Positron emission tomography provides quantitative measurements of radio-tracer concentrations in vivo to study physiological and molecular processes with radio-labelled compounds of biological affinity. Its application in Cardiology includes the measurement of myocardial blood flow. Quantification of regional blood flow across the myocardium may provide insight in the understanding of the physiological mechanisms involved in ischaemia. However, such measurements are restricted by scanner resolution and sensitivity and the influence of organ motion during data acquisition. Significant improvements in sensitivity in 3D mode of acquisition allow the exploitation of the inherent spatial resolution of the latest generation of PET tomographs. In addition, the acquisition of individual events in list mode makes possible the implementation of motion correction schemes. The problem of obtaining accurate attenuation correction factors, in the absence of septa, was addressed by using single photon transmission measurements and an image segmentation technique, the Local Threshold Segmentation of the attenuation coefficients. This approach was found to provide accurate attenuation coefficients and a scheme for generating attenuation correction factors for absolute quantification could be defined. The influence of motion on the spatial resolution on a current generation 3D PET scanner was assessed with experimental measurements at typical levels of respiration- related motion and was found to be significant for quantitative imaging of the myocardium. Simultaneous electrocardiographic and respiratory gating of list-mode data was implemented and validated. This dual gating approach can be used in data of high counting statistics for the elimination of motion within a single image frame. For count-limited measurements of myocardial blood flow, a method for compensating for respiratory motion, at no loss of total counts, was presented. Validation results showed a generally good accuracy and the technique was applied to 18FDG and C15O patient data. Improvement in the recovery coefficient for accurate tracer concentration assessed against well-counter measurements of blood sample tracer concentration was found for the C15O data.

名古屋大学博士学位論文 学位の種類 : 博士(医学)(論文) 学位授与年月日:平成5年9月14日 家田信人氏の博士論文として提出された

名古屋大学博士学位論文 学位の種類 : 博士(医学)(論文) 学位授与年月日:平成5年9月14日 加藤亨嗣氏の博士論文として提出された

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La perfusion est un facteur important dans la viabilité et la fonction du myocarde. Des atteintes microvasculaires diffuses, précédant l'infarctus ou l'insuffisance cardiaque sont impliqués dans bon nombre de pathologies cardiaques. Ce travail vise à améliorer les techniques existantes de mesure quantitatives et non-invasive de la perfusion myocardique par marquage de spins artériels (ASL). La première partie de mon travail de thèse a consisté en la mise place chez la souris d'une technique alternative pour mesurer la perfusion myocardique. Celle-ci est basée sur un marquage pulsé et régulièrement répété afin de construire un état d'équilibre de l'aimantation sous l'influence de la perfusion (approche steady-pulsed ASL). Le modèle théorique associé à cette technique spASL a été développé en parallèle afin de quantifier le flux sanguin tissulaire. Il a été montré que spASL permettait d'obtenir un résultat similaire aux techniques existantes avec en plus, les avantages d'améliorer la sensibilité au signal de perfusion ainsi que de réduire le temps d'acquisition. Dans un second temps, un transfert vers l'imagerie clinique pour une application chez l'homme a été entrepris. Le marquage de type spASL a été conservé et le module de lecture a été adapté aux spécificités de l'imagerie cardiaque chez l'homme pour une acquisition en respiration libre. Un post-traitement dédié qui comprend une correction de mouvement rétrospective a ensuite vu le jour afin d'améliorer la robustesse de nos mesures. Parallèlement aux développements conduits chez l'homme, nous avons exploité l'approche spASL chez l'animal en proposant diverses améliorations en fonction des études menées. / Myocardial blood flow is an important factor of tissue viability and function. Diffuse changes in microcirculation preceding heart failure are involved in various cardiac pathologies. This work aim at improving existing techniques allowing quantitative and non-invasive myocardial perfusion assessment using arterial spin labeling. The first step of my work was to design an alternative approach to quantify myocardial blood flow in mice. The so called steady-pulsed ASL (spASL) is based on a regularly repeated pulsed labeling in order to build up a stationary regime of the magnetization under the influence of perfusion. The associated theoretical model has been developed in parallel to quantify tissue blood flow. We have shown that spASL allows to obtain similar results than the previously employed techniques, with the additional advantages of an increased sensitivity to the perfusion signal and a reduced acquisition time. A transfer towards clinical imaging for human applications was then undertaken. The spASL labeling scheme has been preserved while adapting the readout module to the specificities of cardiac MRI when applied to free-breathing human acquisitions. A dedicated post-processing, which includes a retrospective motion correction, has emerged subsequently to improve the robustness of our measurements. In parallel to the developments made for human studies, some optimization of the spASL technique when applied to rodent have been carried out depending on the conducted studies.

