Physiological and bifidogenic effects of prebiotic supplements in infant formulae.

OBJECTIVES: This randomized controlled trial involving 110 healthy neonates studied physiological and bifidogenic effects of galactooligosaccharides (GOS), oligofructose, and long-chain inulin (fructooligosaccharides, FOS) in formula. METHODS: Subjects were randomized to Orafti Synergy1 (50 oligofructose:50 FOS) 0.4 g/dL or 0.8 g/dL, GOS:FOS (90:10) 0.8 g/dL, or a standard formula according to Good Clinical Practice guidelines. A breast-fed group was included for comparison. Outcome parameters were weight, length, intake, stool characteristics, crying, regurgitation, vomiting, adverse events, and fecal bacterial population counts. Statistical analyses used nonparametric tests. RESULTS: During the first month of life, weight, length, intake, and crying increased significantly in all of the groups. Regurgitation and vomiting scores were low and similar. Stool frequency decreased significantly and similarly in all of the formula groups but was lower than in the breast-fed group. All of the prebiotic groups maintained soft stools, only slightly harder than those of breast-fed infants. The standard group had significantly harder stools at weeks 2 and 4 compared with 1 (P < 0.001 and P = 0.0279). The total number of fecal bacteria increased in all of the prebiotic groups (9.82, 9.73, and 9.91 to 10.34, 10.38, and 10.37, respectively, log10 cells/g feces, P = 0.2298) and more closely resembled the breast-fed pattern. Numbers of lactic acid bacteria, bacteroides, and clostridia were comparable. In the SYN1 0.8 g/dL and GOS:FOS groups, Bifidobacterium counts were significantly higher at D14 and 28 compared with D3 and were comparable with the breast-fed group. Tolerance and growth were normal. CONCLUSIONS: Stool consistency and bacterial composition of infants taking SYN1 0.8 g/dL or GOS:FOS-supplemented formula were closer to the breast-fed pattern. There was no risk of dehydration.

Effect of cyclosporin A administration on the biodistribution and multipinhole muSPECT imaging of [123I]R91150 in rodent brain.

PURPOSE: P-glycoprotein (Pgp) is an efflux protein found amongst other locations in the blood-brain barrier. It is important to investigate the effect of Pgp modulation on clinically used brain tracers, because brain uptake of the tracer can be altered by blocking of the Pgp efflux transporter. The function of Pgp can be blocked with cyclosporin A. METHODS: We investigated the effect of cyclosporin A administration on the biodistribution of [(123)I]R91150 in rodents, and the effect of Pgp blocking on the quality of multipinhole muSPECT imaging with [(123)I]R91150. The influence of increasing doses of cyclosporin A on the brain uptake of [(123)I]R91150 was investigated in NMRI mice. A biodistribution study with [(123)I]R91150 was performed in male Sprague-Dawley rats pretreated with cyclosporin A and not pretreated. Brain uptake of [(123)I]R91150 after cyclosporin A injection was compared to the brain uptake in untreated animals, and a displacement study with ketanserin was performed in both groups. A multipinhole muSPECT brain imaging study was also performed using a Milabs U-SPECT-II camera in male Sprague-Dawley rats. To exclude the effect of possible metabolites, a metabolite study was also performed. RESULTS: At the highest cyclosporin A dose (50 mg/kg), a sevenfold increase in brain radioactivity concentration was observed in NMRI mice. Also, a dose-response relationship was established between the dose of cyclosporin A and the brain uptake of [(123)I]R91150 in mice. Compared to the control group, a five-fold increase in [(123)I]R91150 radioactivity concentration was observed in the brain of Sprague-Dawley rats after cyclosporin A treatment (50 mg/kg). Radioactivity concentration in the frontal cortex increased from 0.24+/-0.0092 to 1.58+/-0.097% injected dose per gram of tissue after treatment with cyclosporin A (at the 1-h time-point). Blood radioactivity concentrations did not increase to the same extent. The cortical activity was displaced by administration of ketanserin. A metabolite study confirmed that there was no increased metabolism of [(123)I]R91150 due to cyclosporin A. The visual quality of multipinhole muSPECT images with [(123)I]R91150 in Sprague-Dawley rats improved markedly after cyclosporin A pretreatment. CONCLUSION: From the results obtained in the biodistribution studies, it can be concluded that [(123)I]R91150 is a substrate for Pgp in rodents. A relationship between the administered dose of cyclosporin A and the increase in [(123)I]R91150 brain radioactivity concentration was established. The overall quality of our multipinhole muSPECT images with [(123)I]R91150 in rats improved markedly after pretreatment of the animals with cyclosporin A.

