The Medical Imaging Laboratory is a research group within the Hospital General Universitario Gregorio Marañón. The main research line of the group is focused
towards the development and exploitation of medical imaging techniques, including the
development of new processing tools for image analysis in clinical and preclinical research.
The group has a multi-disciplinary profile and a priority for translational research topics, derived from real problems faced by the clinical specialists. One of the main research areas is the development of technologies for molecular imaging, some of which have been transferred to the industry and are now among the top products of the market. These systems include high-resolution PET, CT and PET-CT. Over the last years the group has developed
several software tools to enable quantification of multimodal brain images using morphometric and functional data. Some research applications of these hardware and software tools are illustrated in the paper“Ministerio de Sanidad y Consumo”, CDTEAM Programa CÉNIT, Ministerio de Industria. FIS PI052271 “Ministerio de Sanidad y Consumo”. CIBER Salud Mental (CIBERSAM) “Ministerio de Sanidad y Consumo” and Fundación Mutua MadrileñaPublicad

Desco Menéndez, Manuel

García Barreno, P.

Pascau González Garzón, Javier

Reig, S.

Soto Montenegro, M. L.

Vaquero López, Juan José

The European Journal of Psychiatry

Name not available

Research at the medical imaging laboratory, CIBERSAM CB07/09/0031

Reig, Santiago

Soto Montenegro, Mª Luisa

Pascau González-Garzón, Javier

García Barreno, Pedro

Universidad Carlos III de Madrid e-Archivo

Keywords: Neuroimaging; Translational Research;Molecular imaging; PET; CT; PET-CT.Research at the Medical Imaging Laboratory,CIBERSAM CB07/09/0031M. DescoS. ReigM.L. SotoJ. PascauJ.J. VaqueroP. Garcia-BarrenoMedical Imaging Laboratory, Unit ofExperimental Medicine and Surgery.Hospital General Universitario “GregorioMarañón”, MadridCentro de Investigación Biomédica en Redde Salud Mental (CIBERSAM), Ministry ofScience and InnovationSPAINABSTRACT –  The Medical Imaging Laboratory is a research group within the HospitalGeneral Universitario Gregorio Marañón. The main research line of the group is focusedtowards the development and exploitation of medical imaging techniques, including thedevelopment of new processing tools for image analysis in clinical and preclinical rese-arch. The group has a multi-disciplinary profile and a priority for translational research to-pics, derived from real problems faced by the clinical specialists. One of the main researchareas is the development of technologies for molecular imaging, some of which have beentransferred to the industry and are now among the top products of the market. These sys-tems include high-resolution PET, CT and PET-CT. Over the last years the group has de-veloped several software tools to enable quantification of multimodal brain images usingmorphometric and functional data. Some research applications of these hardware and soft-ware tools are illustrated in the paper.Received 8 January 2009Revised 3 April 2009Accepted 3 April 20091ResourcesThe Medical Imaging Laboratory was creat-ed in the early 90’ as a small group embeddedin the general research Department of the Hos-pital General Universitario Gregorio Marañónat Madrid. Parallel to the enormous expansionin the field of medical imaging, during the pastdecade the group underwent an exponentialgrowth in human resources (from less than 5 to35) and technical means. The facilities of theNeuroimaging Research Laboratory include aspace of 350 m2 that include offices, electron-ic workshop, and animal imaging laboratory.The most significant facilities are molecularimaging scanners of several modalities, forpreclinical use (high resolution CT, PET, MRI,SPECT, and Optical Imaging). Funding duringthe last six years has come from more than 30national or international research projectsgranted to the group, from public or privateprograms, as well as from technology transfersto the industry.ResearchThe main research line of the group is fo-cused towards the development and exploita-tion of medical imaging techniques, includingthe development of new processing tools forimage analysis