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Ian Law

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YNIMG Journal 2022 Journal Article

Deep learning based low-activity PET reconstruction of [11C]PiB and [18F]FE-PE2I in neurodegenerative disorders

  • Raphaël Sura Daveau
  • Ian Law
  • Otto Mølby Henriksen
  • Steen Gregers Hasselbalch
  • Ulrik Bjørn Andersen
  • Lasse Anderberg
  • Liselotte Højgaard
  • Flemming Littrup Andersen

PURPOSE: C]PiB PET/CT scans, simulating low injected activity or scanning time reduction, in combination with AI-assisted denoising. METHODS: F]FE-PE2I PET/CT. Simulated low-activity data were obtained by random sampling of 5% of the events from the list-mode file and a 5% time window extraction in the middle of the scan. A three-dimensional convolutional neural network (CNN) was trained to denoise the resulting PET images for each disease cohort. RESULTS: Noise reduction of low-activity PET images was successful for both cohorts using 5% of the original activity with improvement in visual quality and all similarity metrics with respect to the ground-truth images. Clinically relevant metrics extracted from the low-activity images deviated < 2% compared to ground-truth values, which were not significantly changed when extracting the metrics from the denoised images. CONCLUSION: C]PiB, and highly localized, [18F]FE-PE2I). This broad and robust application makes the presented network a good choice for improving the quality of brain images to the level of the standard-activity images without degrading clinical metric extraction. This will allow for reduced dose or scan time in PET/CT to be implemented clinically.

YNIMG Journal 2021 Journal Article

Validation of kinetic modeling of [15O]H2O PET using an image derived input function on hybrid PET/MRI

  • Mark B. Vestergaard
  • Oriol P. Calvo
  • Adam E. Hansen
  • Sverre Rosenbaum
  • Henrik B.W. Larsson
  • Otto M. Henriksen
  • Ian Law

In present study we aimed to validate the use of image-derived input functions (IDIF) in the kinetic modeling of cerebral blood flow (CBF) measured by [15O]H2O PET by comparing with the accepted reference standard arterial input function (AIF). Additional comparisons were made to mean cohort AIF and CBF values acquired by methodologically independent phase-contrast mapping (PCM) MRI. Using hybrid PET/MRI an IDIF was generated by measuring the radiotracer concentration in the internal carotid arteries and correcting for partial volume effects using the intravascular volume measured from MRI-angiograms. Seven patients with carotid steno-occlusive disease and twelve healthy controls were examined at rest, after administration of acetazolamide, and, in the control group, during hyperventilation. Agreement between the techniques was examined by linear regression and Bland-Altman analysis. Global CBF values modeled using IDIF correlated with values from AIF across perfusion states in both patients (p<10−6, R2=0. 82, 95% limits of agreement (LoA)=[-11. 3–9. 9] ml/100 g/min) and controls (p<10−6, R2=0. 87, 95% LoA=[-17. 1–13. 7] ml/100 g/min). The reproducibility of gCBF using IDIF was identical to AIF (15. 8%). Values from IDIF and AIF had equally good correlation to measurements by PCM MRI, R2=0. 86 and R2=0. 84, (p<10−6), respectively. Mean cohort AIF performed substantially worse than individual IDIFs (p<10−6, R2=0. 63, LoA=[-12. 8–25. 3] ml/100 g/min). In the patient group, use of IDIF provided similar reactivity maps compared to AIF. In conclusion, global CBF values modeled using IDIF correlated with values modeled by AIF and similar perfusion deficits could be established in a patient group.

YNIMG Journal 2020 Journal Article

AI-driven attenuation correction for brain PET/MRI: Clinical evaluation of a dementia cohort and importance of the training group size

  • Claes Nøhr Ladefoged
  • Adam Espe Hansen
  • Otto Mølby Henriksen
  • Frederik Jager Bruun
  • Live Eikenes
  • Silje Kjærnes Øen
  • Anna Karlberg
  • Liselotte Højgaard