Fundamento: A artéria torácica interna (ATI) \"in situ\" apresenta predomínio de fluxo sistólico, mas após sua anastomose no sistema coronariano esquerdo torna-se um sistema híbrido com predomínio de fluxo diastólico, sendo a relevância da patência ou não dos grandes ramos proximais da ATI anastomosada controversa quanto à possibilidade de roubo de fluxo. Porém, constata-se que durante o ecocardiograma sob estresse com dobutamina (EED), o estado funcional da ATI anastomosada pode ser avaliado através da reserva coronariana, além da verificação dos distintos efeitos no fluxo sistólico (FS), diastólico (FD) e total (FT = sistólico + diastólico). Objetivo: Verificar por meio da ecocardiografia e Doppler o efeito dos ramos proximais importantes da ATI no fluxo, na reserva de velocidade (RVFC) e de fluxo (RFC) coronariano, em pacientes com fração de ejeção do ventrículo esquerdo (FEVE) preservada (> 50%). Métodos: Em ensaio clínico prospectivo controlado e randomizado, foram avaliados pacientes com (Grupo I) e sem (Grupo II), a ligadura dos ramos proximais importantes da ATI anastomosada na coronária descendente anterior. As avaliações das ATIs em nível supraclavicular e os ecocardiogramas transtorácicos foram realizados no pré-operatório, no pós-operatório precoce, seis meses após a cirurgia em condição basal e durante o EED. Neste, foi alcançada a frequência cardíaca submáxima [(220 - idade) x (0,85)] sem a ocorrência de isquemia no território subjacente à ATI anastomosada em todos os pacientes. Foram medidos o FS, o FD, o FT e o percentual de FD, nos quatro momentos do estudo. O percentual de FD resultou da divisão da integral da velocidade diastólica do fluxo pela integral da velocidade total (sistólica + diastólica) do fluxo. A reserva coronariana foi obtida através do Doppler da ATI anastomosada seis meses após a cirurgia, sendo calculada através da razão entre o valor da variável registrado no EED e em condição basal, utilizando-se para as RVFCs o pico e a média de velocidade diastólica, e para a RFC o FT. As distribuições das variáveis contínuas foram comparadas através do Teste t Student, quando as variáveis eram aproximadamente normais, ou através do Teste da Soma dos Postos de Wilcoxon (Mann-Whitney), quando as variáveis não eram aproximadamente normais. Proporções foram comparadas através do teste exato de Fisher. O valor-p < 0,05 entre os grupos foi considerado estatisticamente significativo. Resultados: O Grupo I (25 pacientes) e o Grupo II (28 pacientes) não foram diferentes quanto às características clínicas e ecocardiográficas, constatando-se a FEVE preservada em todos os casos. O FD não diferiu entre os grupos nos quatro momentos do estudo. Entretanto, verificou-se durante o EED que o FS (19,5 ± 9,3 ml/min vs. 32,7 ± 19,4 ml/min; p < 0,05) e o FT (79,1 ± 21,4 ml/min vs. 101,1 ± 47,4 ml/min; p < 0,05) foram maiores no Grupo II. Contudo, o percentual de FD foi maior no Grupo I (76,4 ± 12,7% vs. 68,9 ± 10%; p < 0,05) durante o EED, em virtude de o Grupo I apresentar menos componente sistólico. O percentual de FD < 50% ocorreu em todos os casos no pré - operatório, em cinco casos no pós - operatório precoce e em dez casos em condição basal seis meses após a cirurgia. Todavia, durante o EED, todos os casos apresentaram o percentual de FD > 50%, sendo este percentual de 100% em cinco casos (quatro no Grupo I). Os grupos não apresentaram diferença entre as RFCs (1,9 ± 0,46 vs. 2,11 ± 0,56; p = 0,143) ou as RVFCs calculadas com o pico (2,17 ± 0,64 vs.2,28 ± 0,63; p = 0,537) e com a média (2,27 ± 0,54 vs.2,50 ± 0,79; p= 0,232) da velocidade diastólica. Conclusão: Concluímos que o adequado estado funcional da ATI anastomosada independe da presença ou ausência dos importantes ramos proximais. Assim, a ligadura dos ramos não determina aumento do fluxo sistólico, diastólico ou total através deste enxerto, e o predomínio diastólico é mais evidente sob a condição estresse. O aumento dos fluxos sistólico e total indicam para a adaptação do fluxo através desta artéria para suprir a ambas, circulação coronariana e não coronariana, nos pacientes que não têm esses ramos ligados durante a cirurgia. Estes achados