in clinical and preclinical re-search. The group has a noticeable multi-disci-plinary profile and its location within the Hos-pital warrants an excellent connection withclinicians and ensures a higher priority fortranslational research topics, derived from realproblems faced by the clinical specialists. Themulti-disciplinary composition of the groupallows for a rapid validation of the results ob-tained in the research projects, also facilitatingthe technology transfer to industry. Some ofthe main research topics of the group in thefield of neuroimaging are presented below.High resolution imaging oflaboratory small animalsMolecular imaging techniques applied toanimal models are an excellent tool to studypathological processes. One of the main re-search areas in our group is the development oftechnologies for molecular imaging, some ofwhich have been transferred to the industryand are now among the top products of themarket. These systems include high-resolutionpositron emission scanners (PET) computer-ized tomography scanners (CT) and its combi-nation (PET-CT) (Figure 1), nowadays one ofthe most useful tools for biomedical researchin the area of molecular imaging1,2. PET en-ables the monitoring of biochemical processes“in vivo” at a molecular level. This techniquehas multiple applications in the developmentof new drugs, in the study of human diseaseson animal models or in the characterization ofthe genomic expression and phenotypicalchanges caused by genetic manipulation(transgenic, knock-out or knock-in animals).An ongoing imaging project deals with thecerebral damage produced by the new “de-sign” drugs (MDMA, methamphetamine).The main objective of the study is to combinePET and CT techniques to evaluate the dam-age to serotonergic neurons and to determinewhether there is damage to dopaminergic neu-rons, taking into account factors such as sex,type of drug and dosage scheme. The two sub-stances selected were MDMA and metham-phetamine, the former with a clear preferencefor the serotonergic system and perhaps forthe dopaminergic system; and the latter with apreference for the dopaminergic system3.With the help of high-resolution animal PET-CT we can correlate serotoninergic anddopaminergic changes with changes in brainfunction and with its exact location in thebrain. Furthermore, the study aims to deter-mine to what extent the neurons may recoverfrom the damage induced by MDMA. 2Brain Imaging quantificationOver the last years the group has devel-oped several software tools to enable quan-tification of multimodal brain images usingmorphometric and functional data. One ofthese software tools is based on the Talairachproportional grid system4,5. Using this toolwe can benefit from the anatomical informa-tion of structural images to quantify func-tional images that have poor spatial resolu-tion, like such as PET or perfusion (cerebralblood volume) scans (Figure 2).The Talairach quantification tool is an ap-plication of the Talairach proportional gridsystem6, used as a method for semiautomat-ic segmentation and analysis of MRI andfunctional images (PET, or Cerebral BloodVolume maps obtained by MR Perfusionweighted images). The method can be de-scribed as a multimodal application wherethe anatomical information of the MRI isused to build the Talairach grid and a co-reg-istered functional image is superimposed onthe same grid. By doing so, the Talairach-normalized tessellation of the brain is di-rectly extended to functional images, allow-Figure 1. An illustration of molecular imaging. Triplanar view of an 18F-FDG PET rat study fused with a CT of the sameanimal. Images were acquired with the VrPET/CT, a system developed in our group.Figure 2. A screenshot of the software tool developed for volumetric and functional quantification of brain images. The triplanarview shows a Talairach grid built upon an MRI and a co-registered PET superimposed for quantification. For each of the 1,065cells of the grid, volume and metabolic data is obtained for each brain tissue (total or WM, GM, CSF separately).3ing for a convenient regional analysis ofvolume and activity rates of brain struc-tures, defined in the Talairach Atlas as setsof cells. This procedure requires minimalmanipulation of