INTRODUCTION: Robust and reliable attenuation correction (AC) is a prerequisite for accurate quantification of activity concentration. In combined PET/MRI, AC is challenged by the lack of bone signal in the MRI from which the AC maps has to be derived. Deep learning-based image-to-image translation networks present itself as an optimal solution for MRI-derived AC (MR-AC). High robustness and generalizability of these networks are expected to be achieved through large training cohorts. In this study, we implemented an MR-AC method based on deep learning, and investigated how training cohort size, transfer learning, and MR input affected robustness, and subsequently evaluated the method in a clinical setup, with the overall aim to explore if this method could be implemented in clinical routine for PET/MRI examinations. METHODS: F]FDG) PET patient studies performed for suspected neurodegenerative disorder using statistical surface projections. RESULTS: Robustness increased with group size in the training data set: 100 subjects were required to reduce the number of outliers compared to a state-of-the-art segmentation-based method, and a cohort >400 subjects further increased robustness in terms of reduced variation and number of outliers. When using transfer learning to adapt to changes in the MRI input, as few as five subjects were sufficient to minimize outliers. Full robustness was achieved at 20 subjects. Comparable robust and accurate results were obtained using all three types of MRI input with a bias below 1% relative to CT-AC in any brain region. The clinical PET evaluation using DeepDixon showed no clinically relevant differences compared to CT-AC. CONCLUSION: Deep learning based AC requires a large training cohort to achieve accurate and robust performance. Using transfer learning, only five subjects were needed to fine-tune the method to large changes to the input images. No clinically relevant differences were found compared to CT-AC, indicating that clinical implementation of our deep learning-based MR-AC method will be feasible across MRI system types using transfer learning and a limited number of subjects.

YNIMG Journal 2017 Journal Article

A multi-centre evaluation of eleven clinically feasible brain PET/MRI attenuation correction techniques using a large cohort of patients

  • Claes N. Ladefoged
  • Ian Law
  • Udunna Anazodo
  • Keith St. Lawrence
  • David Izquierdo-Garcia
  • Ciprian Catana
  • Ninon Burgos
  • M. Jorge Cardoso

Aim To accurately quantify the radioactivity concentration measured by PET, emission data need to be corrected for photon attenuation; however, the MRI signal cannot easily be converted into attenuation values, making attenuation correction (AC) in PET/MRI challenging. In order to further improve the current vendor-implemented MR-AC methods for absolute quantification, a number of prototype methods have been proposed in the literature. These can be categorized into three types: template/atlas-based, segmentation-based, and reconstruction-based. These proposed methods in general demonstrated improvements compared to vendor-implemented AC, and many studies report deviations in PET uptake after AC of only a few percent from a gold standard CT-AC. Using a unified quantitative evaluation with identical metrics, subject cohort, and common CT-based reference, the aims of this study were to evaluate a selection of novel methods proposed in the literature, and identify the ones suitable for clinical use. Methods In total, 11 AC methods were evaluated: two vendor-implemented (MR-ACDIXON and MR-ACUTE), five based on template/atlas information (MR-ACSEGBONE (Koesters et al. , 2016), MR-ACONTARIO (Anazodo et al. , 2014), MR-ACBOSTON (Izquierdo-Garcia et al. , 2014), MR-ACUCL (Burgos et al. , 2014), and MR-ACMAXPROB (Merida et al. , 2015)), one based on simultaneous reconstruction of attenuation and emission (MR-ACMLAA (Benoit et al. , 2015)), and three based on image-segmentation (MR-ACMUNICH (Cabello et al. , 2015), MR-ACCAR-RiDR (Juttukonda et al. , 2015), and MR-ACRESOLUTE (Ladefoged et al. , 2015)). We selected 359 subjects who were scanned using one of the following radiotracers: [18F]FDG (210), [11C]PiB (51), and [18F]florbetapir (98). The comparison to AC with a gold standard CT was performed both globally and regionally, with a special focus on robustness and outlier analysis. Results The average performance in PET tracer uptake was within ±5% of CT for all of the proposed methods, with the average±SD global percentage bias in PET FDG uptake for each method being: MR-ACDIXON (−11. 3±3. 5)%, MR-ACUTE (−5. 7±2. 0)%, MR-ACONTARIO (−4. 3±3. 6)%, MR-ACMUNICH (3. 7±2. 1)%, MR-ACMLAA (−1. 9±2. 6)%, MR-ACSEGBONE (−1. 7±3. 6)%, MR-ACUCL (0. 8±1. 2)%, MR-ACCAR-RiDR (−0. 4±1. 9)%, MR-ACMAXPROB (−0. 4±1. 6)%, MR-ACBOSTON (−0. 3±1. 8)%, and MR-ACRESOLUTE (0. 3±1. 7)%, ordered by average bias. The overall best performing methods (MR-ACBOSTON, MR-ACMAXPROB, MR-ACRESOLUTE and MR-ACUCL, ordered alphabetically) showed regional average errors within ±3% of PET with CT-AC in all regions of the brain with FDG, and the same four methods, as well as MR-ACCAR-RiDR, showed that for 95% of the patients, 95% of brain voxels had an uptake that deviated by less than 15% from the reference. Comparable performance was obtained with PiB and florbetapir. Conclusions All of the proposed novel methods have an average global performance within likely acceptable limits (±5% of CT-based reference), and the main difference among the methods was found in the robustness, outlier analysis, and clinical feasibility. Overall, the best performing methods were MR-ACBOSTON, MR-ACMAXPROB, MR-ACRESOLUTE and MR-ACUCL, ordered alphabetically. These methods all minimized the number of outliers, standard deviation, and average global and local error. The methods MR-ACMUNICH and MR-ACCAR-RiDR were both within acceptable quantitative limits, so these methods should be considered if processing time is a factor. The method MR-ACSEGBONE also demonstrates promising results, and performs well within the likely acceptable quantitative limits. For clinical routine scans where processing time can be a key factor, this vendor-provided solution currently outperforms most methods. With the performance of the methods presented here, it may be concluded that the challenge of improving the accuracy of MR-AC in adult brains with normal anatomy has been solved to a quantitatively acceptable degree, which is smaller than the quantification reproducibility in PET imaging.