Estimation of and correction for finite motion sampling errors in small animal PET rigid motion correction.

Motion tracking with finite time sampling causing an associated unknown residual motion between two motion measurements is one of the factors contributing to resolution loss in small animal PET motion correction. The aim of this work is (i) to provide a means to estimate the effect of the finite motion sampling on the spatial resolution of the motion correction reconstructions and (ii) to correct for this residual motion thereby minimizing resolution loss. We calculate a tailored spatially variant deconvolution kernel from the measured motion data which is then used to deconvolve the motion corrected image using a 3D Richardson-Lucy algorithm. A simulation experiment of numerical phantoms as well as a microDerenzo phantom experiment wherein the phantom was manually moved at different speeds was performed to assess the performance of our proposed method. In the motion corrected images of the microDerenzo phantom there was an average rod FWHM differences between the slow and fast motion cases of 9.7%. This difference was reduced to 5.8% after applying the residual motion deconvolution. In awake animal experiments, the proposed method can serve to mitigate the finite sampling factor degrading the spatial resolution as well as the resolution differences between fast-moving and slow-moving animals. Graphical abstract Motion correction of positron emission tomography (PET) scans of moving subjects can be performed by measuring the motion of the subject during the PET scan with an optical tracking camera. The motion tracking data obtained from the tracking camera is then used to correct the PET image reconstructions for motion. Due to finite time sampling of the motion data, the motion corrected reconstructions suffer from loss of spatial resolution. In the proposed method, a spatially variant deconvolution kernel is calculated from the motion tracking data, which is then used to correct the motion-corrected PET reconstructions for the blurring effect of the finite motion sampling through a Richardson-Lucy deconvolution.

Preclinical molecular imaging of glutamatergic and dopaminergic neuroreceptor kinetics in obsessive compulsive disorder.

BACKGROUND: Molecular neuroimaging was applied in the quinpirole rat model for compulsive checking in OCD to visualize the D2- and mGluR5-receptor occupancy with Raclopride and ABP-688 microPET/CT. METHODS: Animals (n=48) were exposed to either saline (CTRL; 1mL/kg) or quinpirole (QP; dopamine D2-agonist, 0.5mg/kg) in a single injection (RAC and ABP acute groups) or twice-weekly during 7weeks (chronic group). Animals underwent PET/CT after the 1st injection (acute) or before initial exposure and following the 10th injection in week 5 (chronic). For the latter, each injection was paired with an open field test and video tracking. RESULTS: The QP animals displayed a strong increase in visiting frequency (checking) in the chronic group (+699.29%) compared to the control animals. Acute administration of the drug caused significant (p<0.01) decreases in D2R occupancy in the CP (-42.03%±4.01%). Chronical exposure resulted in significantly stronger decreases in the CP (-52.29%±3.79%). Furthermore significant increases in mGluR5 occupancy were found in the CP (10.36%±4.09%), anterior cingulate cortex (13.26%±4.01%), amygdala (24.36%±6.86%), entorhinal cortex (18.49%±5.14%) and nucleus accumbens (13.8%±4.87%) of the chronic group, not present after acute exposure. CONCLUSIONS: Compared to acute exposure, sensitisation to QP as a model for OCD differs both on a dopaminergic and glutamateric level, indicating involvement of processes such as receptor internalization and changes in extracellular availability of both neurotransmitters.

Compression and reconstruction of sorted PET listmode data.

