack of reliable biomarkers for non-AD neurodegenerative diseases.
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http://dx.doi.org/10.1055/s-0039-1681041DOI Listing
April 2019

Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology.

J Alzheimers Dis 2018 ;64(s1):S47-S105

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

The Precision Neurology development process implements systems theory with system biology and neurophysiology in a parallel, bidirectional research path: a combined hypothesis-driven investigation of systems dysfunction within distinct molecular, cellular, and large-scale neural network systems in both animal models as well as through tests for the usefulness of these candidate dynamic systems biomarkers in different diseases and subgroups at different stages of pathophysiological progression. This translational research path is paralleled by an "omics"-based, hypothesis-free, exploratory research pathway, which will collect multimodal data from progressing asymptomatic, preclinical, and clinical neurodegenerative disease (ND) populations, within the wide continuous biological and clinical spectrum of ND, applying high-throughput and high-content technologies combined with powerful computational and statistical modeling tools, aimed at identifying novel dysfunctional systems and predictive marker signatures associated with ND. The goals are to identify common biological denominators or differentiating classifiers across the continuum of ND during detectable stages of pathophysiological progression, characterize systems-based intermediate endophenotypes, validate multi-modal novel diagnostic systems biomarkers, and advance clinical intervention trial designs by utilizing systems-based intermediate endophenotypes and candidate surrogate markers. Achieving these goals is key to the ultimate development of early and effective individualized treatment of ND, such as Alzheimer's disease. The Alzheimer Precision Medicine Initiative (APMI) and cohort program (APMI-CP), as well as the Paris based core of the Sorbonne University Clinical Research Group "Alzheimer Precision Medicine" (GRC-APM) were recently launched to facilitate the passageway from conventional clinical diagnostic and drug development toward breakthrough innovation based on the investigation of the comprehensive biological nature of aging individuals. The APMI movement is gaining momentum to systematically apply both systems neurophysiology and systems biology in exploratory translational neuroscience research on ND.
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http://dx.doi.org/10.3233/JAD-179932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008221PMC
June 2019

Effects of n-3 polyunsaturated fatty acid supplementation on cognitive functions, electrocortical activity and neurogenesis in a non-human primate, the grey mouse lemur (Microcebus murinus).

Behav Brain Res 2018 07 24;347:394-407. Epub 2018 Feb 24.

UMR CNRS MNHN 7179 MECADEV, BioAdapt Team, 1, Avenue du Petit Château, 91800 Brunoy, France. Electronic address:

Among environmental factors that may affect on brain function, some nutrients and particularly n-3 polyunsaturated fatty acids (n-3 PUFA) are required for optimal brain development. Their effects on cognitive functions, however, are still unclear, and studies in humans and rodents have yielded contradictory results. We used a non-human primate model, the grey mouse lemur, phylogenetically close to human. The aim of this study was to demonstrate the impact of n-3 PUFA supplementation on cognitive functions, neuronal activity and neurogenesis. Two groups of animals whose diet was supplemented with either fish oil (rich in n-3 PUFA) or olive oil as a control. These two groups were subjected to a visual discrimination task and to a test of anxiety in the open-field. In parallel, cortical activity was measured with telemetric ECoG recordings. Finally, adult neurogenesis was investigated ex vivo by means of immunohistochemistry. Animals supplemented with fish oil exhibited better visual discrimination performance and tended to have lower anxiety levels. Furthermore, supplementation increased the power of alpha, beta and gamma frequency bands in the EEG, which are related to various aspects of memory and decision-making. This study also provides the first evidence of the existence of adult neurogenesis process in a prosimian primate. Notably, lemurs supplemented with n-3 PUFAs for 21 months exhibited a higher number of newly born neurons in brain areas related to memory and emotions, compared to control animals. Altogether, these results point to long-term positive effects of dietary n-3 PUFAs on various functions of the primate brain. Further studies will be needed to determine a formal causal link between behavioral improvement and creation of new neurons.
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http://dx.doi.org/10.1016/j.bbr.2018.02.029DOI Listing
July 2018

Neural Correlates of Self-Reference Effect in Early Alzheimer's Disease.

J Alzheimers Dis 2017 ;56(2):717-731

U1077, INSERM, GIP Cyceron, Caen, France.

