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For the 2011 FDA approved Parkinson's Disease (PD) SPECT imaging agent I-123 labeled DaTscan, the volume of interest (VOI) is the interior portion of the brain. However imaging of the occipital lobe is also required with PD for calculation of the striatal binding ratio (SBR), a parameter of significance in early diagnosis, differentiation of PD from other disorders with similar clinical presentations, and monitoring progression. Thus we propose the usage of a combination of a multi-pinhole (MPH) collimator on one head of the SPECT system and a fan-beam on the other. The MPH would be designed to provide high resolution and sensitivity for imaging of the interior portion of the brain. The fan-beam collimator would provide lower resolution but complete sampling of the brain addressing data sufficiency and allowing a volume-of-interest to be defined over the occipital lobe for calculation of SBR's. Herein we focus on the design of the MPH component of the combined system. Combined reconstruction will be addressed in a subsequent publication. An analysis of 46 clinical DaTscan studies was performed to provide information to define the VOI, and design of a MPH collimator to image this VOI. The system spatial resolution for the MPH was set to 4.7 mm, which is comparable to that of clinical PET systems, and significantly smaller than that of fan-beam collimators employed in SPECT. With this set, we compared system sensitivities for three aperture array designs, and selected the 3 × 3 array due to it being the highest of the three. The combined sensitivity of the apertures for it was similar to that of an ultra-high resolution fan-beam (LEUHRF) collimator, but smaller than that of a high-resolution fan-beam collimator (LEHRF). On the basis of these results we propose the further exploration of this design through simulations, and the development of combined MPH and fan-beam reconstruction.

Unlabelled: In vivo imaging of adenosine 2A receptors (A2A) in the brain has attracted significant interest from the scientific community, because studies have shown that dysregulation of these receptors is implicated in a variety of neurodegenerative and psychiatric disorders, including Parkinson and Huntington diseases. This work aimed to describe the kinetic properties, test-retest results, and dosimetry estimates of (123)I-MNI-420, a SPECT radiotracer for the in vivo imaging of A2A in the brain., Methods: Nine healthy human subjects were enrolled in this study; 7 completed (123)I-MNI-420 brain SPECT studies, and 2 participated in whole-body planar imaging evaluating (123)I-MNI-420 biodistribution and dosimetry. For 3 of the brain SPECT studies, arterial blood was collected for invasive modeling. Noninvasive models were also explored, including Logan graphical analysis and simplified reference tissue models. Test-retest reliability was assessed in 4 subjects. To evaluate radiotracer biodistribution and dosimetry, serial whole-body images were acquired immediately after injection and at selected time points after injection. Urine samples were collected over a period of 21 h to calculate urinary excretion., Results: (123)I-MNI-420 rapidly entered the human brain and displayed uptake consistent with known A2A densities. At pseudoequilibrium (reached at 90 min after radiotracer injection), stable target-to-cerebellum ratios of around 1.4-2.0 were determined. Binding potentials around 0.8-1.2 were estimated using different kinetic models and the cerebellum as the reference region. Average test-retest variability in the striatum was 4.8%, 3.5%, and 6.5% for the simplified reference tissue model, Logan graphical analysis, and standardized uptake value ratio methods, respectively. The estimated radiation effective dose determined from whole-body studies was 0.036 mSv/MBq., Conclusion: The data indicate that (123)I-MNI-420 is a useful SPECT radiotracer for imaging A2A in the brain and has radiation doses that would allow for multiple scans in the same research subject each year. The availability of (123)I-MNI-420 offers the possibility of investigating A2A activity in specific conditions and evaluating drug occupancy for A2A candidate therapeutics.

Current therapeutic approaches for Alzheimer's disease (AD) have evolved to target specific molecular biological, metabolic and neuropathologic hallmarks of the disease. Since these approaches are hypothesized to be most effective at the earliest stages of the degenerative process, the ability to accurately detect and monitor progression of AD pathology and metabolic changes in vivo may accelerate the discovery and development of disease-modifying drugs. The use of molecular imaging biomarkers can not only enhance diagnostic accuracy and facilitate patient selection/stratification, but can also serve as key outcomes for clinical trials. In this review, we discuss emerging trends in the use of PET in AD drug development and provide a roadmap for harnessing its promise in multicenter clinical trials.

The incorporation of imaging biomarkers and clinical trials is now common. Because of the multiple technical, clinical, and regulatory demands to ensure high-quality quantitative information, the core laboratory serves as a critical intermediary between the study sponsor and the site. It provides unique expertise not found in typical clinical research organizations. This expertise goes far beyond the passive receipt of images for conductance of central reads of data and includes the proactive and early involvement in the selection of sites for imaging, the qualification and assistance for managing the local site logistics, on-the-fly and active quality control of imaging data in close working relationship with sites, and preparation for and conductance of central image reads or quantification in a manner which bears up to regulatory scrutiny., (Copyright 2010 Elsevier Inc. All rights reserved.)

Partial seizures produce increased cerebral blood flow in the region of seizure onset. These regional cerebral blood flow increases can be detected by single photon emission computed tomography (ictal SPECT), providing a useful clinical tool for seizure localization. However, when partial seizures secondarily generalize, there are often questions of interpretation since propagation of seizures could produce ambiguous results. Ictal SPECT from secondarily generalized seizures has not been thoroughly investigated. We analysed ictal SPECT from 59 secondarily generalized tonic-clonic seizures obtained during epilepsy surgery evaluation in 53 patients. Ictal versus baseline interictal SPECT difference analysis was performed using ISAS (http://spect.yale.edu). SPECT injection times were classified based on video/EEG review as either pre-generalization, during generalization or in the immediate post-ictal period. We found that in the pre-generalization and generalization phases, ictal SPECT showed significantly more regions of cerebral blood flow increases than in partial seizures without secondary generalization. This made identification of a single unambiguous region of seizure onset impossible 50% of the time with ictal SPECT in secondarily generalized seizures. However, cerebral blood flow increases on ictal SPECT correctly identified the hemisphere (left versus right) of seizure onset in 84% of cases. In addition, when a single unambiguous region of cerebral blood flow increase was seen on ictal SPECT, this was the correct localization 80% of the time. In agreement with findings from partial seizures without secondary generalization, cerebral blood flow increases in the post-ictal period and cerebral blood flow decreases during or following seizures were not useful for localizing seizure onset. Interestingly, however, cerebral blood flow hypoperfusion during the generalization phase (but not pre-generalization) was greater on the side opposite to seizure onset in 90% of patients. These findings suggest that, with appropriate cautious interpretation, ictal SPECT in secondarily generalized seizures can help localize the region of seizure onset.