BACKGROUND: In nuclear medicine data can be stored in histogram or listmode format. The most popular histogram format is the planar projection format. Due to the increase in detector blocks, the improved energy resolution and the trends towards time of flight, dynamic and gated imaging, it can be more appropriate to store the data in listmode format. The size of the storage in this format increases linearly with the number of properties (positions, energy, time info) while the histogram format increases exponentially. However, the datasize of listmode data also increases linearly with the number of coincidences. Due to the high number of counts in 3D PET this will lead to very large datasets. Therefore a good compression algorithm for listmode data is very important. METHODS: A sorting and compression method is proposed to reduce the amount of space needed to store the listmode dataset. One event is represented by one number without any information loss compared to the original listmode file. The next step is to sort all events into an array of increasing numbers. These data are compressed by the gzip routine. One of the advantages of 3D PET listmode reconstructions is that they result in a more uniform resolution across the field of view (FOV), which is not always true for other reconstruction algorithms. This improved resolution is shown for the listmode data of a gamma camera operating in PET mode. RESULTS: First the effect of positional accuracy in the listmode dataset is evaluated by comparing resolution in the reconstructions. It is shown that the highest accuracy is not necessary and a significant reduction in the size of the dataset can be obtained prior to lossless compression. A further reduction can be obtained by using the proposed sorting and compression techniques. It is shown that the storage space decreases linearly with the logarithm of the number of coincidences. The compression obtained by different acquisition matrices was compared. Finally it is shown that the 3D listmode reconstruction of sorted listmode data is faster because of improved cache behaviour. The method can be applied to any kind of listmode data. The compression factors will improve when the ratio of measured events to possible events increases.

New approaches for antithrombotic antiplatelet therapies.

Cardiovascular diseases are one of the major causes of mortality in the western world. As platelet dependent thrombosis is of central importance in their pathophysiology, several successful strategies, targeting a specific platelet function or interaction, have been developed to prevent or treat these disorders. However, as the current antiplatelet strategies are limited in efficacy and safety, and often influence normal haemostatic functions, new compounds are being developed with improved characteristics. This review deals with the development of novel antiplatelet compounds for which evidence is available on their antithrombotic action in vivo. In a first part, these compounds, their targets and their potential applicability are discussed. The second part of this review focuses on BT tests and bleeding models and their usefulness for determination and/or prediction of the safety of novel antiplatelet compounds.

Validation of the GATE Monte Carlo simulation platform for modelling a CsI(Tl) scintillation camera dedicated to small-animal imaging.

Monte Carlo simulations are increasingly used in scintigraphic imaging to model imaging systems and to develop and assess tomographic reconstruction algorithms and correction methods for improved image quantitation. GATE (GEANT4 application for tomographic emission) is a new Monte Carlo simulation platform based on GEANT4 dedicated to nuclear imaging applications. This paper describes the GATE simulation of a prototype of scintillation camera dedicated to small-animal imaging and consisting of a CsI(Tl) crystal array coupled to a position-sensitive photomultiplier tube. The relevance of GATE to model the camera prototype was assessed by comparing simulated 99mTc point spread functions, energy spectra, sensitivities, scatter fractions and image of a capillary phantom with the corresponding experimental measurements. Results showed an excellent agreement between simulated and experimental data: experimental spatial resolutions were predicted with an error less than 100 microns. The difference between experimental and simulated system sensitivities for different source-to-collimator distances was within 2%. Simulated and experimental scatter fractions in a [98-182 keV] energy window differed by less than 2% for sources located in water. Simulated and experimental energy spectra agreed very well between 40 and 180 keV. These results demonstrate the ability and flexibility of GATE for simulating original detector designs. The main weakness of GATE concerns the long computation time it requires: this issue is currently under investigation by the GEANT4 and the GATE collaborations.

GATE: a simulation toolkit for PET and SPECT.

Monte Carlo simulation is an essential tool in emission tomography that can assist in the design of new medical imaging devices, the optimization of acquisition protocols and the development or assessment of image reconstruction algorithms and correction techniques. GATE, the Geant4 Application for Tomographic Emission, encapsulates the Geant4 libraries to achieve a modular, versatile, scripted simulation toolkit adapted to the field of nuclear medicine. In particular, GATE allows the description of time-dependent phenomena such as source or detector movement, and source decay kinetics. This feature makes it possible to simulate time curves under realistic acquisition conditions and to test dynamic reconstruction algorithms. This paper gives a detailed description of the design and development of GATE by the OpenGATE collaboration, whose continuing objective is to improve, document and validate GATE by simulating commercially available imaging systems for PET and SPECT. Large effort is also invested in the ability and the flexibility to model novel detection systems or systems still under design. A public release of GATE licensed under the GNU Lesser General Public License can be downloaded at http:/www-lphe.epfl.ch/GATE/. Two benchmarks developed for PET and SPECT to test the installation of GATE and to serve as a tutorial for the users are presented. Extensive validation of the GATE simulation platform has been started, comparing simulations and measurements on commercially available acquisition systems. References to those results are listed. The future prospects towards the gridification of GATE and its extension to other domains such as dosimetry are also discussed.