Information that is processed with reference to the self (i.e., self-referential processing, SRP) is generally associated with better remembering than information processed in a semantic condition. This benefit of self on memory performance is called self-reference effect (SRE). In the present study, we assessed changes in the SRE and SRP-related brain activity in patients diagnosed with mild cognitive impairment or early Alzheimer's disease (MCI/AD). Fifteen patients with confirmed amyloid-β deposits (positive florbetapir-PET scan) and 28 healthy controls (negative florbetapir-PET scan) were included. Participants either had to judge personality trait adjectives with reference to themselves (self condition) or to a celebrity (other condition), or determine whether these adjectives were positive or not (semantic condition). These adjectives were then presented with distractors in a surprise recognition task. Functional MRI data were acquired during both the judgment and recognition tasks. The SRE was observed in controls, but reduced in patients. Both controls and patients activated cortical midline structures when judging items with reference to themselves, but patients exhibited reduced activity in the angular gyrus. In patients, activity at encoding in the angular gyrus positively correlated with subsequent recognition accuracy in the self condition (self accuracy). This region also exhibited significant hypometabolism and Aβ burden, both related to self accuracy. By contrast, there were no differences in brain activity during recognition, either between the self and semantic conditions, or between groups. These results highlight SRE impairment in patients with MCI/AD, despite intact activity in cortical midline structures, and suggest that dysfunction of the angular gyrus is related to this impairment.
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http://dx.doi.org/10.3233/JAD-160561DOI Listing
February 2018

Neurolymphomatosis as a relapse of primary cerebral nervous system lymphoma.

Leuk Lymphoma 2017 03 9;58(3):729-731. Epub 2016 Aug 9.

a Service de Neurologie 2-Mazarin , AP-HP, Groupe Hospitalier Pitié-Salpêtrière , Paris , France.

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http://dx.doi.org/10.1080/10428194.2016.1211277DOI Listing
March 2017

Jumping Stand Apparatus Reveals Rapidly Specific Age-Related Cognitive Impairments in Mouse Lemur Primates.

PLoS One 2015 30;10(12):e0146238. Epub 2015 Dec 30.

Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay UMR 9199, Neurodegenerative Diseases Laboratory, F-92265 Fontenay-aux-Roses, France.

The mouse lemur (Microcebus murinus) is a promising primate model for investigating normal and pathological cerebral aging. The locomotor behavior of this arboreal primate is characterized by jumps to and from trunks and branches. Many reports indicate insufficient adaptation of the mouse lemur to experimental devices used to evaluate its cognition, which is an impediment to the efficient use of this animal in research. In order to develop cognitive testing methods appropriate to the behavioral and biological traits of this species, we adapted the Lashley jumping stand apparatus, initially designed for rats, to the mouse lemur. We used this jumping stand apparatus to compare performances of young (n = 12) and aged (n = 8) adults in acquisition and long-term retention of visual discriminations. All mouse lemurs completed the tasks and only 25 trials, on average, were needed to master the first discrimination problem with no age-related differences. A month later, all mouse lemurs made progress for acquiring the second discrimination problem but only the young group reached immediately the criterion in the retention test of the first discrimination problem. This study shows that the jumping stand apparatus allows rapid and efficient evaluation of cognition in mouse lemurs and demonstrates that about half of the old mouse lemurs display a specific deficit in long-term retention but not in acquisition of visual discrimination.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146238PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696676PMC
July 2016

Social huddling and physiological thermoregulation are related to melanism in the nocturnal barn owl.

Oecologia 2016 Feb 9;180(2):371-81. Epub 2015 Nov 9.

Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland.

Endothermic animals vary in their physiological ability to maintain a constant body temperature. Since melanin-based coloration is related to thermoregulation and energy homeostasis, we predict that dark and pale melanic individuals adopt different behaviours to regulate their body temperature. Young animals are particularly sensitive to a decrease in ambient temperature because their physiological system is not yet mature and growth may be traded-off against thermoregulation. To reduce energy loss, offspring huddle during periods of cold weather. We investigated in nestling barn owls (Tyto alba) whether body temperature, oxygen consumption and huddling were associated with melanin-based coloration. Isolated owlets displaying more black feather spots had a lower body temperature and consumed more oxygen than those with fewer black spots. This suggests that highly melanic individuals display a different thermoregulation strategy. This interpretation is also supported by the finding that, at relatively low ambient temperature, owlets displaying more black spots huddled more rapidly and more often than those displaying fewer spots. Assuming that spot number is associated with the ability to thermoregulate not only in Swiss barn owls but also in other Tytonidae, our results could explain geographic variation in the degree of melanism. Indeed, in the northern hemisphere, barn owls and allies are less spotted polewards than close to the equator, and in the northern American continent, barn owls are also less spotted in colder regions. If melanic spots themselves helped thermoregulation, we would have expected the opposite results. We therefore suggest that some melanogenic genes pleiotropically regulate thermoregulatory processes.
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http://dx.doi.org/10.1007/s00442-015-3491-3DOI Listing
February 2016

Brain activity and functional coupling changes associated with self-reference effect during both encoding and retrieval.