Generalized tonic-clonic seizures are among the most dramatic physiological events in the nervous system. The brain regions involved during partial seizures with secondary generalization have not been thoroughly investigated in humans. We used single photon emission computed tomography (SPECT) to image cerebral blood flow (CBF) changes in 59 secondarily generalized seizures from 53 patients. Images were analysed using statistical parametric mapping to detect cortical and subcortical regions most commonly affected in three different time periods: (i) during the partial seizure phase prior to generalization; (ii) during the generalization period; and (iii) post-ictally. We found that in the pre-generalization period, there were focal CBF increases in the temporal lobe on group analysis, reflecting the most common region of partial seizure onset. During generalization, individual patients had focal CBF increases in variable regions of the cerebral cortex. Group analysis during generalization revealed that the most consistent increase occurred in the superior medial cerebellum, thalamus and basal ganglia. Post-ictally, there was a marked progressive CBF increase in the cerebellum which spread to involve the bilateral lateral cerebellar hemispheres, as well as CBF increases in the midbrain and basal ganglia. CBF decreases were seen in the fronto-parietal association cortex, precuneus and cingulate gyrus during and following seizures, similar to the 'default mode' regions reported previously to show decreased activity in seizures and in normal behavioural tasks. Analysis of patient behaviour during and following seizures showed impaired consciousness at the time of SPECT tracer injections. Correlation analysis across patients demonstrated that cerebellar CBF increases were related to increases in the upper brainstem and thalamus, and to decreases in the fronto-parietal association cortex. These results reveal a network of cortical and subcortical structures that are most consistently involved in secondarily generalized tonic-clonic seizures. Abnormal increased activity in subcortical structures (cerebellum, basal ganglia, brainstem and thalamus), along with decreased activity in the association cortex may be crucial for motor manifestations and for impaired consciousness in tonic-clonic seizures. Understanding the networks involved in generalized tonic-clonic seizures can provide insights into mechanisms of behavioural changes, and may elucidate targets for improved therapies.

Unlabelled: The uncoupling between brain perfusion and metabolism was evaluated as a potential tool for seizure localization by creating an interictal SPET divided by interictal PET functional ratio-image and by evaluating its sensitivity and specificity to areas subsequently surgically resected. The uncoupling between brain perfusion and metabolism was evaluated through the creation of a functional SPET/PET ratio-image relying on interictal single-photon emission computed tomography (SPET) and positron emission tomography (PET) scans in epilepsy patients. The uncoupling of these two physiological brain functions has been demonstrated to be a characteristic of epileptogenic tissue in temporal lobe epilepsy and could potentially serve as a diagnostic measure for localization of seizure onset areas in the brain. The accuracy of hemispheric localization, sensitivity, and specificity of perfusion to metabolism ratio-images were evaluated as compared to standard methods of PET reading., Methods: Interictal HMPAO-SPET and FDG-PET scans were obtained from 21 patients who then went on to remain seizure free for a minimum of 1 year post surgical resection. Using Statistical Parametric Mapping (SPM2), the SPET and PET scans were spatially registered and spatially normalized to a standard template (geometric warping). A functional image was created by calculating the ratio of perfusion to metabolism. Discrete areas of uncoupling in the ratio-images were selected, quantified, and compared to visually interpreted PET readings as well as the actual site of subsequent surgical resection. Localization was determined by comparing the hemispheric location of these areas to sites of surgical resection. Sensitivity and specificity of ratio-images and PET readings were calculated by dividing the brains into four sections per hemisphere., Results: When compared to known sites of successful surgical resection, the pre-surgical visually interpreted PET readings had a correct hemispheric localization in 69.6% of cases, while the regions of uncoupling selected in the pre-surgical ratio-images had a correct hemispheric localization of 82.6%. In addition, the regional sensitivity of visually interpreted PET readings was 63.0% with a specificity of 95.7%, while the sensitivity of the ratio-images was 68.0% with a specificity of 96.0%., Conclusion: Compared to the PET readings, the ratio-images yielded similar sensitivity and specificity measures, but had an improved hemispheric localization. Hence, ratio-images may be a valuable diagnostic tool in the hemispheric localization, which could enhance the use of PET readings alone.

Unlabelled: Reliable quantitative dopamine transporter imaging is critical for early and accurate diagnosis of Parkinson's disease (PD). Image quantitation is made difficult by the variability introduced by manual interventions during the quantitative processing steps. A fully automated objective striatal analysis (OSA) program was applied to dopamine transporter images acquired from PD subjects with early symptoms of suspected parkinsonism and compared with manual analysis by a trained image-processing technologist., Methods: A total of 101 (123)I-beta-CIT SPECT scans were obtained of subjects recruited to participate in the Query-PD Study. Data were reconstructed and then analyzed according to a package of scripts (OSA) that reorients the SPECT brain volume to the standard geometry of an average scan, automatically locates the striata and occipital structures, locates the caudate and putamen, and calculates the background-subtracted striatal uptake ratio (V3''). The striatal uptake ratio calculated by OSA was compared with manual analysis by a trained image-processing technologist. Several parameters were varied in the automated analysis, including the number of summed transverse slices and the size and separation of the regions of interest applied to the caudate and putamen to determine the optimum OSA analysis. The parameters giving V3'' with the closest correlation to the manual analysis were accepted as optimal., Results: The optimal comparison between the V3'' obtained by the human analyst and that obtained by the automated OSA analysis yielded a correlation coefficient of 0.96., Conclusion: Our optimized OSA delivers V3'' evaluations that closely correlate with a similar evaluation manually applied by a highly trained image-processing technologist.