Imaging brain inflammation in epilepsy.

Epilepsy is a highly common chronic neurological disorder. Although symptomatic treatment is available, 30-40% of epilepsy patients still remain resistant to anti-epileptic drugs. The primary identification and extensive characterization of the pathological substrates underlying epilepsy would facilitate the development of novel treatments, including disease-modifying and anti-epileptogenic therapies. A plethora of evidence points toward an undeniable role of brain inflammation in epileptogenesis. However, the exact role of this process remains unfortunately not clear. Non-invasive imaging of brain inflammation can promote our fundamental knowledge, which may lead to better insights into the role of brain inflammation in disease ontogenesis. Moreover, it will allow us to investigate whether the visualization of this process can serve as a validated biomarker for epilepsy. In turn, such can lead to major perspectives regarding the development and evaluation of anti-inflammatory treatments, and screening possibilities for patients at risk. Here, we first discuss the applications for imaging of the different brain inflammation constituents. Secondly, we review the available approaches for molecular imaging of brain inflammation in general and finally present the current research on the imaging of brain inflammation in patients and experimental models of epilepsy. The current imaging toolbox is limited by the range of neuroinflammatory targets, which can be visualized at present, and in addition, the often indirect approaches used. We believe that research in this field will further advance as highly specific ligands, and producible and practical imaging approaches will become available.

Small-animal repetitive transcranial magnetic stimulation combined with [¹8F]-FDG microPET to quantify the neuromodulation effect in the rat brain.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neurostimulation technique for the treatment of various neurological and psychiatric disorders. To investigate the working mechanism of this treatment approach, we designed a small-animal coil for dedicated use in rats and we combined this neurostimulation method with small-animal positron emission tomography (microPET or µPET) to quantify regional 2-deoxy-2-((18)F)fluoro-d-glucose ([(18)F]-FDG) uptake in the rat brain, elicited by a low- (1 Hz) and a high- (50 Hz) frequency paradigm. Rats (n=6) were injected with 1 mCi of [(18)F]-FDG 10 min after the start of 30 min of stimulation (1 Hz, 50 Hz or sham), followed by a 20-min µPET image acquisition. Voxel-based statistical parametric mapping (SPM) image analysis of 1-Hz and 50-Hz versus sham stimulation was performed. For both the 1-Hz and 50-Hz paradigms we found a large [(18)F]-FDG hypermetabolic cluster (2.208 mm(3) and 2.616 mm(3), resp.) (analysis of variance (ANOVA), p<0.05) located in the dentate gyrus complemented with an additional [(18)F]-FDG hypermetabolic cluster (ANOVA, p<0.05) located in the entorhinal cortex (2.216 mm(3)) for the 50-Hz stimulation. The effect on [(18)F]-FDG metabolism was 2.9 ± 0.8% at 1 Hz and 2.5 ± 0.8% at 50 Hz for the dentate gyrus clusters and 3.3 ± 0.5% for the additional cluster in the entorhinal cortex at 50 Hz. The maximal (4.19 vs. 2.58) and averaged (2.87 vs. 2.21) T-values are higher for 50 Hz versus 1 Hz. This experimental study demonstrates the feasibility to combine µPET imaging in rats stimulated with rTMS using a custom-made small-animal magnetic stimulation setup to quantify changes in the cerebral [(18)F]-FDG uptake as a measure for neuronal activity.

Subspace electrode selection methodology for the reduction of the effect of uncertain conductivity values in the EEG dipole localization: a simulation study using a patient-specific head model.

The simulation of the electroencephalogram (EEG) using a realistic head model needs the correct conductivity values of several tissues. However, these values are not precisely known and have an influence on the accuracy of the EEG source analysis problem. This paper presents a novel numerical methodology for the increase of accuracy of the EEG dipole source localization problem. The presented subspace electrode selection (SES) methodology is able to limit the effect of uncertain conductivity values on the solution of the EEG inverse problem, yielding improved source localization accuracy. We redefine the traditional cost function associated with the EEG inverse problem and introduce a selection procedure of EEG potentials. In each iteration of the presented EEG cost function minimization procedure, potentials are selected that are affected as little as possible by the uncertain conductivity value. Using simulation data, the proposed SES methodology is able to enhance the neural source localization accuracy dependent on the dipole location, the assumed versus actual conductivity and the possible noise in measurements.