PLoS One 2014 7;9(3):e90488. Epub 2014 Mar 7.

Inserm, U1077, Caen, France; Université de Caen Basse-Normandie, UMR-S1077, Caen, France; Ecole Pratique des Hautes Etudes, UMR-S1077, Caen, France; CHU de Caen, U1077, Caen, France.

Information that is processed with reference to oneself, i.e. Self-Referential Processing (SRP), is generally associated with better remembering compared to information processed in a condition not related to oneself. This positive effect of the self on subsequent memory performance is called as Self-Reference Effect (SRE). The neural basis of SRE is still poorly understood. The main goal of the present work was thus to highlight brain changes associated with SRE in terms of activity and functional coupling and during both encoding and retrieval so as to assess the relative contribution of both processes to SRE. For this purpose, we used an fMRI event-related self-referential paradigm in 30 healthy young subjects and measured brain activity during both encoding and retrieval of self-relevant information compared to a semantic control condition. We found that SRE was associated with brain changes during the encoding phase only, including both greater activity in the medial prefrontal cortex and hippocampus, and greater functional coupling between these brain regions and the posterior cingulate cortex. These findings highlight the contribution of brain regions involved in both SRP and episodic memory and the relevance of the communication between these regions during the encoding process as the neural substrates of SRE. This is consistent with the idea that SRE reflects a positive effect of the reactivation of self-related memories on the encoding of new information in episodic memory.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090488PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946483PMC
December 2014

Amyloid imaging in cognitively normal individuals, at-risk populations and preclinical Alzheimer's disease.

Neuroimage Clin 2013 5;2:356-65. Epub 2013 Mar 5.

INSERM, U1077 Caen, France ; Université de Caen Basse-Normandie, UMR-S1077, Caen, France ; Ecole Pratique des Hautes Etudes, UMR-S1077, Caen, France ; CHU de Caen, U1077 Caen, France.

Recent developments of PET amyloid ligands have made it possible to visualize the presence of Aβ deposition in the brain of living participants and to assess the consequences especially in individuals with no objective sign of cognitive deficits. The present review will focus on amyloid imaging in cognitively normal elderly, asymptomatic at-risk populations, and individuals with subjective cognitive decline. It will cover the prevalence of amyloid-positive cases amongst cognitively normal elderly, the influence of risk factors for AD, the relationships to cognition, atrophy and prognosis, longitudinal amyloid imaging and ethical aspects related to amyloid imaging in cognitively normal individuals. Almost ten years of research have led to a few consensual and relatively consistent findings: some cognitively normal elderly have Aβ deposition in their brain, the prevalence of amyloid-positive cases increases in at-risk populations, the prognosis for these individuals is worse than for those with no Aβ deposition, and significant increase in Aβ deposition over time is detectable in cognitively normal elderly. More inconsistent findings are still under debate; these include the relationship between Aβ deposition and cognition and brain volume, the sequence and cause-to-effect relations between the different AD biomarkers, and the individual outcome associated with an amyloid positive versus negative scan. Preclinical amyloid imaging also raises important ethical issues. While amyloid imaging is definitely useful to understand the role of Aβ in early stages, to define at-risk populations for research or for clinical trial, and to assess the effects of anti-amyloid treatments, we are not ready yet to translate research results into clinical practice and policy. More researches are needed to determine which information to disclose from an individual amyloid imaging scan, the way of disclosing such information and the impact on individuals and on society.
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http://dx.doi.org/10.1016/j.nicl.2013.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777672PMC
November 2013

Cardiac electrophysiological activation pattern estimation from images using a patient-specific database of synthetic image sequences.

IEEE Trans Biomed Eng 2014 Feb;61(2):235-45

While abnormal patterns of cardiac electrophysiological activation are at the origin of important cardiovascular diseases (e.g., arrhythmia, asynchrony), the only clinically available method to observe detailed left ventricular endocardial surface activation pattern is through invasive catheter mapping. However, this electrophysiological activation controls the onset of the mechanical contraction; therefore, important information about the electrophysiology could be deduced from the detailed observation of the resulting motion patterns. In this paper, we present the study of this inverse cardiac electrokinematic relationship. The objective is to predict the activation pattern knowing the cardiac motion from the analysis of cardiac image sequences. To achieve this, we propose to create a rich patient-specific database of synthetic time series of the cardiac images using simulations of a personalized cardiac electromechanical model, in order to study this complex relationship between electrical activity and kinematic patterns in the context of this specific patient. We use this database to train a machine-learning algorithm which estimates the depolarization times of each cardiac segment from global and regional kinematic descriptors based on displacements or strains and their derivatives. Finally, we use this learning to estimate the patient’s electrical activation times using the acquired clinical images. Experiments on the inverse electrokinematic learning are demonstrated on synthetic sequences and are evaluated on clinical data with promising results. The error calculated between our prediction and the invasive intracardiac mapping ground truth is relatively small (around 10 ms for ischemic patients and 20 ms for nonischemic patient). This approach suggests the possibility of noninvasive electrophysiological pattern estimation using cardiac motion imaging.
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http://dx.doi.org/10.1109/TBME.2013.2281619DOI Listing
February 2014

Age effect on the default mode network, inner thoughts, and cognitive abilities.