YNICL Journal 2017 Journal Article

The use of amino acid PET and conventional MRI for monitoring of brain tumor therapy

  • Norbert Galldiks
  • Ian Law
  • Whitney B. Pope
  • Javier Arbizu
  • Karl-Josef Langen

Routine diagnostics and treatment monitoring of brain tumors is usually based on contrast-enhanced MRI. However, the capacity of conventional MRI to differentiate tumor tissue from posttherapeutic effects following neurosurgical resection, chemoradiation, alkylating chemotherapy, radiosurgery, and/or immunotherapy may be limited. Metabolic imaging using PET can provide relevant additional information on tumor metabolism, which allows for more accurate diagnostics especially in clinically equivocal situations. This review article focuses predominantly on the amino acid PET tracers 11C-methyl-l-methionine (MET), O-(2-[18F]fluoroethyl)-l-tyrosine (FET) and 3, 4-dihydroxy-6-[18F]-fluoro-l-phenylalanine (FDOPA) and summarizes investigations regarding monitoring of brain tumor therapy.

YNIMG Journal 2014 Journal Article

Combined PET/MR imaging in neurology: MR-based attenuation correction implies a strong spatial bias when ignoring bone

  • Flemming Littrup Andersen
  • Claes Nøhr Ladefoged
  • Thomas Beyer
  • Sune Høgild Keller
  • Adam Espe Hansen
  • Liselotte Højgaard
  • Andreas Kjær
  • Ian Law

Aim Combined PET/MR systems have now become available for clinical use. Given the lack of integrated standard transmission (TX) sources in these systems, attenuation and scatter correction (AC) must be performed using the available MR-images. Since bone tissue cannot easily be accounted for during MR-AC, PET quantification can be biased, in particular, in the vicinity of the skull. Here, we assess PET quantification in PET/MR imaging of patients using phantoms and patient data. Materials and methods Nineteen patients referred to our clinic for a PET/CT exam as part of the diagnostic evaluation of suspected dementia were included in our study. The patients were injected with 200MBq [18F]FDG and imaged with PET/CT and PET/MR in random sequence within 1h. Both, PET/CT and PET/MR were performed as single-bed acquisitions without contrast administration. PET/CT and PET/MR data were reconstructed following CT-based and MR-based AC, respectively. MR-AC was performed based on: (A) standard Dixon-Water–Fat segmentation (DWFS), (B) DWFS with co-registered and segmented CT bone values superimposed, and (C) with co-registered full CT-based attenuation image. All PET images were reconstructed using AW-OSEM, with neither resolution recovery nor time-of-flight option employed. PET/CT (D) or PET/MR (A–C) images were decay-corrected to the start time of the first examination. PET images following AC were evaluated visually and quantitatively using 10 homeomorphic regions of interest drawn on a transaxial T1w-MR image traversing the central basal ganglia. We report the relative difference (%) of the mean ROI values for (A)–(C) in reference to PET/CT (D). In a separate phantom experiment a 2L plastic bottle was layered with approximately 12mm of Gypsum plaster to mimic skull bone. The phantom was imaged on PET/CT only and standard MR-AC was performed by replacing hyperdense CT attenuation values corresponding to bone (plaster) with attenuation values of water. PET image reconstruction was performed with CT-AC (D) and CT-AC using the modified CT images corresponding to MR-AC using DWFS (A). Results PET activity values in patients following MR-AC (A) showed a substantial radial dependency when compared to PET/CT. In all patients cortical PET activity was lower than the activity in the central region of the brain (10–15%). When adding bone attenuation values to standard MR-AC (B and C) the radial gradient of PET activity values was removed. Further evaluation of PET/MR activity following MR-AC (A) relative to MR-AC (C) using the full CT for attenuation correction showed an underestimation of 25% in the cortical regions and 5–10% in the central regions of the brain. Observations in patients were replicated by observations from the phantom study. Conclusion Our phantom and patient data demonstrate a spatially varying bias of the PET activity in PET/MR images of the brain when bone tissue is not accounted for during attenuation correction. This has immediate implications for PET/MR imaging of the brain. Therefore, refinements to existing MR-AC methods or alternative strategies need to be found prior to adopting PET/MR imaging of the brain in clinical routine and research.