Accurate Monte Carlo modelling of the back compartments of SPECT cameras.

Today, new single photon emission computed tomography (SPECT) reconstruction techniques rely on accurate Monte Carlo (MC) simulations to optimize reconstructed images. However, existing MC scintillation camera models which usually include an accurate description of the collimator and crystal, lack correct implementation of the gamma camera's back compartments. In the case of dual isotope simultaneous acquisition (DISA), where backscattered photons from the highest energy isotope are detected in the imaging energy window of the second isotope, this approximation may induce simulation errors. Here, we investigate the influence of backscatter compartment modelling on the simulation accuracy of high-energy isotopes. Three models of a scintillation camera were simulated: a simple model (SM), composed only of a collimator and a NaI(Tl) crystal; an intermediate model (IM), adding a simplified description of the backscatter compartments to the previous model and a complete model (CM), accurately simulating the materials and geometries of the camera. The camera models were evaluated with point sources ((67)Ga, (99m)Tc, (111)In, (123)I, (131)I and (18)F) in air without a collimator, in air with a collimator and in water with a collimator. In the latter case, sensitivities and point-spread functions (PSFs) simulated in the photopeak window with the IM and CM are close to the measured values (error below 10.5%). In the backscatter energy window, however, the IM and CM overestimate the FWHM of the detected PSF by 52% and 23%, respectively, while the SM underestimates it by 34%. The backscatter peak fluence is also overestimated by 20% and 10% with the IM and CM, respectively, whereas it is underestimated by 60% with the SM. The results show that an accurate description of the backscatter compartments is required for SPECT simulations of high-energy isotopes (above 300 keV) when the backscatter energy window is of interest.

Longitudinal quantification of inflammation in the murine dextran sodium sulfate-induced colitis model using µPET/CT.

BACKGROUND: This study investigates whether deoxy-2-[18F]fluoro-d-glucose (FDG) micro-positron emission tomography (µPET)/computed tomography (CT) can serve as a tool for monitoring of the commonly used dextran sodium sulfate (DSS)-induced murine model of inflammatory bowel disease (IBD). METHODS: DSS-colitis was induced in Sv129 mice. In a first experiment, four animals were serially scanned with CT and FDG-µPET on days 0, 3, 7, 11, and 14. The ratio of the mean voxel count of the PET images in the colon and the brain was compared with the histological inflammation score and the colonic myeloperoxidase levels. A second experiment was performed to investigate whether FDG-µPET was able to detect differences in inflammation between two DSS-treated groups, one receiving placebo (n = 4) and one receiving dimethyloxalylglycine (DMOG) (n = 4), a compound that protects against DSS-induced colitis. RESULTS: The progression of the colonic/brain FDG-signal ratio (over days 0-14) agreed with the predicted histological inflammation score, obtained from a parallel DSS-experiment. Moreover, the quantification of normalized colonic FDG-activity at the final timepoint (day 14) showed an excellent correlation with both the MPO levels (Spearman's rho = 1) and the histological inflammation score (Spearman's rho = 0.949) of the scanned mice. The protective action of DMOG in DSS colitis was clearly demonstrated with FDG-µPET/CT (normalized colonic FDG-activity DMOG versus placebo: P < 0.05). CONCLUSIONS: FDG-µPET-CT is a feasible and reliable noninvasive method to monitor murine DSS-induced colitis. The implementation of this technique in this widely used IBD model opens a new window for pathophysiological research and high-throughput screening of potential therapeutic compounds in preclinical IBD research.

Effect of the static magnetic field of the MR-scanner on ERPs: evaluation of visual, cognitive and motor potentials.

OBJECTIVE: This work investigates the influence of the static magnetic field of the MR-scanner on ERPs extracted from simultaneous EEG-fMRI recordings. The quality of the ERPs after BallistoCardioGraphic (BCG) artifact removal, as well as the reproducibility of the waveforms in different environments is investigated. METHODS: We consider a Detection, a Go-Nogo and a Motor task, eliciting peaks that differ in amplitude, latency and scalp topography, repeated in two situations: outside the scanner room (0T) and inside the MR-scanner but without gradients (3T). The BCG artifact is removed by means of three techniques: the Average Artifact Subtraction (AAS) method, the Optimal Basis Set (OBS) method and the Canonical Correlation Analysis (CCA) approach. RESULTS: The performance of the three methods depends on the amount of averaged trials. Moreover, differences are found on both amplitude and latency of ERP components recorded in two environments (0T vs 3T). CONCLUSIONS: We showed that, while ERPs can be extracted from simultaneous EEG-fMRI data at 3T, the static magnetic field might affect the physiological processes under investigation. SIGNIFICANCE: The reproducibility of the ERPs in different recording environments (0T vs 3T) is a relevant issue that deserves further investigation to clarify the equivalence of cognitive processes in both behavioral and imaging studies.