Purpose: Regions of seizure onset and propagation in human generalized tonic-clonic seizures are not well understood. Cerebral blood flow (CBF) measurements with single photon emission computed tomography (SPECT) during electroconvulsive therapy (ECT)-induced seizures provide a unique opportunity to investigate seizure onset and propagation under controlled conditions., Methods: ECT stimulation induces a typical generalized tonic-clonic seizure, resembling spontaneous generalized seizures in both clinical and electroencephalogram (EEG) manifestations. Patients were divided into two groups based on timing of ictal (during seizure) SPECT tracer injections: 0 s after ECT stimulation (early group), and 30 s after ECT (late group). Statistical parametric mapping (SPM) was used to determine regions of significant CBF changes between ictal and interictal scans on a voxel-by-voxel basis., Results: In the early injection group, we saw increases near the regions of the bitemporal stimulating electrodes as well as some thalamic and basal ganglia activation. With late injections, we observed increases mainly in the parietal and occipital lobes, regions that were quiescent 30 s prior. Significant decreases occurred only at the later injection time, and these were localized to the bilateral cingulate gyrus and left dorsolateral frontal cortex., Conclusions: Activations in distinct regions at the two time points, as well as sparing of intermediary brain structures, suggest that ECT-induced seizures propagate from the site of initiation to other specific brain regions. Further work will be needed to determine if this propagation occurs through cortical-cortical or cortico-thalamo-cortical networks. A better understanding of seizure propagation mechanisms may lead to improved treatments aimed at preventing seizure generalization.

Purpose: The goal of neuroimaging in epilepsy is to localize the region of seizure onset. Single-photon emission computed tomography with tracer injection during seizures (ictal SPECT) is a promising tool for localizing seizures. However, much uncertainty exists about how to interpret late injections, or injections done after seizure end (postictal SPECT). A widely available and objective method is needed to interpret ambiguous ictal and postictal scans, with changes in multiple brain regions., Methods: Ictal or postictal SPECT scans were performed by using [99mTc]-labeled hexamethyl-propylene-amine-oxime (HMPAO), and images were analyzed by comparison with interictal scans for each patient. Forty-seven cases of localized epilepsy were studied. We used methods that can be implemented anywhere, based on freely downloadable software and normal SPECT databases (http://spect.yale.edu). Statistical parametric mapping (SPM) was used to localize a single region of seizure onset based on ictal (or postictal) versus interictal difference images for each patient. We refer to this method as ictal-interictal SPECT analyzed by SPM (ISAS)., Results: With this approach, ictal SPECT identified a single unambiguous region of seizure onset in 71% of mesial temporal and 83% of neocortical epilepsy cases, even with late injections, and the localization was correct in all (100%) cases. Postictal SPECT, conversely, with injections performed soon after seizures, was very poor at localizing a single region based on either perfusion increases or decreases, often because changes were similar in multiple brain regions. However, measuring which hemisphere overall had more decreased perfusion with postictal SPECT, lateralized seizure onset to the correct side in approximately 80% of cases., Conclusions: ISAS provides a validated and readily available method for epilepsy SPECT analysis and interpretation. The results also emphasize the need to obtain SPECT injections during seizures to achieve unambiguous localization.

Temporal lobe seizures are accompanied by complex behavioral phenomena including loss of consciousness, dystonic movements and neuroendocrine changes. These phenomena may arise from extended neural networks beyond the temporal lobe. To investigate this, we imaged cerebral blood flow (CBF) changes during human temporal lobe seizures with single photon emission computed tomography (SPECT) while performing continuous video/EEG monitoring. We found that temporal lobe seizures associated with loss of consciousness produced CBF increases in the temporal lobe, followed by increases in bilateral midline subcortical structures. These changes were accompanied by marked bilateral CBF decreases in the frontal and parietal association cortex. In contrast, temporal lobe seizures in which consciousness was spared were not accompanied by these widespread CBF changes. The CBF decreases in frontal and parietal association cortex were strongly correlated with increases in midline structures such as the mediodorsal thalamus. These results suggest that impaired consciousness in temporal lobe seizures may result from focal abnormal activity in temporal and subcortical networks linked to widespread impaired function of the association cortex.

Are "generalized" seizures truly generalized? Generalized tonic-clonic seizures are classified as either secondarily generalized with local onset or primarily generalized, without known focal onset. In both types of generalized seizures widespread regions of the nervous system engage in abnormally synchronous and high-frequency neuronal firing. However, emerging evidence suggests that all neurons are not homogeneously involved; specific nodes within the network may be crucial for the propagation and behavioral manifestations of generalized tonic-clonic seizures. Study of human tonic-clonic seizures has been limited by problems with patient movement and variable seizure types. To circumvent these problems, we imaged generalized tonic-clonic seizures during electroconvulsive therapy, in which seizure type and timing are well controlled. (99m)Tc-hexamethylpropylene amine oxime injections during seizures provide a "snapshot" of cerebral blood flow that can be imaged by single photon emission computed tomography (SPECT) after seizure termination. Here we show that focal regions of frontal and parietal association cortex show the greatest relative signal increases. Involvement of the higher-order association cortex may explain the profound impairment of consciousness seen in generalized seizures. In addition, focal involvement of the dominant temporal lobe was associated with impaired retrograde verbal memory. Similar focal increases were also seen in imaging of spontaneous secondarily generalized tonic-clonic seizures. Relative sparing of many brain regions during both spontaneous and induced seizures suggests that specific networks may be more important than others in so-called generalized seizures.

The anatomical brain regions involved in the therapeutic and adverse actions of electroconvulsive therapy (ECT) are unknown. Previous studies suggest that bifrontal vs. bitemporal ECT differ in therapeutic efficacy and cognitive side effects. We therefore performed cerebral blood flow (CBF) imaging during bitemporal vs. bifrontal ECT-induced seizures to identify regions crucial for the differences between these treatments. Patients with major depression, undergoing bitemporal or bifrontal ECT, were studied. Ictal-interictal SPECT images were analyzed with statistical parametric mapping for bitemporal (n=11 image pairs in 8 patients) and bifrontal (n=4 image pairs in 2 patients) ECT-induced seizures to identify regions of ictal CBF changes. Bifrontal ECT was found to cause increases in CBF in prefrontal and anterior cingulate regions. Bitemporal ECT, however, caused CBF increases in the lateral frontal cortex and in the anterior temporal lobes. In bifrontal ECT, a greater increase in prefrontal activation, while sparing the temporal lobes, may result in a better therapeutic response and fewer adverse effects on memory than bitemporal ECT.