apontam para o entendimento de que a hipótese do roubo de fluxo pelos ramos não ligados é improvável / Background: The internal thoracic artery (ITA) \"in situ\" has systolic flow predominance, but when grafted to the left coronary artery system, the ITA becomes a hybrid system with diastolic flow predominance. The relevance of the patency or not-patency of the large proximal branches of the ITA graft is controversial in regards to the possibility of flow steal. During dobutamine stress echocardiography (DSE), the functional status of the ITA graft can be assessed by the coronary reserve in addition to assessment of the distinct effects of DSE on systolic (SF), diastolic (DF), and total flow (TF = systolic + diastolic). Objective: To assess, by Doppler echocardiography, the effects of the significant proximal branches of ITA graft in the flow, coronary flow velocity reserve (CFVR) and coronary flow reserve (CFR), in patients with preserved (> 50%) left ventricular ejection fraction (LVEF). Methods: In a prospective randomized controlled clinical trial we evaluate patients with (Group I) and without (Group II) ligation of important proximal branches of the ITA grafted to the anterior descending coronary artery. Supraclavicular assessment of the ITAs and transthoracic echocardiograms were performed, at rest and during DSE, on pre-operative, early and six months post-operative. In all patients, the submaximal heart rate [(220 - age) x (0.85)] was achieved during DSE with no ischemia to the area matching the ITA graft. The SF, DF, TF and percentage of DF were measured in the four moments of this study. The percentage of DF was calculated by the ratio of the integral of the diastolic flow velocity by the integral of the total flow velocity (systolic + diastolic). The coronary reserve was assessed at six months post-operative, and it was calculated by the ratio of the variable during DSE and at rest, using the maximum and the mean of the diastolic flow velocity to calculate the CFVR; and the TF to calculate the CFR. Student\'s t-tests or Wilcoxon\'s rank sum test (Mann-Whitney) were used to examine differences between the groups in normally distributed or not-normally-distributed continuous variables, respectively. Fisher exact test was used to examine the difference in proportions. A p value < 0.05 was considered statistically significant. Results: Group I (25 patients) and Group II (28 patients) were not different regarding to clinical and echocardiographic characteristics, with preservation of the LVEF in all cases. The DF was not different between the groups in the four moments of this study. However, during the DSE, the SF (19.5 ± 9.3 ml/min vs. 32.7 ± 19.4 ml/min, p < 0.05) and TF (79.1 ± 21.4 ml/min vs. 101 1 ± 47.4 ml/min; p < 0.05) were higher in Group II. On the other hand, during the DSE, the percentage of DF was higher in Group I (76.4 ± 12.7% vs. 68.9 ± 10%; p < 0.05), due to its lower systolic component. The percentage of DF < 50% occurred in all cases in the pre-operative, in five cases in the early post-operative and in ten cases, at rest, six months postoperatively. However, during the DSE, all cases showed the percentage of DF > 50%, furthermore five cases (four in Group I) had the percentage of DF of 100%. There was no difference between the groups in regards to CFR (1.9 ± 0.46 vs. 2.11 ± 0.56; p = 0.143), or CFVR calculated using the maximum (2.17 ± 0.64 vs. 2.28 ± 0.63; p = 0.537) and the mean (2.27 ± 0.54 vs. 2.50 ± 0.79; p = 0.232) of the diastolic velocity. Conclusion: The appropriate functional status of the ITA graft does not depend on the ligation or preservation of important proximal ITA branches. Thus, ligation of ITA branches does not determine increase in systolic, diastolic or total flow through the ITA graft, and its diastolic predominance is more evident under stress. The increase in the systolic and total flow indicates an adaptation of the flow through the ITA graft to supply both coronary and non-coronary systems, in those patients that don\'t have the branches ligated during surgery. These findings point towards the hypothesis that the flow steal by unligated branches is unlikely.