Automated identification of ERP peaks through Dynamic Time Warping: an application to developmental dyslexia.

OBJECTIVE: This article proposes a method to automatically identify and label event-related potential (ERP) components with high accuracy and precision. METHODS: We present a framework, referred to as peak-picking Dynamic Time Warping (ppDTW), where a priori knowledge about the ERPs under investigation is used to define a reference signal. We developed a combination of peak-picking and Dynamic Time Warping (DTW) that makes the temporal intervals for peak-picking adaptive on the basis of the morphology of the data. We tested the procedure on experimental data recorded from a control group and from children diagnosed with developmental dyslexia. RESULTS: We compared our results with the traditional peak-picking. We demonstrated that our method achieves better performance than peak-picking, with an overall precision, recall and F-score of 93%, 86% and 89%, respectively, versus 93%, 80% and 85% achieved by peak-picking. CONCLUSION: We showed that our hybrid method outperforms peak-picking, when dealing with data involving several peaks of interest. SIGNIFICANCE: The proposed method can reliably identify and label ERP components in challenging event-related recordings, thus assisting the clinician in an objective assessment of amplitudes and latencies of peaks of clinical interest.

Development of monoclonal antibodies that inhibit platelet adhesion or aggregation as potential anti-thrombotic drugs.

Cardiovascular disease is the major cause of mortality in Western countries. Platelets play a crucial role in the development of arterial thrombosis and other pathophysiologies leading to clinical ischemic events. In the damaged vessel wall, platelets adhere to the subendothelium through an interaction with von Willebrand factor (VWF), which forms a bridge between subendothelial collagen and the platelet receptor glycoprotein (GP) Ib/IX/V. This reversible adhesion allows platelets to roll over the damaged area, decreasing their velocity and resulting in strong platelet activation. This leads to the conformational activation of the platelet GPIIb/IIIa receptor, fibrinogen binding and finally to platelet aggregation. As each interaction (collagen-VWF, VWF-GPIb and GPIIb/IIIa-fibrinogen) plays an essential role in primary haemostasis, loss of either of these interactions results in a bleeding diathesis, implying that interfering with these interactions might result in an anti-thrombotic effect. Whereas GPIIb/IIIa antagonists indeed are effective anti-thrombotics, it has been suggested that drugs which block the initial steps of thrombus formation (collagen-VWF or VWF-GPIb interaction) might have advantages over the ones that merely inhibit platelet aggregation. In this review we will discuss and compare the development of monoclonal antibodies (moAbs) that inhibit platelet adhesion or platelet aggregation. The effect of the moAbs in in vitro experiments, in in vivo models and in clinical trials will be described. Benefits, limitations, current applications and the future perspectives in the development of antibodies for each target will be discussed.

Geometrical importance sampling and pulse height tallies in GATE.

Monte Carlo simulations are widely used to study the behavior and detection of gamma photons in medical imaging devices. Such simulations are computationally expensive. This is why geometrical importance sampling, a variance reduction technique, was recently incorporated into the GEANT4 Monte Carlo code. In order to use this technique for single photon emission computed tomography (SPECT) imaging, it needed to be made compatible with pulse height tallies. These tallies correspond to the number of detected pulses in distinct energy bins, covering an energy spectrum relevant to SPECT. Since each pulse is the combination of different detector hits, the tally bin is not known until the end of an event. In an analog simulation (without variance reduction) this poses no problems as each detected hit can be stored and the pulse can be calculated at the end of each event. Geometrical importance sampling combined with Russian Roulette however introduces branches into the particle history, which results in a much more complicated pulse calculation. This work describes how pulse height tallies are adjusted to geometrical importance sampling and Russian Roulette within GATE, a medical imaging and simulation application based on GEANT4. The validation of this technique is done through SPECT simulations comparing the analog result with the new method.