brain geometry, thus fullypreserving individual brain morphology.The brain standardization proposed in theTalairach grid system begins with a reorien-tation centered on the anterior and posteriorcommissures and the inter-hemisphericplane as the vertical axis, followed by apiecewise linear transformation that pro-duces a tessellation of the brain into a 3Dgrid of 1,056 cells representing homologousbrain regions across subjects. This subdivi-sion of the brain according to the Talairachgrid system allowed us to use it as the basisfor a segmentation method for inter-subjectcomparisons, by defining brain regions of in-terest (ROI) as sets of 3D volume grid cellsor ‘boxels’. Following this procedure fordefining ROI’s we have been identified over20 brain regions, from which we can obtainvolume data for each tissue (Gray Matter,White Matter, and CSF), metabolic activity(PET) or perfusion (cerebral blood volume),for the whole brain parenchyma or separate-ly for each tissue. Using this tool, we obtaindata for more than 400 anatomical and func-tional variables4,5. This software have beenused in numerous publications related tostructural and functional alterations of psy-chiatric patients.Effect of spatial normalizationon voxel-wise studiesIn pathologic brains with morphologicalalterations, the process of spatial normaliza-tion, as performed by Statistical ParametricMapping (SPM) methods, may introduce aconfounding effect in the measurement offunctional (metabolic) activity data. We haveinvestigated the effect of the spatial normal-ization of PET images, using MRI and PETstudies of schizophrenic patients and con-trols7. Using the Talairach-based segmenta-tion tool mentioned above, and manual seg-mentation, we measured regional metabolicactivity in the untransformed brains and aftertheir spatial normalization. We observed thatthe spatial normalization has little effect forlarge ROIs, such as the main brain lobes, evenin brains showing pronounced morphologicalabnormalities. However, smaller structures asthe caudate nucleus show a considerablechange in metabolic activity values after nor-malization. This normalization bias is muchlarger in patients than in controls, and maylead to artifactual differences between bothgroups if the data are assessed by means ofvoxel-wise methods (SPM). We concludedthat spatial normalization of the PET imagesof pathologic brains may introduce a poten-tial source of error that should be taken intoaccount in the analysis of functional data, inparticular, when studying small brain nucleias the caudate7.Neuroimaging studies inneurogical and mentaldiseases In the field of medical imaging, the neurog-ical and mental diseases are one of the mosttypical examples of problems which require amultidisciplinary approach. Following a mul-timodality strategy to describe structural andfunctional brain alterations, in our researchgroup we make use of the following tech-niques: structural imaging (MR, CT), for vol-umetric and morphometric studies; magneticresonance spectroscopy (MRS), for measure-ments of some neural metabolites (N-acetil-4aspartate, creatine, choline, mio-inositol);perfusion, to measure microvascularization ofcerebral tissue; diffusion tensor imaging, formeasurements of White Matter anisotropyand tractography; and PET imaging using18F-FDG as tracer, for measurement of glu-cose metabolism as a marker of neuronalactivity.Schizophrenia The interest of quantitative data extractedfrom the neuroimaging studies in schizo-phrenia derives from multiple previous find-ings of groups of schizophrenic patientswho show functional and structural brain al-terations (e.g., atrophy of frontal cortex),sometimes related to clinical manifestations(predominating symptoms, evolution, phar-macological response) or to treatment. Togenerate accurate quantitative data, we mea-sure the volume of the main brain lobes andtheir tissues (WM, GM and CSF), exploringthe structural alterations detectable in chron-ic and recent onset patients. Among the keyfindings in our studies, we have found signif-icant clinical and biological differences be-tween treatment resistant and non treatmentresistant schizophrenia patients8. These dif-ferences included greater clinical severity inthe treatment