Neurobiol Aging 2013 Apr 18;34(4):1292-301. Epub 2012 Oct 18.

INSERM, U1077 Caen, France.

Age-related effects on the default mode network (DMN) connectivity as measured at rest using functional magnetic resonance imaging (fMRI) are now well described. Little is known however about the relationships between these changes and age-related effects on cognition or on the unconstrained thoughts which occur during the resting-state scan, called inner experience. Brain resting-state activity, inner experience, and cognitive ability measurements were obtained in 70 participants aged 19-80 years. The anterior-posterior disruption of DMN activity with age reported in previous studies was recovered here. A significant effect of age was also found on cognitive abilities but not on inner experience. Finally, age-related changes in DMN connectivity were found to correlate with cognitive abilities, and more specifically with autobiographical memory performance. These findings provide new information to fuel the debate on the role of the brain default mode and more specifically on the effect of age-related changes in resting-state activity as measured with fMRI.
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http://dx.doi.org/10.1016/j.neurobiolaging.2012.08.018DOI Listing
April 2013

Generation of synthetic but visually realistic time series of cardiac images combining a biophysical model and clinical images.

IEEE Trans Med Imaging 2013 Jan 21;32(1):99-109. Epub 2012 Sep 21.

Asclepios Research Project, Inria Sophia Antipolis, 06902 Sophia Antipolis, France.

We propose a new approach for the generation of synthetic but visually realistic time series of cardiac images based on an electromechanical model of the heart and real clinical 4-D image sequences. This is achieved by combining three steps. The first step is the simulation of a cardiac motion using an electromechanical model of the heart and the segmentation of the end diastolic image of a cardiac sequence. We use biophysical parameters related to the desired condition of the simulated subject. The second step extracts the cardiac motion from the real sequence using nonrigid image registration. Finally, a synthetic time series of cardiac images corresponding to the simulated motion is generated in the third step by combining the motion estimated by image registration and the simulated one. With this approach, image processing algorithms can be evaluated as we know the ground-truth motion underlying the image sequence. Moreover, databases of visually realistic images of controls and patients can be generated for which the underlying cardiac motion and some biophysical parameters are known. Such databases can open new avenues for machine learning approaches.
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http://dx.doi.org/10.1109/TMI.2012.2220375DOI Listing
January 2013

Repetition enhancement and perceptual processing of visual word form.

Front Hum Neurosci 2012 12;6:206. Epub 2012 Jul 12.

INSERM, U1077 Caen, France.

The current study investigated the cerebral basis of word perceptual repetition priming with fMRI during a letter detection task that manipulated the familiarity of perceptual word form and the number of repetitions. Some neuroimaging studies have reported increases, instead of decreases, in brain activations (called "repetition enhancement") associated with repetition priming of unfamiliar stimuli which have been interpreted as the creation of new perceptual representations for unfamiliar items. According to this interpretation, several repetitions of unfamiliar items would then be necessary for the repetition priming to occur, a hypothesis not explicitly tested in prior studies. In the present study, using a letter detection task on briefly flashed words, we explored the effect of familiarity on brain response for word visual perceptual priming using both words with usual (i.e., familiar) and unusual (i.e., unfamiliar) font, presented up to four times for stimuli with unusual font. This allows potential changes in the brain responses for unfamiliar items to be assessed over several repetitions, i.e., repetition enhancement to suppression. Our results reveal significant increases of activity in the bilateral occipital areas related to repetition of words in both familiar and unfamiliar conditions. Our findings support the sharpening hypothesis, showing a lack of cerebral economy with repetition when the task requires the processing of all word features, whatever the familiarity of the material, and emphasize the influence of the nature of stimuli processing on its neuronal manifestation.
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http://dx.doi.org/10.3389/fnhum.2012.00206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3395033PMC
October 2012

Regional dynamics of amyloid-β deposition in healthy elderly, mild cognitive impairment and Alzheimer's disease: a voxelwise PiB-PET longitudinal study.

Brain 2012 Jul 23;135(Pt 7):2126-39. Epub 2012 May 23.