Fundamento: A artéria torácica interna (ATI) \"in situ\" apresenta predomínio de fluxo sistólico, mas após sua anastomose no sistema coronariano esquerdo torna-se um sistema híbrido com predomínio de fluxo diastólico, sendo a relevância da patência ou não dos grandes ramos proximais da ATI anastomosada controversa quanto à possibilidade de roubo de fluxo. Porém, constata-se que durante o ecocardiograma sob estresse com dobutamina (EED), o estado funcional da ATI anastomosada pode ser avaliado através da reserva coronariana, além da verificação dos distintos efeitos no fluxo sistólico (FS), diastólico (FD) e total (FT = sistólico + diastólico). Objetivo: Verificar por meio da ecocardiografia e Doppler o efeito dos ramos proximais importantes da ATI no fluxo, na reserva de velocidade (RVFC) e de fluxo (RFC) coronariano, em pacientes com fração de ejeção do ventrículo esquerdo (FEVE) preservada (> 50%). Métodos: Em ensaio clínico prospectivo controlado e randomizado, foram avaliados pacientes com (Grupo I) e sem (Grupo II), a ligadura dos ramos proximais importantes da ATI anastomosada na coronária descendente anterior. As avaliações das ATIs em nível supraclavicular e os ecocardiogramas transtorácicos foram realizados no pré-operatório, no pós-operatório precoce, seis meses após a cirurgia em condição basal e durante o EED. Neste, foi alcançada a frequência cardíaca submáxima [(220 - idade) x (0,85)] sem a ocorrência de isquemia no território subjacente à ATI anastomosada em todos os pacientes. Foram medidos o FS, o FD, o FT e o percentual de FD, nos quatro momentos do estudo. O percentual de FD resultou da divisão da integral da velocidade diastólica do fluxo pela integral da velocidade total (sistólica + diastólica) do fluxo. A reserva coronariana foi obtida através do Doppler da ATI anastomosada seis meses após a cirurgia, sendo calculada através da razão entre o valor da variável registrado no EED e em condição basal, utilizando-se para as RVFCs o pico e a média de velocidade diastólica, e para a RFC o FT. As distribuições das variáveis contínuas foram comparadas através do Teste t Student, quando as variáveis eram aproximadamente normais, ou através do Teste da Soma dos Postos de Wilcoxon (Mann-Whitney), quando as variáveis não eram aproximadamente normais. Proporções foram comparadas através do teste exato de Fisher. O valor-p < 0,05 entre os grupos foi considerado estatisticamente significativo. Resultados: O Grupo I (25 pacientes) e o Grupo II (28 pacientes) não foram diferentes quanto às características clínicas e ecocardiográficas, constatando-se a FEVE preservada em todos os casos. O FD não diferiu entre os grupos nos quatro momentos do estudo. Entretanto, verificou-se durante o EED que o FS (19,5 ± 9,3 ml/min vs. 32,7 ± 19,4 ml/min; p < 0,05) e o FT (79,1 ± 21,4 ml/min vs. 101,1 ± 47,4 ml/min; p < 0,05) foram maiores no Grupo II. Contudo, o percentual de FD foi maior no Grupo I (76,4 ± 12,7% vs. 68,9 ± 10%; p < 0,05) durante o EED, em virtude de o Grupo I apresentar menos componente sistólico. O percentual de FD < 50% ocorreu em todos os casos no pré - operatório, em cinco casos no pós - operatório precoce e em dez casos em condição basal seis meses após a cirurgia. Todavia, durante o EED, todos os casos apresentaram o percentual de FD > 50%, sendo este percentual de 100% em cinco casos (quatro no Grupo I). Os grupos não apresentaram diferença entre as RFCs (1,9 ± 0,46 vs. 2,11 ± 0,56; p = 0,143) ou as RVFCs calculadas com o pico (2,17 ± 0,64 vs.2,28 ± 0,63; p = 0,537) e com a média (2,27 ± 0,54 vs.2,50 ± 0,79; p= 0,232) da velocidade diastólica. Conclusão: Concluímos que o adequado estado funcional da ATI anastomosada independe da presença ou ausência dos importantes ramos proximais. Assim, a ligadura dos ramos não determina aumento do fluxo sistólico, diastólico ou total através deste enxerto, e o predomínio diastólico é mais evidente sob a condição estresse. O aumento dos fluxos sistólico e total indicam para a adaptação do fluxo através desta artéria para suprir a ambas, circulação coronariana e não coronariana, nos pacientes que não têm esses ramos ligados durante a cirurgia. Estes achados