The use of integrated visualization for medical images aims at assisting clinicians in the difficult task of mentally translating and integrating medical image data from multiple sources into a three-dimensional (3D) representation of the patient. This interpretation of the enormous amount and complexity of contemporary, multiparameter, and multimodal image data demands efficient methods for integrated presentation. This article reviews methods for fused display with the main focus on integration of functional with anatomical images. First, an overview of integrated two-dimensional (2D) and 3D medical image display techniques is presented, and topics related to the interpretation of the integrated images are discussed. Then we address the key issue for clinical acceptance, ie, whether these novel visualization techniques lead to diagnostic improvements. Methods for fused display appear to be powerful tools to assist the clinician in the retrieval of relevant information from multivariate medical image data. Evaluation of the different methods for fused display indicates that the diagnostic process improves, notably as concerns the anatomical localization (typically of functional processes), the registration procedure, enhancement of signal, and efficiency of information presentation (which increases speed of interpretation and comprehension). Consequently, fused display improves communication with referring specialists, increases confidence in the observations, and facilitates the intra- and intersubject comparison of a large part of the data from the different sources, thereby simplifying the extraction of additional, valuable information. In most diagnostic tasks the clinician is served best by providing several (interactive and flexible) 2D and 3D methods for fused display for a thorough assessment of the wealth of image information from multiple sources., (Copyright 2003 Elsevier Inc. All rights reserved.)

Instrumentation for emission computed tomography continues to evolve, taking advantage of developments in detector technology, data processing and correction methods, and reconstruction algorithms. This article reviews the basic principles and latest developments in emission computed tomography instrumentation, for both positron emission tomography and single-photon emission computed tomography applications.

Purpose: Statistical parametric mapping (SPM) is an image-analysis tool that assesses the statistical significance of cerebral blood flow (CBF) changes on a voxel-by-voxel basis, thereby removing the subjectivity inherent in conventional region-of-interest (ROI) analysis. Our platform of single-photon emission computed tomography (SPECT) ictal-interictal difference imaging in clinical epilepsy has been validated for localizing seizure onset. We extend the tools of SPM by further applying statistical measures for the significance of perfusion changes in individual patients to localize epileptogenic foci in patients with defined temporal lobe epilepsy by using paired scans in this preliminary study., Methods: Twelve patients with pairs of periictal and interictal SPECT scans were analyzed in this comparison study between SPECT difference imaging and SPM difference analysis by using a reference database of paired normal healthy images. These 12 patients possessed seizure foci localized to the mesial temporal lobe as confirmed by surgical outcome and by hippocampal sclerosis on pathology. SPM was used to identify clusters of increased or decreased CBF in each patient in contrast to our control group., Results: The regions having the most significant increased or decreased CBF by SPM analysis were in agreement with regions identified by conventional difference imaging and visual analysis by viewers blinded to the results of the SPM analysis. Differentiated further by time of radiopharmaceutical injection, six of seven patients injected within 100 s of seizure onset displayed hyperperfusion changes localized to the corresponding epileptogenic temporal lobe by both techniques. Among patients receiving injections after 100 s, both techniques showed primarily regions of hypoperfusion, which again were similar between these two methods., Conclusions: The results provide strong evidence supporting SPM difference analysis in assessing regions of significant CBF change from baseline in concordance with our current clinically used technique of SPECT ictal--interictal difference imaging in epilepsy patients. Difference analysis using SPM could serve as a useful diagnostic tool in the evaluation of seizure focus in temporal lobe epilepsy.

Purpose: Factors affecting blood flow observed by interictal single-photon emission computed tomography (SPECT) images in temporal lobe epilepsy (TLE) have not been systematically studied or consistently demonstrated. We evaluated interictal SPECT results with respect to many clinical variables in a large population of TLE patients, all of whom underwent temporal lobectomy., Methods: Interictal 99mTc-HMPAO SPECT scans from 61 TLE patients were obtained before an anterior temporal lobectomy. SPECT was analyzed using a region of interest analysis (ROI) in the cerebellum, anterior temporal lobe, lateral temporal lobe, mesial temporal lobe, whole temporal lobe, and inferior frontal lobe. Asymmetry indices (AIs) were calculated. Correlative analysis of AIs and clinical variables was performed., Results: The AIs from TLE patients differed significantly from those of controls in the anterior temporal (p < 0.01), lateral temporal (p < 0.001), and whole temporal (p < 0.01) regions. No consistent overall correlation between the AIs and clinical variables existed. In right TLE (RTLE) only, AIs in the lateral and whole temporal lobe were positively correlated with age of onset (r = 0.470, p < 0.05; r = 0.548, p < 0.01, respectively). Similarly, in RTLE only, duration of epilepsy was negatively correlated with the anterior (r = -0.395, p < 0.05) and mesial (r = -0.45, p < 0.05) temporal lobe AI. No correlations were found between clinical variables and AIs in left TLE (LTLE) patients., Conclusions: Significant correlation of age at onset and duration of epilepsy with AIs in RTLE but not LTLE suggests physiologic processes may be determined in part by laterality of TLE. Clinical applications are problematic.

This paper examines a solution to the general problem of accurately relating points within functional data acquired before and after subdural intracranial electrode implantation. We develop an approach based on nonrigid registration of high resolution anatomical MRI acquired together with the functional data. This makes use of a free-form B-Spline deformation model and registration is recovered by maximizing the normalized mutual information between the preimplant MRI and the postimplant MRI. We apply the approach to estimate the tissue deformation induced by the presence of intracranial electrodes over 15 patient studies. Maximum tissue displacements of 4 mm or greater were observed in all cases either in the cortex or around the ventricles due to CSF loss. In studies involving larger 4 x 4 grids, local tissue displacement estimates exceeded 10 mm from the preimplant brain shape. The key issue with this approach is whether the deformation estimates are contaminated by the presence of susceptibility-induced imaging artifacts. We therefore evaluate the deformation estimates in recovering alignment of essentially identical SPECT studies of eight patients acquired before and after electrode placement. An ROI-based analysis of the variance of resulting subtraction values between pre- and postimplant SPECT was carried out in regions of tissue below electrode grids. Results indicate for all cases a substantial reduction in residual SPECT subtraction artifacts to a level comparable to that in an equivalent region of undeformed tissue., (Copyright 2001 Academic Press.)