INSERM, U1077, Caen 14000, France.

Amyloid-β deposition in Alzheimer's disease is thought to start while individuals are still cognitively unimpaired and it is hypothesized that after an early phase of fast accumulation, a plateau is reached by the time of cognitive decline. However, few longitudinal Pittsburgh compound B-positron emission tomography studies have tested this hypothesis, and with conflicting results. The purpose of this work is to further our understanding of the dynamics of amyloid-β deposition in a large longitudinal cohort. A total of 32 patients with Alzheimer's disease, 49 subjects with mild cognitive impairment and 103 healthy controls underwent two Pittsburgh compound B-positron emission tomography scans 18 months apart. For each participant, a parametric map of Pittsburgh compound B-positron emission tomography rate of change was created [(follow-up scan - baseline scan)/follow-up duration] and entered in a voxelwise three-way analysis of covariance, with clinical status (healthy controls, mild cognitive impairment or Alzheimer's disease), disease progression (clinical conversion from healthy controls to mild cognitive impairment or Alzheimer's disease, or from mild cognitive impairment to Alzheimer's disease) and Pittsburgh compound B status (positive versus negative) as independent factors. Only a significant effect of the Pittsburgh compound B status was found: both Pittsburgh compound B-positive and -negative subjects showed a significant increase in amyloid-β deposition, with this increase being significantly higher in Pittsburgh compound B-positive individuals. This finding suggests either that Pittsburgh compound B-negative individuals have slower rates of amyloid-β accumulation than positive, or that the proportion of individuals showing significant increase in amyloid-β deposition, termed 'Pittsburgh compound B accumulators', is higher within the Pittsburgh compound B-positive group than within the Pittsburgh compound B-negative group. The bimodal distribution of the individual rates of neocortical amyloid-β accumulation observed support the existence of 'Pittsburgh compound B non-accumulators' and 'Pittsburgh compound B accumulators' and different clustering analyses led to a consistent threshold to separate these two subgroups (0.014-0.022 standardized uptake value ratio(pons)/year). The voxelwise three-way analysis of covariance was thus recomputed with the 'Pittsburgh compound B accumulators' only and the results were almost unchanged, with the Pittsburgh compound B-positive group showing higher accumulation than the Pittsburgh compound B-negative group. Finally, a significant negative correlation was found between Pittsburgh compound B rate of change and Pittsburgh compound B baseline burden, but only in the Pittsburgh compound B-positive group (r= -0.24; P=0.025). Higher rates of amyloid-β deposition are associated with higher amyloid-β burden suggesting that amyloid-β deposition does not reach a plateau when cognitive impairments manifest but is instead an ongoing process present even at the Alzheimer's disease stage. amyloid-β accumulation also seems to slow down at the latest stages of the process, i.e. in participants with the highest amyloid burden. Furthermore, this study identified the existence of Pittsburgh compound 'accumulators' and 'non-accumulators', notably within the Pittsburgh compound B-negative group, which may be a relevant concept for future studies.
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http://dx.doi.org/10.1093/brain/aws125DOI Listing
July 2012

Synthetic echocardiographic image sequences for cardiac inverse electro-kinematic learning.

Med Image Comput Comput Assist Interv 2011 ;14(Pt 1):500-7

Asclepios Research Project, INRIA Sophia-Antipolis, France.

In this paper, we propose to create a rich database of synthetic time series of 3D echocardiography (US) images using simulations of a cardiac electromechanical model, in order to study the relationship between electrical disorders and kinematic patterns visible in medical images. From a real 4D sequence, a software pipeline is applied to create several synthetic sequences by combining various steps including motion tracking and segmentation. We use here this synthetic database to train a machine learning algorithm which estimates the depolarization times of each cardiac segment from invariant kinematic descriptors such as local displacements or strains. First experiments on the inverse electrokinematic learning are demonstrated on the synthetic 3D US database and are evaluated on clinical 3D US sequences from two patients with Left Bundle Branch Block.
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http://dx.doi.org/10.1007/978-3-642-23623-5_63DOI Listing
November 2011

[Neuroimaging in Alzheimer's disease: a synthesis and a contribution to the understanding of physiopathological mechanisms].

Biol Aujourdhui 2010 21;204(2):145-58. Epub 2010 Jun 21.

Universite de Caen, Caen, France.