YNIMG Journal 2012 Journal Article

Negative BOLD signal changes in ipsilateral primary somatosensory cortex are associated with perfusion decreases and behavioral evidence for functional inhibition

  • Katharina Schäfer
  • Felix Blankenburg
  • Ron Kupers
  • Julie M. Grüner
  • Ian Law
  • Martin Lauritzen
  • Henrik B.W. Larsson

We used functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) to study the negative blood oxygenation level dependent (BOLD) signal and its underlying blood flow changes in healthy human subjects. This was combined with psychophysiological measurements to test that the negative BOLD signal is associated with functional inhibition. Electrical stimulation of the median nerve at 7Hz evoked robust negative BOLD signals in the primary somatosensory cortex (SI) ipsilateral to stimulation, and positive BOLD signals in contralateral SI. The negative BOLD signal in ipsilateral SI was accompanied by commensurate decreases in relative regional cerebral blood flow (rCBF). Conjunction analysis of the fMRI and PET data revealed a region in the ipsilateral postcentral gyrus showing overlap of negative BOLD signals and relative rCBF decreases. The current perception threshold (CPT) at the ipsilateral finger during concomitant stimulation of the contralateral median nerve increased significantly, suggesting augmented functional inhibition. Since the CPT in the ipsilateral hallux did not significantly change in response to median nerve stimulation, it is more likely that the CPT-increase for the finger is due to functional inhibition (Kastrup et al. , 2008) than to changes in selective attention. In conclusion, our data provide evidence that stimulus-induced reductions in relative rCBF may underlie the negative BOLD signal, which in turn may reflect increments in functional inhibition.

YNIMG Journal 2006 Journal Article

Similar brain networks for detecting visuo-motor and visuo-proprioceptive synchrony

  • Daniela Balslev
  • Finn Å. Nielsen
  • Torben E. Lund
  • Ian Law
  • Olaf B. Paulson

The ability to recognize feedback from own movement as opposed to the movement of someone else is important for motor control and social interaction. The neural processes involved in feedback recognition are incompletely understood. Two competing hypotheses have been proposed: the stimulus is compared with either (a) the proprioceptive feedback or with (b) the motor command and if they match, then the external stimulus is identified as feedback. Hypothesis (a) predicts that the neural mechanisms or brain areas involved in distinguishing self from other during passive and active movement are similar, whereas hypothesis (b) predicts that they are different. In this fMRI study, healthy subjects saw visual cursor movement that was either synchronous or asynchronous with their active or passive finger movements. The aim was to identify the brain areas where the neural activity depended on whether the visual stimulus was feedback from own movement and to contrast the functional activation maps for active and passive movement. We found activity increases in the right temporoparietal cortex in the condition with asynchronous relative to synchronous visual feedback from both active and passive movements. However, no statistically significant difference was found between these sets of activated areas when the active and passive movement conditions were compared. With a posterior probability of 0. 95, no brain voxel had a contrast effect above 0. 11% of the whole-brain mean signal. These results do not support the hypothesis that recognition of visual feedback during active and passive movement relies on different brain areas.