Purpose: Image processing techniques were applied to interictal positron emission tomography (PET) and single-photon emission computed tomography (SPECT) brain images to aid in the localization of epileptogenic foci by calculating a functional image that represents the degree of coupling between perfusion and metabolism. Uncoupling of these two functions has been demonstrated to be a characteristic of epileptogenic tissue in temporal lobe epilepsy and has the potential to serve as a diagnostic measure for localization in other areas as well., Methods: Interictal PET ((18)F-FDG) and interictal SPECT ((99m)Tc-HMPAO) scans were acquired from 11 epilepsy patients. The metabolism and perfusion images were three-dimensionally spatially registered, and a functional ratio-image was computed. These functional maps are overlaid onto a three-dimensional rendering of the same patient's magnetic resonance imaging anatomy., Results: In all patients, an average uniform perfusion-to-metabolism ratio showed approximately constant values throughout most of the whole brain. However, the epileptogenic area (confirmed on surgery) demonstrated an area of elevated perfusion/metabolism in the grey matter., Conclusions: Although hypometabolism in the PET image was observed in most of these patients, the calculation of a functional ratio-image demonstrated localized foci that in some cases could not be observed on the PET image alone. The ratio-image also yields a quantitative measure of the uncoupling phenomenon.

Increased regional cerebral blood flow (rCBF) at the epileptogenic site has been consistently reported for single photon emission computed tomography (SPECT) injections made during seizure activity, and the increased rCBF has been shown to remain elevated at the epileptogenic site in some cases, even when SPECT injections are made after seizure termination (postictal). A sustained increase in rCBF after seizure cessation was recently confirmed, but for no more than 100 s from seizure onset [Avery, R.A., Spencer, S.S., Spanaki, M.V., Corsi, M., Seibyl, J.P., Zubal, I.G., 1999. Effect of injection time on postictal SPET perfusion changes in medically refractory epilepsy. Eur. J. Nucl. Med. 26, 830-836]. In the current study, it is examined whether ictal SPECT injections demonstrate a similar change in rCBF around 100 s from seizure onset. Twenty-one patients with medically refractory epilepsy and a known area of seizure onset receiving ictal and interictal 99mTc-Hexamethyl-propyleneamineoxime (HMPAO) SPECT scans were studied. The results of SPECT subtraction analysis which visualize increased and decreased rCBF were compared to seizure duration and HMPAO injection time. Five patients received ictal SPECT injections (during ongoing seizure activity) more than 90 s after seizure onset and demonstrated decreased rCBF. Two of these patients also demonstrated areas of increased rCBF. Decreased rCBF was localized to the epileptogenic lobe in four of the five patients. By examining ictal SPECT injections made 90 s after seizure onset, evidence was found that reduced rCBF may exist during ictus. The change in rCBF around 90 s is also observed in postictal injections, suggesting a common metabolic mechanism may be responsible.

Peri-ictal single-photon emission tomography (SPET) difference images co-registered to magnetic resonance imaging (MRI) visualize regional cerebral blood flow (rCBF) changes and help localize the epileptogenic area in medically refractory epilepsy. Few reports have examined the reproducibility of SPET difference image results. Epilepsy patients having two peri-ictal and at least one interictal SPET scan who later underwent surgical resection were studied. Localization accuracy of peri-ictal SPET difference images results, interictal electroencephalography (EEG), and ictal EEG from the first (seizure 1) and second (seizure 2) seizure, as well as MRI and positron emission tomography (PET) findings, were compared using surgical resection site as the standard. Thirteen patients underwent surgical resection (11 temporal lobe and 2 extratemporal). SPET results from seizure 1 were localized to the surgical site in 12/13 (92%) patients, while SPET results from seizure 2 were localized in 13/13 (100%) patients. All other modalities were less accurate than the SPET results interictal EEG--seizure 1 6/13 (46%); ictal EEG--seizure 1 5/13 (38%); interictal intracranial EEG--seizure 2 4/9 (44%); ictal intracranial EEG--seizure 2 results 8/9 (89%); MRI 6/13 (46%); PET 9/13 (69%)[. SPET results were reproducible in 12/13 (92%) patients. SPET difference images calculated from two independent peri-ictal scans appear to be reproducible and accurately localize the epileptogenic area. While SPET difference images visualize many areas of rCBF change, the quantification of these results along with consideration of injection time improves the diagnostic interpretation of the results.

Unlabelled: True ictal SPECT can accurately demonstrate perfusion increases in the epileptogenic area but often requires dedicated personnel waiting at the bedside to accomplish the injection. We investigated the value of perfusion changes as measured by ictal or immediate postictal SPECT in localizing the epileptogenic region in refractory partial epilepsy., Methods: Quantitative perfusion difference images were calculated by registering, normalizing and subtracting ictal (or immediate postictal) from interictal SPECT for 53 patients with refractory epilepsy. Perfusion difference SPECT results were compared with visually interpreted SPECT, scalp electroencephalography (EEG), MRI, PET and intracranial EEG., Results: In 43 patients (81%), discrete areas of increased perfusion (with ictal injections) or decreased perfusion (with postictal injections) were noted. Interictal scalp EEG was localizing in 28 patients (53%), ictal scalp EEG was localizing in 35 patients (66%) and intracranial EEG was localizing in 22 patients (85%) (of 26 patients who underwent invasive study). MRI was localizing in 34 patients (64%), PET was localizing in 32 of 45 patients (71%), interictal SPECT was localizing in 26 patients (49%) and peri-ictal SPECT (visual interpretation) was localizing in 30 patients (57%). By comparison with an intracranial EEG standard of localization, SPECT subtraction analysis had 86% sensitivity and 75% specificity., Conclusion: Our data provide evidence that SPECT perfusion difference analysis has higher sensitivity and specificity than any other noninvasive localizing criterion and can localize epileptogenic regions with accuracy comparable with that of intracranial EEG. To obtain these results, one must apply knowledge of the timing of the ictal injection relative to seizure occurrence.