Alzheimer's disease has become a major public health issue for occidental societies. Since animal models of Alzheimer's disease currently fail to perfectly mimic pathophysiological mechanisms or the manifestations of the disease, in vivo neuroimaging has a key role in better understanding the pathophysiology of Alzheimer's disease. The diversity of anatomical and functional neuroimaging techniques - anatomical (T1-MRI), functional (fMRI) and diffusion tensor imaging (DTI) via magnetic resonance imaging (MRI) as well as position emission tomography coupled to fluorodeoxyglucose ((18)FDG-PET) - offers a large possibility of investigation of brain alterations in Alzheimer's disease. These techniques have thus provided morphological and functional brain alterations mapping of Alzheimer's disease: on one hand grey matter atrophy first concerns the medial temporal lobe before extending to the temporal neocortex and then other neocortical areas; on the other hand, metabolic alterations are first located within the posterior cingulate cortex and then reach the temporo-parietal area as well as the prefrontal cortex, especially in its medial part. Assessments of white matter alterations with DTI have highlighted a variety of tract alterations including the cingulum bundle, a white matter tract connecting the medial temporal lobe to the posterior cingulate cortex. Finally fMRI activation studies have evidenced compensatory mechanisms through hyperactivations in Alzheimer's disease patients. Altogether these results have led to the hypothesis of two major pathophysiological mechanisms in Alzheimer's disease: on one hand compensatory mechanisms in regions where atrophy exceeds metabolic alterations, on the other disconnection between medial temporal lobe and posterior cingulate cortex through the cingulum bundle, accounting for higher metabolic than structural alterations in the posterior cingulate cortex. Our work has extensively contributed to this disconnection hypothesis thanks to the use of cross-sectional and longitudinal multi-modal neuroimaging approaches. It has underlined the relevance of distant over local mechanisms in the pathophysiology of Alzheimer's disease and offers new perspectives to the exploration of the neural bases of cognitive impairments in this disorder.
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http://dx.doi.org/10.1051/jbio/2010010DOI Listing
November 2010

Sequential relationships between grey matter and white matter atrophy and brain metabolic abnormalities in early Alzheimer's disease.

Brain 2010 Nov 5;133(11):3301-14. Epub 2010 Aug 5.

Inserm-EPHE-Université de Caen/Basse-Normandie, Unité U923, GIP Cyceron, Bd H. Becquerel, BP 5229, 14074 Caen Cedex, France.

Hippocampal atrophy, posterior cingulate and frontal glucose hypometabolism, and white-matter tract disruption are well described early macroscopic events in Alzheimer's disease. The relationships between these three types of alterations have been documented in previous studies, but their chronology still remains to be established. The present study used multi-modal fluorodeoxyglucose-positron emission tomography and magnetic resonance imaging longitudinal data to address this question in patients with amnestic mild cognitive impairment. We found unidirectional, specific sequential relationships between: (i) baseline hippocampal atrophy and both cingulum bundle (r = 0.70; P = 3 × 10⁻³) and uncinate fasciculus (r = 0.75; P = 7 × 10⁻⁴) rate of atrophy; (ii) baseline cingulum bundle atrophy and rate of decline of posterior (r = 0.72; P = 2 × 10⁻³); and anterior (r = 0.74; P = 1 × 10⁻³) cingulate metabolism; and (iii) baseline uncinate white matter atrophy and subgenual metabolism rate of change (r = 0.65; P = 6 × 10⁻³). Baseline local grey matter atrophy was not found to contribute to hypometabolism progression within the posterior and anterior cingulate as well as subgenual cortices. These findings suggest that hippocampal atrophy progressively leads to disruption of the cingulum bundle and uncinate fasciculus, which in turn leads to glucose hypometabolism of the cingulate and subgenual cortices, respectively. This study reinforces the relevance of remote mechanisms above local interactions to account for the pattern of metabolic brain alteration observed in amnestic mild cognitive impairment, and provides new avenues to assess the sequence of events in complex diseases characterized by multiple manifestations.
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http://dx.doi.org/10.1093/brain/awq203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291528PMC
November 2010

Functional brain imaging of trigeminal neuralgia.

Eur J Pain 2011 Feb 6;15(2):124-31. Epub 2010 Jul 6.

INSERM U-987, Physiopathologie et Pharmacologie Clinique de la Douleur, Hôpital Ambroise Paré, Boulogne-Billancourt F-92100, France.