resistant sample at baseline,and different baseline anatomical (volumet-ric) and electrophysiological (response toP300) parameters, together with longitudinalchanges in cerebral volumes after treatmentwith atypical neuroleptics. The structural dif-ferences showed a significant degree of sen-sitivity and specificity, which supports theexistence of a distinct subgroup of patientswith marked frontal deficits and a poorer re-sponse to treatment within the spectrum ofschizophrenia8.Alzheimer’s diseaseAn early diagnosis of AD and its discrim-ination against other types of dementias(Lewy, fronto-temporal) are key issues toestablish the appropriate treatment, theprognosis and a forecast of the forthcomingsocial needs of the patient. To achieve anearlier and more reliable diagnosis, a com-bined used of several imaging techniqueshave been proposed, with the aim of detect-ing early changes associated with the dis-ease. In order to detect structural and func-tional alterations, 18F-FDG PET images areused in combination with four MRI tech-niques: 1) Anatomical image sequences T1and T2, for volumetric measurements; 2)spectroscopic studies, to assess the bio-chemical changes in neurological metabo-lite markers such as N-acetyl-aspartate,Choline, and Creatine; 3) perfusion studies,to assess the functionality of parenchymalmicrovasculature and 4) DTI studies, toasses the integrity of white matter tracts.Preliminary results show lower volumes ofGM and less blood volume flow in the tem-poral lobe of patients with severe dementiasymptoms compared with patients with milddementia, suggesting that we can distinguishbetween different degrees of cognitive im-pairment at early stages of AD9.AcknowledgmentsCIBER CB06/01/0079 “Ministerio de Sani-dad y Consumo”, CDTEAM ProgramaCÉNIT, Ministerio de Industria. FIS PI052271“Ministerio de Sanidad y Consumo”. CIBERSalud Mental (CIBERSAM) “Ministerio deSanidad y Consumo” and Fundación MutuaMadrileña.5References1. Vaquero JJ, Lage E, Ricón L, Redondo S, Pascau J,Sánchez J, et al. Co-Planar PET/CT for Small Animal Ima-ging. 2005 Nuclear Science Symposium and Medical Ima-ging Conference (IEEE) 2005:235-236.2. Vaquero JJ, Desco M, Pascau J, Santos A, Lee I, Sei-del J, et al. PET, CT, and MR Image Registration of the RatBrain and Skull. IEEE T Nucl Sci 2001; 48(4):1440-1445.3. Soto-Montenegro ML, Vaquero JJ, Molins A, Reig S,Desco M. FDG-PET studies of the effect of MDMA in ratbrain, in 10th Annual Meeting of the Organization forHuman Brain Mapping. Budapest, Hungary, 2004.4. Desco M, Pascau J, Reig S, Gispert JD, Santos A,Benito C, et al. Multimodality Image Quantification usingTalairach Grid, in Medical Imaging 2001 Conference(SPIE). San Diego, California, 2001.5. Desco M, López J, Benito C, Santos A, Domínguez P,Reig S, et al. A Multimodality Workstation in Practice.CARS’99. Computer Assisted Radiology and Surgery1999: 218-222.6. Talairach J, Tournoux P. Co-planar Stereotaxic Atlasof the Human Brain. New York: Thieme Medical; 1988.7. Reig S, Penedo M, Gispert JD, Pascau J, Sánchez-González J, García-Barreno P, et al. Impact of ventricular en-largement on the measurement of metabolic activity in spa-tially normalized PET. Neuroimage 2007; 35(2):748-758.8. Molina V, Reig S, Sanz J, Palomo T, Benito C, SarrameaF, et al. Differential clinical, structural and P300 parameters inschizophrenia patients resistant to conventional neuroleptics.Prog Neuro-Psychoph 2008; 32(1):257-266.9. Guzmán J, Reig S, Olazarán J, Cruz I, Navarro E,Ezpeleta D, et al. Regional quantification of brain cerebralblood volume maps using the Talairach proportional gridsystem. Eur Radiol 2008; 18(Suppl 1):S749.Author for correspondence:Manuel DescoLaboratorio de Imagen MédicaUnidad de Medicina y Cirugía ExperimentalCIBERSAM Hospital General Universitario “Gregorio Marañón”Dr. Esquerdo, 4628007 MadridSpainPhone: +34 91 586 6678Fax: +34 91 426 5108E-mail:desco@mce.hggm.es6

Desco, Manuel

Soto-Montenegro, M. L.

Pascau, Javier

Vaquero, Juan José

García-Barreno, P.

http://e-archivo.uc3m.es/bitstream/handle/10016/12221/research_EJP_2009_ps.pdf?sequence=1&isAllowed=y

Research at the medical imaging laboratory, CIBERSAM CB07/09/0031

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