Purpose: We investigated whether blood-flow changes measured by ictal or immediate postictal single photon emission computed tomography (SPECT) reflect with accuracy the actual location of ictal discharge as measured by simultaneous intracranial EEG. In addition, we evaluated the reliability of ictal SPECT obtained with implanted electrodes by comparing results with those of ictal SPECT performed during scalp EEG monitoring in selected patients., Methods: Eleven patients with intractable partial epilepsy who had both ictal and interictal SPECT scans during invasive EEG monitoring were studied. We analyzed perfusion differences based on registration, normalization, and subtraction of periictal and interictal SPECT images. SPECT results were interpreted in relation to location and evolution of ictal EEG change, as reflected by simultaneous intracranial EEG. In five patients, we also compared ictal SPECT results that were obtained during both scalp and intracranial EEG monitoring., Results: In 10 of 11 patients, localized increases or decreases in blood flow or both were identified in regions of ongoing or prior seizure discharge, respectively, at the time of SPECT brain perfusion. In one patient, SPECT localization could not be verified by the available electrode array., Conclusions: Localization of ictal discharge during or before SPECT injection accurately determines increase or decrease in perfusion, respectively, and both are of equal validity in reflecting the region of epileptic discharge. SPECT perfusion changes can be reliably obtained during intracranial monitoring.

By digitally computing perfusion changes from ictal or postictal (peri-ictal) injections referenced to those acquired interictally, an enhanced method for localizing the epileptogenic area is reported. Computer-based image processing methods for quantifying regional percent change in the brain are applied to a group of 19 epilepsy patients after the injection of technetium-99m hexamethylpropylene amine oxime (HMPAO) and after acquiring single-photon emission tomography (SPET) data. Each patient's region of epileptogenesis was independently localized through pathology and/or successful surgery. The positive and negative quantitative perfusion changes were plotted as a function of the time of the 99mTc-HMPAO ictal injection. This time scale was normalized relative to the seizure duration and is referenced to the time of seizure termination. Eight patients, injected ictally, demonstrated perfusion increases of 25%-100% in the area of known epileptogenesis. Five patients, injected immediately after seizure cessation, demonstrated excessive perfusion decreases of 30%-92% associated with the region of seizure onset. Six patients, injected well after seizure termination, demonstrated hypoperfusion changes less than 30% at the epileptogenic area. Observations on perfusion changes calculated from 99mTc-HMPAO SPET scans, as a function of normalized time, support a progression from ictal hyper- to excessive hypo-, then finally to persistent interictal hypoperfusion. By applying this perfusion pattern model and by noting the time of injection for peri-ictal images, an improved method for localizing the epileptogenic area is demonstrated.

Unlabelled: The purposes of this study were to develop a method for nonuniform attenuation correction of 123I emission brain images based on transmission imaging with a longer-lived isotope (i.e., 57Co) and to evaluate the relative improvement in quantitative SPECT images achieved with nonuniform attenuation correction., Methods: Emission and transmission SPECT scans were acquired on three different sets of studies: a heterogeneous brain phantom filled with 1231 to simulate the distribution of dopamine transporters labeled with 2beta-carbomethoxy-3beta-(4-123I-iodophenyl)tropane (123I-beta-CIT); nine healthy human control subjects who underwent transmission scanning using two separate line sources (57Co and 123I); and a set of eight patients with Parkinson's disease and five healthy control subjects who received both emission and transmission scans after injection of 123I-beta-CIT. Attenuation maps were reconstructed using a Bayesian transmission reconstruction algorithm, and attenuation correction was performed using Chang's postprocessing method. The spatial distribution of errors within the brain was obtained from attenuation correction factors computed from uniform and nonuniform attenuation maps and was visualized on a pixel-by-pixel basis as an error image., Results: For the heterogeneous brain phantom, the uniform attenuation correction had errors of 2%-6.5% for regions corresponding to striatum and background, whereas nonuniform attenuation correction was within 1%. Analysis of 123I transmission images of the nine healthy human control subjects showed differences between uniform and nonuniform attenuation correction to be in the range of 6.4%-16.0% for brain regions of interest (ROIs). The human control subjects who received transmission scans only were used to generate a curvilinear function to convert 57Co attenuation values into those for 123I, based on a pixel-by-pixel comparison of two coregistered transmission images for each subject. These values were applied to the group of patients and healthy control subjects who received transmission 57Co scans and emission 123I scans after injection of 123I-beta-CIT. In comparison to nonuniform attenuation correction as the gold standard, uniform attenuation with the ellipse drawn around the transmission image caused an approximately 5% error, whereas placement of the ellipse around the emission image caused a 15% error., Conclusion: Nonuniform attenuation correction allowed a moderate improvement in the measurement of absolute activity in individual brain ROIs. When images were analyzed as target-to-background activity ratios, as is commonly performed with 123I-beta-CIT, these outcome measures showed only small differences when Parkinson's disease patients and healthy control subjects were compared using nonuniform, uniform or even no attenuation correction.

Unlabelled: Increased extracardiac activity confounds conventional cardiac SPECT image reconstruction using a filtered backprojection method. Others have proposed that simultaneously acquired transmission-emission (STE) images that are reconstructed with a maximum likelihood (ML) method incorporating a nonuniform attenuation correction would less likely be affected by the presence of extracardiac activity. However, this approach corrects only for decreased myocardial counts from attenuation and not for increased myocardial counts from extracardiac activity. Therefore, STE with nonuniform attenuation correction may also result in reconstruction artifacts when extracardiac activity is present., Methods: Acquisitions of phantoms with nonuniform and uniform attenuation were performed using STE and conventional approaches, in the absence and presence of extracardiac activity. All acquisitions used a triple-headed SPECT camera. STE acquisitions used fanbeam collimation and a 153Gd transmission source. STE images were reconstructed using ML, with and without nonuniform attenuation correction. Reconstructed short-axis images were quantitated, and percentage variability for each count profile was calculated., Results: In a nonuniform phantom configuration, STE reconstruction with nonuniform attenuation correction significantly improved image uniformity. This improvement in image uniformity was diminished with the addition of increasing extracardiac activity. In a uniform phantom, STE reconstruction with nonuniform attenuation correction significantly improved uniformity only in the presence of extracardiac activity., Conclusion: The addition of attenuation correction in the presence of extracardiac activity can have complex effects on ML reconstruction with nonuniform attenuation correction, which depends on the amount of extracardiac activity and pattern of attenuation.