apontam para o entendimento de que a hipótese do roubo de fluxo pelos ramos não ligados é improvável / Background: The internal thoracic artery (ITA) \"in situ\" has systolic flow predominance, but when grafted to the left coronary artery system, the ITA becomes a hybrid system with diastolic flow predominance. The relevance of the patency or not-patency of the large proximal branches of the ITA graft is controversial in regards to the possibility of flow steal. During dobutamine stress echocardiography (DSE), the functional status of the ITA graft can be assessed by the coronary reserve in addition to assessment of the distinct effects of DSE on systolic (SF), diastolic (DF), and total flow (TF = systolic + diastolic). Objective: To assess, by Doppler echocardiography, the effects of the significant proximal branches of ITA graft in the flow, coronary flow velocity reserve (CFVR) and coronary flow reserve (CFR), in patients with preserved (> 50%) left ventricular ejection fraction (LVEF). Methods: In a prospective randomized controlled clinical trial we evaluate patients with (Group I) and without (Group II) ligation of important proximal branches of the ITA grafted to the anterior descending coronary artery. Supraclavicular assessment of the ITAs and transthoracic echocardiograms were performed, at rest and during DSE, on pre-operative, early and six months post-operative. In all patients, the submaximal heart rate [(220 - age) x (0.85)] was achieved during DSE with no ischemia to the area matching the ITA graft. The SF, DF, TF and percentage of DF were measured in the four moments of this study. The percentage of DF was calculated by the ratio of the integral of the diastolic flow velocity by the integral of the total flow velocity (systolic + diastolic). The coronary reserve was assessed at six months post-operative, and it was calculated by the ratio of the variable during DSE and at rest, using the maximum and the mean of the diastolic flow velocity to calculate the CFVR; and the TF to calculate the CFR. Student\'s t-tests or Wilcoxon\'s rank sum test (Mann-Whitney) were used to examine differences between the groups in normally distributed or not-normally-distributed continuous variables, respectively. Fisher exact test was used to examine the difference in proportions. A p value < 0.05 was considered statistically significant. Results: Group I (25 patients) and Group II (28 patients) were not different regarding to clinical and echocardiographic characteristics, with preservation of the LVEF in all cases. The DF was not different between the groups in the four moments of this study. However, during the DSE, the SF (19.5 ± 9.3 ml/min vs. 32.7 ± 19.4 ml/min, p < 0.05) and TF (79.1 ± 21.4 ml/min vs. 101 1 ± 47.4 ml/min; p < 0.05) were higher in Group II. On the other hand, during the DSE, the percentage of DF was higher in Group I (76.4 ± 12.7% vs. 68.9 ± 10%; p < 0.05), due to its lower systolic component. The percentage of DF < 50% occurred in all cases in the pre-operative, in five cases in the early post-operative and in ten cases, at rest, six months postoperatively. However, during the DSE, all cases showed the percentage of DF > 50%, furthermore five cases (four in Group I) had the percentage of DF of 100%. There was no difference between the groups in regards to CFR (1.9 ± 0.46 vs. 2.11 ± 0.56; p = 0.143), or CFVR calculated using the maximum (2.17 ± 0.64 vs. 2.28 ± 0.63; p = 0.537) and the mean (2.27 ± 0.54 vs. 2.50 ± 0.79; p = 0.232) of the diastolic velocity. Conclusion: The appropriate functional status of the ITA graft does not depend on the ligation or preservation of important proximal ITA branches. Thus, ligation of ITA branches does not determine increase in systolic, diastolic or total flow through the ITA graft, and its diastolic predominance is more evident under stress. The increase in the systolic and total flow indicates an adaptation of the flow through the ITA graft to supply both coronary and non-coronary systems, in those patients that don\'t have the branches ligated during surgery. These findings point towards the hypothesis that the flow steal by unligated branches is unlikely.