We used functional magnetic resonance imaging (fMRI) to analyze changes in brain activity associated with stimulation of the cutaneous trigger zone in patients with classic trigeminal neuralgia (CTN). Fifteen consecutive patients with CTN in the second or third division of the nerve, were included in this study. The fMRI paradigm consisted of light tactile stimuli of the trigger zone and the homologous contralateral area. Stimulation of the affected side induced pain in seven patients, but was not painful in eight patients on the day of the experiment. Painful stimuli were associated with significantly increased activity in the spinal trigeminal nucleus (SpV), thalamus, primary and secondary somatosensory cortices (S1, S2), anterior cingulate cortex (ACC), insula, premotor/motor cortex, prefrontal areas, putamen, hippocampus and brainstem. Nonpainful stimulation of the trigger zone activated all but three of these structures (SpV, brainstem and ACC). After a successful surgical treatment, activation induced by stimulation of the operated side was confined to S1 and S2. Our data demonstrate the pathological hyperexcitability of the trigeminal nociceptive system, including the second order trigeminal sensory neurons during evoked attacks of CTN. Such sensitization may depend on pain modulatory systems involving both the brainstem (i.e. periaqueductal gray and adjacent structures) and interconnected cortical structures (i.e. ACC). The fact that large portions of the classical 'pain neuromatrix' were also activated during nonpainful stimulation of the trigger zone, could reflect a state of maintained sensitization of the trigeminal nociceptive systems in CTN.
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http://dx.doi.org/10.1016/j.ejpain.2010.06.006DOI Listing
February 2011

Differential effect of age on hippocampal subfields assessed using a new high-resolution 3T MR sequence.

Neuroimage 2010 Nov 16;53(2):506-14. Epub 2010 Jun 16.

Inserm-EPHE, Université de Caen/Basse-Normandie, Unité U923, GIP Cyceron, CHU Côte de Nacre, Caen, France.

Recent advances in neuroimaging have highlighted the interest to differentiate hippocampal subfields for cognitive neurosciences and more notably in assessing the effects of normal and pathological aging. The main goal of the present study is to investigate the effects of normal aging onto the volume of the different hippocampal subfields. For this purpose, we developed a new magnetic resonance sequence together with reliable tracing guidelines to assess the volume of different subfields of the hippocampus using a 3 Tesla scanner, and estimated the validity of a simpler and less time-consuming method based on the widely-used automatic Voxel-Based Morphometry (VBM) technique. Three hippocampal regions of interest were delineated on the right and left hippocampi of 50 healthy subjects between 18 and 68 years old corresponding to the CA1, subiculum and other (including CA2-3-4 and Dentate Gyrus) subfields. A strong effect of age was found on the volume of the subiculum only, with a decrease paralleling that of the global gray matter volume, while CA1 and other subfields seemed relatively spared. Although less precise than the ROI-tracing technique, the VBM-based method appeared as a reliable alternative especially to distinguish CA1 and subiculum subfields. Our findings of a specific effect of age on the subiculum are consistent with the developmental hypothesis ("last-in first-out" theory). This contrasts with the predominant vulnerability of the CA1 subfield to Alzheimer's disease reported in several previous studies, suggesting that the assessment of hippocampal subfields may improve the discrimination between normal and pathological aging.
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http://dx.doi.org/10.1016/j.neuroimage.2010.06.024DOI Listing
November 2010

A simple way to improve anatomical mapping of functional brain imaging.

J Neuroimaging 2010 Oct;20(4):324-33

Inserm-EPHE-Université de Caen/Basse-Normandie, Unité U923, GIP Cyceron, CHU Côte de Nacre, Caen, France.

Background And Purpose: Advances in functional neuroimaging studies have led to the need for improved anatomical precision to face with more and more specific challenges. Nevertheless, functional magnetic resonance imaging (MRI) (fMRI) suffers from geometrical distortions, which limit the matching between functional and anatomical data necessary to interpret fMRI results. The "FieldMap" method is the most widely used technique to correct for geometrical distortions but in some cases cannot be applied or provides unsatisfactory results. The objective of this study is thus to provide a very simple alternative method for distortion correction and to demonstrate its efficiency.

Methods: This correction relies on the nonlinear registration of echo-planar imaging (EPI) acquisitions onto their corresponding undistorted non-EPI T2 Star volume, and was tested on two independent groups of subjects undertaking the same paradigm but scanned with distinct EPI sequences.

Results: This procedure was found to considerably decrease the mismatch between functional and anatomical data in both groups, as revealed through several quantitative and qualitative measures on both EPI volumes and activation maps.

Conclusion: This study describes a simple, rapid, and easily implementable method to significantly improve neuroanatomical accuracy of fMRI results localization, which may be relevant for future neuroimaging studies.
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http://dx.doi.org/10.1111/j.1552-6569.2010.00470.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021536PMC
October 2010

Relationships between hippocampal atrophy, white matter disruption, and gray matter hypometabolism in Alzheimer's disease.

J Neurosci 2008 Jun;28(24):6174-81

Institut National de la Santé et de la Recherche Médicale-Ecole Pratique des Hautes Etudes-Université de Caen/Basse-Normandie, Unité U923, Groupement d'Intérêt Public Cyceron, Centre Hospitalier Universitaire Côte de Nacre, 14074 Caen, France.