Unlabelled: We have developed an image-based compartmental analysis for estimating effective renal plasma flow (ERPF in units of milliliters per minute) from the full time-activity curves of regions of interest (ROI) placed over the heart, kidneys and bladder., Methods: Kidney or time-activity curves are corrected for physical attenuation using estimates of kidney depth derived from patient height and weight. Estimates of the calibration factors, Kp and Kb (mCl/counts/sec), for the plasma and bladder time-activity curves are determined by applying the following ROI analysis to each frame of the dynamic scan: (Kp)Pc(t) + (Kb)Bc(t) = Di - Rq(t), where P c(t) and Bc(t) represent the counting rates measured in ROI placed over the left ventricle blood pool and bladder at time t; Di is the known total injected dose, and Rq(t) represents the millicurie of tracer in the kidneys at time t. Once Kp and Kb have been determined by regression, the calibrated time activity curves are used to solve for the physiological parameter fERPF (min-1), which represents the fraction of the total body plasma cleared of mertiatide per min. The ERPF calculated by the product of fERPF and plasma volume, determined from patient weight, was compared to the ERPF as calculated by blood samples and the Schlegel and renal uptake plasma volume product scintigraphic techniques., Results: Twenty-five adult patients with a wide range of ages and renal function were studied. The results of this image-based method for calculating ERPF correlated well with the values obtained from blood samples (linear regression slope = 1.06; y-int = -34.68 ml/min, r = 0.905) and offered a significant improvement over both the Schlegel and renal uptake plasma volume product estimates (p < 0.05)., Conclusion: A scintigraphic estimation of ERPF without blood samples using time-activity data from the heart, kidneys and bladder acquired over the entire renogram is feasible and correlates well with more invasive techniques requiring blood samples.

Unlabelled: To further validate the rate of renal uptake of the 99mTc-DTPA-plasma volume product (RUPV) method to estimate glomerular filtration rate (GFR), 104 determinations were performed and compared to blood sample of GFR assays. The interassay consistency was also studied in 42 patients., Methods: The studies were performed with 370-550 MBq (10-15 mCi) of 99mTc-DTPA and a gamma camera. The 3-min cumulative renal uptake was calculated from the renogram curves and expressed as the rate of renal uptake in min-1. The plasma volume, in milliliters, was estimated from the patient's body weight. The GFR (ml/min) was calculated from [RU] x [PV] and by using two blood samples. To study interassay consistency, two determinations of GFR were performed on separate days., Results: The regression equation relating the rate of renal uptake (RU) in the abscissa and the GFR obtained from plasma samples in the ordinate is: y = 3.13 + 10.5x (n = 104; r = 0.90). The regression equation of RUPV estimated GFR (x) compared to the GFR calculated from blood samples (y) is: y = 6.9 + 0.91x (n = 104; r = 0.94). The interassay consistency study showed no statistically significant difference between measurements obtained on Days 1 and 2. The mean +/- s.e.m. GFR for each determination were 84.3 +/- 6.12 and 81.9 +/- 6.21. For the blood sample method, the mean s.e.m. for each day were 87.26 +/- 6.69 and 96.86 +/- 6.58 (p < 0.05). The percent variation coefficient for the RUPV method was: CV% = 6.8 +/- 2.7 and 12.1 +/- 3.3 (p < 0.03) for the blood sample method., Conclusion: The observed accuracy of the determination is comparable to that in our previous study of a separate patient population at another hospital. This method would be suitable for interinstitutional comparison and for longitudinal patient studies.

Unlabelled: Image processing techniques were applied to SPECT brain images to aid in the localization of epileptic foci., Methods: Ictal and interictal cerebral perfusion SPECT images were acquired from 12 epilepsy patients (6 temporal, 6 extratemporal) after injection of 20 mCi 99mTc-HMPAO. Each ictal scan was registered to the same patient's interictal scan. Normalization of the three-dimensional data was applied to account for global percent brain uptake and total injected activity. After registration, normalization and subtraction of the SPECT images and functional difference images were computed. Difference images were calculated, which give a quantitative measure of perfusion alterations during ictus. The resulting difference images were also registered with each patient's MRI scan which permits localization of perfusion changes onto anatomical structures., Results: Areas in the brain where significant perfusion increases occur correlate with areas confirmed to be seizure foci. Four of the six patients with known temporal lobe seizure foci exhibited significant perfusion increases on the difference images. These areas demonstrate a percent increase of perfusion larger than 40%. For the extratemporal seizure patients, four of the four confirmed seizure sites were diagnosed with difference images. Results on the remaining two patients were inconclusive., Conclusion: When compared to side-by-side visual interpretation of the ictal and interictal SPECT images, registration of SPECT and MR images together with calculated difference maps greatly enhances the ability to localize epileptic seizure foci. This offers the potential to locate epileptic seizure foci using a noninvasive, inexpensive imaging procedure and data processing algorithm.

Unlabelled: SPECT imaging of the brain with [123I]iomazenil has shown avid uptake of the radioligand in a distribution consistent with benzodiazepine receptor binding. The purposes of this study were to measure the whole-body distribution of activity following i.v. administration of [123I]iomazenil and to evaluate the resulting organ radiation burdens., Methods: Serial total body scans were obtained in healthy volunteers after thyroid blockade and demonstrated avid brain uptake of radioligand., Results: Abdominal imaging showed significant activity retention within the urinary and gastrointestinal tracts consistent with excretion via these routes. Absorbed dose to the urinary bladder was calculated to be 0.19 mGy/MBq, to the lower large intestine 0.079 mGy/MBq, to the upper large intestine 0.066 mGy/MBq, and to the thyroid 0.063 mGy/MBq., Conclusion: Thyroid uptake may in part have represented binding to benzodiazepine receptors, since radioligand binding to tissue homogenates prepared from human thyroid showed the presence of benzodiazepine binding sites.