Les maladies cardiovasculaires et en particulier les maladies coronariennes représentent la principale cause de mortalité mondiale avec 17,9 millions de décès en 2012. L’IRM cardiaque est un outil particulièrement intéressant pour la compréhension et l’évaluation des cardiopathies, notamment ischémiques. Son apport diagnostique est souvent majeur et elle apporte des informations non accessibles par d’autres modalités d’imagerie. Les travaux menés pendant cette thèse portent plus particulièrement sur l’examen dit de perfusion myocardique qui consiste à étudier la distribution d’un agent de contraste au sein du muscle cardiaque lors de son premier passage. En pratique clinique cet examen est souvent limité à la seule analyse visuelle du clinicien qui recherche un hyposignal lui permettant d’identifier l’artère coupable et d’en déduire le territoire impacté. Cependant, cette technique est relative et ne permet pas de quantifier le flux sanguin myocardique. Au cours de ces dernières années, un nombre croissant de techniques sont apparues pour permettre cette quantification et ce à toutes les étapes de traitement, depuis l’acquisition jusqu’à la mesure elle-même. Nous avons dans un premier temps établi un pipeline de traitement afin de combiner ces approches et de les évaluer à l’aide d’un fantôme numérique et à partir de données cliniques. Nous avons pu démontrer que l’approche Bayésienne permettait de quantifier la perfusion cardiaque et sa supériorité à évaluer le délai d’arrivé du bolus d’indicateur par rapport au modèle de Fermi. De plus l’approche Bayésienne apporte en supplément des informations intéressantes telles que la fonction de densité de probabilité de la mesure et l’incertitude sur la fonction résidu qui permettent de connaitre la fiabilité de la mesure effectuée notamment en observant la répartition de la fonction de densité de probabilité de la mesure. Enfin, nous avons proposé un algorithme de segmentation des lésions myocardiques, exploitant les dimensions spatiotemporelles des données de perfusion. Cette technique permet une segmentation objective et précise de la région hypoperfusée permettant une mesure du flux sanguin myocardique sur une zone de tissu dont le comportement est homogène et dont la mesure du signal moyen permet une augmentation du rapport contraste à bruit. Sur la cohorte de 30 patients, la variabilité des mesures du flux sanguin myocardique effectuées sur les voxels détectés par cette technique était significativement inférieure à celle des mesures effectuées sur les voxels des zones définies manuellement (différence moyenne=0.14, 95% CI [0.07, 0.2]) et de celles effectuées sur les voxels des zones définies à partir de la méthode bullseye (différence moyenne =0.25, 95% CI [0.17, 0.36]) / Cardiovascular diseases and in particular coronary heart disease are the main cause of death worldwide with 17.9 million deaths in 2012. Cardiac MRI is a particularly interesting tool for understanding and evaluating heart disease, including ischemic heart disease. Its diagnostic contribution is often major and it provides information that is not accessible by other imaging modalities. The work carried out during this thesis focuses more specifically on the so-called myocardium perfusion test, which consists in studying the distribution of a contrast agent within the heart muscle during its first passage. In clinical practice, this examination is often limited to the clinician's visual analysis, allowing him to identify the culprit artery and deduce the impacted territory. However, this technique is relative and does not quantify myocardial blood flow. In recent years, an increasing number of techniques have emerged to enable this quantification at all stages of processing, from acquisition to the measurement itself. We first established a treatment pipeline to combine these approaches and evaluate them using a digital phantom and clinical data. We demonstrated that the Bayesian approach is able to quantify myocardium perfusion and its superiority in evaluating the arrival time of the indicator bolus compared to the Fermi model. In addition, the Bayesian approach provides additional interesting information such as the probability density function of the measurement and the uncertainty of the residual function, which makes it possible to know the reliability of the measurement carried out, in particular by observing the distribution of the probability density function of the measurement. Finally, we proposed an algorithm for segmentation of myocardial lesions, using the spatial and temporal dimensions of infusion data. This technique allows an objective and precise segmentation of the hypoperfused region allowing a measurement of myocardial blood flow over an area of tissue which behavior is homogeneous and which average signal measurement allows an increase in the contrast-to-noise ratio. In the cohort of 30 patients, the variability of myocardial blood flow measurements performed on voxels detected by this technique was significantly lower than that of measurements performed on voxels in manually defined areas (mean difference=0.14, 95% CI[0.07, 0.2]) and those performed on voxels in areas defined using the bullseye method (mean difference=0.25, 95% CI[0.17, 0.36])