In early Alzheimer's disease (AD), the hippocampal region is the area most severely affected by cellular and structural alterations, yet glucose hypometabolism predominates in the posterior association cortex and posterior cingulate gyrus. One prevalent hypothesis to account for this discrepancy is that posterior cingulate hypometabolism results from disconnection from the hippocampus through disruption of the cingulum bundle. However, only partial and indirect evidence currently supports this hypothesis. Thus, using structural magnetic resonance imaging and 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography in 18 patients with early AD, we assessed the relationships between hippocampal atrophy, white matter integrity, and gray matter metabolism by means of a whole-brain voxel-based correlative approach. We found that hippocampal atrophy is specifically related to cingulum bundle disruption, which is in turn highly correlated to hypometabolism of the posterior cingulate cortex but also of the middle cingulate gyrus, thalamus, mammillary bodies, parahippocampal gyrus, and hippocampus (all part of Papez's circuit), as well as the right temporoparietal associative cortex. These results provide the first direct evidence supporting the disconnection hypothesis as a major factor contributing to the early posterior hypometabolism in AD. Disruption of the cingulum bundle also appears to relate to hypometabolism in a large connected network over and above the posterior cingulate cortex, encompassing the whole memory circuit of Papez (consistent with the key location of this white matter tract within this loop) and also, but indirectly, the right posterior association cortex.
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http://dx.doi.org/10.1523/JNEUROSCI.1392-08.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902815PMC
June 2008

[Cerebral imaging and physiopathology of Alzheimer's disease].

Psychol Neuropsychiatr Vieil 2007 Dec;5(4):269-79

Inserm E0218, EPHE, Université de Caen Basse-Normandie, GIP Cyceron, CHU Côte de Nacre, Caen, France.

Alzheimer's disease (AD) is characterised by macroscopic cerebral damages which can be studied in vivo with neuroimaging techniques, even at the earliest stage. Studies were conducted in patients with amnestic Mild Cognitive Impairment (MCI) who best represent incipient AD. Right temporo-parietal hypometabolism, assessed by resting-state (18)FDG-PET, distinguishes patients who further develop AD from those who remain stable. From the pre-dementia stage of MCI, atrophy of the hippocampal region detected with structural MRI contrasts with functional alteration of the posterior cingulate gyrus measured with (18)FDG-PET and SPECT. Results from resting-state fMRI confirm this pattern of functional abnormalities and highlight changes in the hippocampal region functional connectivity, decreased with the posterior cingulate region, and increased with some frontal areas. Altogether with a structural connectivity impairment highlighted by DTI, those results support the hypothesis of a dysconnexion between the hippocampal and the posterior cingulate regions. Finally, activation fMRI data support the hypothesis of a functional compensation involving not only the frontal cortex but also, at the pre-dementia stage, the hippocampal region. Thus, this synthesis focuses on the hypotheses of dysconnexion and functional compensation, suggested to explain the discrepancies between the structural and functional alteration patterns, as well as on relevant results from resting-state fMRI, DTI and activation fMRI studies. Furthermore, this synthesis emphasizes the relevance of neuroimaging for the early detection of AD.
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December 2007

Three-dimensional edge-preserving image enhancement for computed tomography.

IEEE Trans Med Imaging 2003 Oct;22(10):1275-87

Biomedical Engineering Institute, Ecole Polytechnique, Montreal, QC H3C 3A7, Canada.

Computed tomography (CT) images exhibit a variable amount of noise and blur, depending on the physical characteristics of the apparatus and the selected reconstruction method. Standard algorithms tend to favor reconstruction speed over resolution, thereby jeopardizing applications where accuracy is critical. In this paper, we propose to enhance CT images by applying half-quadratic edge-preserving image restoration (or deconvolution) to them. This approach may be used with virtually any CT scanner, provided the overall point-spread function can be roughly estimated. In image restoration, Markov random fields (MRFs) have proven to be very flexible a priori models and to yield impressive results with edge-preserving penalization, but their implementation in clinical routine is limited because they are often viewed as complex and time consuming. For these practical reasons, we focused on numerical efficiency and developed a fast implementation based on a simple three-dimensional MRF model with convex edge-preserving potentials. The resulting restoration method provides good recovery of sharp discontinuities while using convex duality principles yields fairly simple implementation of the optimization. Further reduction of the computational load can be achieved if the point-spread function is assumed to be separable. Synthetic and real data experiments indicate that the method provides significant improvements over standard reconstruction techniques and compares well with convex-potential Markov-based reconstruction, while being more flexible and numerically efficient.
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http://dx.doi.org/10.1109/TMI.2003.817767DOI Listing
October 2003
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