Manual segmentation of 129 x-ray CT transverse slices of a living male human has been done and a computerized 3-dimensional volume array modeling all major internal structures of the body has been created. Each voxel of the volume contains a index number designating it as belonging to a given organ or internal structure. The original x-ray CT images were reconstructed in a 512 x 512 matrix with a resolution of 1 mm in the x,y plane. The z-axis resolution is 1 cm from neck to midthigh and 0.5 cm from neck to crown of the head. This volume array represents a high resolution model of the human anatomy and can serve as a voxel-based anthropomorphic phantom suitable for many computer-based modeling and simulation calculations.

Retrospective analysis of precaptopril and postcaptopril DTPA renograms from 88 hypertensive patients was performed to refine the quantitative criteria used to diagnose renal artery stenosis (RAS). Of the 88 patients, 45 had RAS and 43 had normal renal arteries at angiography. Using time-activity curves from the essential hypertensive group, diagnostic washout criteria for a positive DTPA renogram were developed. These were based on the 20 and 30 min/peak activity ratios in each kidney. When the washout criteria were retrospectively applied to patient data as a whole, sensitivity and specificity for RAS were 67% and 79%, respectively. When previously described uptake criteria, based on the time to peak activity in each kidney and the GFR ratio between the kidneys, were applied to the same data, sensitivity and specificity for RAS were 89% and 84%, respectively. Quantitative analysis of the DTPA renogram using the time to peak and GFR ratio was both sensitive and specific for RAS. Measurement of 20 and 30 min/peak renal activity ratios did not improve the accuracy of the test.

Proposes a Bayesian method whereby maximum a posteriori (MAP) estimates of functional (PET and SPECT) images may be reconstructed with the aid of prior information derived from registered anatomical MR images of the same slice. The prior information consists of significant anatomical boundaries that are likely to correspond to discontinuities in an otherwise spatially smooth radionuclide distribution. The authors' algorithm, like others proposed recently, seeks smooth solutions with occasional discontinuities; the contribution here is the inclusion of a coupling term that influences the creation of discontinuities in the vicinity of the significant anatomical boundaries. Simulations on anatomically derived mathematical phantoms are presented. Although computationally intense in its current implication, the reconstructions are improved (ROI-RMS error) relative to filtered backprojection and EM-ML reconstructions. The simulations show that the inclusion of position-dependent anatomical prior Information leads to further improvement relative to Bayesian reconstructions without the anatomical prior. The algorithm exhibits a certain degree of robustness with respect to errors in the location of anatomical boundaries.

An image-based method for estimating quantitative renal glomerular filtration rates (GFR) by calculating the product of the renal uptake rate and plasma volume is presented. By using the relationship GFR = F.PV/t, F represents renal 99mTc-DTPA uptake after bolus injection, PV is the plasma volume and t is time. This GFR evaluation was carried out on 96 patients and compared to GFR values determined in the same patients using radiotracer blood clearance techniques relying on two venous blood samples. When estimating patient plasma volumes using patient's weight and measured hematocrit values, the image-based method for calculating GFR accurately approximates the values obtained from blood samples (linear regression slope = 1.03; y-intercept = -2.81 ml/min). The two techniques correlate with a value of r = 0.89.

The ability of changes in the distribution of technetium-99m-hexamethylpropylene amine oxime (99mTc-HMPAO) to reflect physiologic changes in regional cerebral blood flow (rCBF) was evaluated using photic stimulation, a procedure known to increase rCBF in the striate cortex. Seven healthy subjects were injected with 740 MBq 99mTc-HMPAO on two separate days. On one day, the injection was performed following closure of the eyes and patching for 5 min. On the other day, subjects were exposed to a stroboscopic light to produce photic simulation. Images of distribution of 99mTc-HMPAO were obtained using a Strichman 810X single-photon emission computed tomogram (SPECT) brain scanner. Comparison of images obtained during light occluded versus stimulation conditions revealed a significant increase in distribution of radiopharmaceutical in visual cortex relative to whole brain (peak increase corrected for radiopharmaceutical backdiffusion 36.7% +/- 6.6%). HMPAO appears to provide a useful method for detecting relative rCBF increases with SPECT.

Fifty patients with suspected renal artery stenosis (RAS) were studied with renal scintigraphy before and after administration of captopril. Twenty-three patients had RAS (greater than or equal to 75% RAS or greater than or equal to 50% RAS with poststenotic dilatation) and 27 had normal renal arteries at angiography. Angiotensin-converting enzyme inhibitors were discontinued 24 hours prior to renal scintigraphy; all other medications were continued. Each patient was evaluated with a simplified captopril renal scintigraphic protocol: renal imaging after administration of 12 mCi (444 MBq) of technetium-99m diethylenetriaminepentaacetic acid (DTPA), a 3-hour wait, oral administration of 50 mg of captopril, a 1-hour wait, and another scintigram obtained after administration of 12 mCi (444 MBq) of Tc-99m DTPA. Times of peak renal activity (Tmax) were determined from renal time-activity curves, and glomerular filtration rates (GFRs) were calculated with the Gates technique. A Tmax greater than or equal to 11 minutes after injection or a GFR ratio (larger GFR/smaller GFR) greater than 1.5 enabled detection of RAS with 91% sensitivity, 93% specificity, and 92% accuracy. Renal scintigraphy without captopril had only 43%-68% sensitivity in detecting RAS, depending on the criteria used.

The meaning of 81Krm counts obtained in a dynamic series of gated lung ventilation scans was evaluated in terms of flow rate, lung volume, or the flow/volume ratio. Flow and volume signals were recorded together with scintigraphic events in 29 subjects breathing 81Krm and after its decay, 127Xe as a tracer of lung volume. Gated ventilation scans and respiratory signals were reconstructed. Statistical analyses were carried out for linear regressions between total normalized counts detected by the gamma camera and (1) flow rate, (2) lung volume and (3) flow/volume ratio. Inspiration and expiration were analysed separately. For both isotopes, the best correlation was obtained between counts and lung volume (r greater than 0.93). No correlation was obtained between counts and flow rate or flow/volume ratio. Thus, we conclude that 81Krm count variations in gated scans correlate well with tidal volume.