YNIMG Journal 2005 Journal Article

The relationship between cerebral blood flow and volume in humans

  • Egill Rostrup
  • Gitte M. Knudsen
  • Ian Law
  • Søren Holm
  • Henrik B.W. Larsson
  • Olaf B. Paulson

The purpose of this study was to establish the relationship between regional CBF and CBV at normal, resting cerebral metabolic rates. Eleven healthy volunteers were investigated with PET during baseline conditions, and during hyper- and hypocapnia. Values for rCBF and rCBV were obtained using 15O-labelled water and carbon monoxide, respectively. The mean value of rCBF using PET was 62 ± 18 ml·100 g−1 min−1 during baseline conditions, with an average increase of 46% during hypercapnia, and a decrease of 29% during hypocapnia; baseline rCBV was 7. 7 ml/100 g, with 27% increase during hypercapnia and no significant decrease during hypocapnia. A regionally uniform exponential relationship was confirmed between P a CO2 and rCBF as well as rCBV. It is shown that the theoretical implication of this is that the rCBV vs. rCBF relationship should be modelled by a power function; however, due to pronounced intersubject variability, the goodness of fit for linear and nonlinear models were not significantly different. The results of the study are applied to a numerical estimation of regional brain deoxy-haemoglobin content. Independently of the choice of model for the rCBV vs. rCBF relationship, a nonlinear deoxy-haemoglobin vs. rCBF relationship was predicted, and the implications for the BOLD response are discussed.

YNIMG Journal 2002 Journal Article

Cortical Deactivation Induced by Visual Stimulation in Human Slow-Wave Sleep

  • Alfred Peter Born
  • Ian Law
  • Torben E. Lund
  • Egill Rostrup
  • Lars G. Hanson
  • Gordon Wildschiødtz
  • Hans C. Lou
  • Olaf B. Paulson

It has previously been demonstrated that sleeping and sedated young children respond with a paradoxical decrease in the blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal in the rostro-medial occipital visual cortex during visual stimulation. It is unresolved whether this negative BOLD response pattern is of developmental neurobiological origin particular to a given age or to a general effect of sleep or sedative drugs. To further elucidate this issue, we used fMRI and positron emission tomography (PET) to study the brain activation pattern during visual stimulation in spontaneously sleeping adult volunteers. In five sleeping volunteers fMRI studies confirmed a robust signal decrease during stimulation in the rostro-medial occipital cortex. A similar relative decrease at the same location was found during visual stimulation and polysomnographically verified slow-wave sleep in a separate group of six subjects using H2 15O PET measures of the regional cerebral blood flow (rCBF). This decrease was more rostro-dorsal compared to the relative rCBF increase along the calcarine sulcus found during visual stimulation in the awake state. This study reconfirms the previously described paradoxical stimulation-correlated negative BOLD signal change in the rostro-medial occipital cortex, expanding this response mode to an age spectrum ranging from the newborn to the adult. Further, the use of complementary brain mapping techniques suggests that this decrease was secondary to a relative rCBF decrease. Possible mechanisms for the paradoxical response pattern during sleep include an active inhibition of the visual cortex or a disruption of an energy-consuming process.

YNIMG Journal 1998 Journal Article

Brain Activation during Word Identification and Word Recognition

  • Terry L. Jernigan
  • Arne L. Ostergaard
  • Ian Law
  • Claus Svarer
  • Christian Gerlach
  • Olaf B. Paulson

Previous memory research has suggested that the effects of prior study observed in priming tasks are functionally, and neurobiologically, distinct phenomena from the kind of memory expressed in conventional (explicit) memory tests. Evidence for this position comes from observed dissociations between memory scores obtained with the two kinds of tasks. However, there is continuing controversy about the meaning of these dissociations. In recent studies, Ostergaard (1998a, Memory Cognit. 26: 40–60; 1998b, J. Int. Neuropsychol. Soc. ,in press) showed that simply degrading visual word stimuli can dramatically alter the degree to which word priming shows a dissociation from word recognition; i. e. , effects of a number of factors on priming paralleled their effects on recognition memory tests when the words were degraded at test. In the present study, cerebral blood flow changes were measured while subjects performed the word identification (reading) and recognition memory tasks used previously by Ostergaard. The results are the direct comparisons of the two tasks and the effects of stimulus degradation on blood flow patterns during the tasks. Clear differences between word identification and word recognition were observed: the latter task evoked considerably more prefrontal activity and stronger cerebellar activation. Stimulus degradation was associated with focal increases in bilateral fusiform regions within the occipital lobe. No task, degradation, or item repetition effects were demonstrated in mesial temporal regions, no repetition effects were observed in any region, and there was no evidence for different effects of stimulus degradation in the priming and recognition memory conditions. Power limitations may have contributed to the null effects.

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